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/Title (BRAF p.Val600Glu \(V600E\) Testing for Assessment of Treatment Options in Metastatic Colorectal Cancer � PLOS Currents Evidence on Genomic Tests)
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0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(BRAF p.Val600Glu \(V600E\) Testing for Assessment of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Treatment Options in Metastatic Colorectal Cancer)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(October 18, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 663.247 Td /F1 9.8 Tf  [(Andrew Lea)] TJ ET
0.271 0.267 0.267 rg
BT 78.276 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 83.697 663.247 Td /F1 9.8 Tf  [(Diane Allingham-Hawkins)] TJ ET
0.271 0.267 0.267 rg
BT 194.759 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 200.180 663.247 Td /F1 9.8 Tf  [(Susan Levine)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Lea A, Allingham-Hawkins D, Levine S. BRAF p.Val600Glu \(V600E\) Testing for Assessment of Treatment Options in Metastatic )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(Colorectal Cancer. PLOS Currents Evidence on Genomic Tests. 2010 Oct 18 . Edition 1. doi: 10.1371/currents.RRN1187.)] TJ ET
q
15.000 35.065 577.500 601.991 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Colon and rectal cancer \(CRC\) are the third most common cancer in the United States and cause approximately 50,000 deaths )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(per year. The anti-epidermal growth factor receptor \(EGFR\) monoclonal antibodies cetuximab \(Erbitux�\) and panitumumab )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(\(Vectibix�\) have been recently introduced to treat CRC. However, the response rate with these agents is low and they are )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(associated with serious adverse effects. Accordingly biomarkers that can predict those patients that will respond to treatment )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(may have clinical utility. The p.Val600Glu sequence variant \(often called V600E\) in the BRAF gene has been investigated as a )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(biomarker to predict patients that will not respond to treatment with the anti-EGFR monoclonal antibodies.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Together, colon and rectal cancer \(colorectal cancer, or CRC\) comprise the third most common cancer in the United States, )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(with an estimated 50,000 deaths caused by CRC in 2009 )] TJ ET
0.267 0.267 0.267 rg
BT 275.002 462.396 Td /F1 9.8 Tf  [([1] [2] [3] [4])] TJ ET
0.271 0.267 0.267 rg
BT 326.501 462.396 Td /F1 9.8 Tf  [(. The 5-year survival rate for the 150,000 individuals )] TJ ET
BT 26.250 450.491 Td /F1 9.8 Tf  [(diagnosed each year with CRC is 65.2% for all stages, but drops to 11.3% in those with metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 489.043 450.491 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 499.885 450.491 Td /F1 9.8 Tf  [( . Single or )] TJ ET
BT 26.250 438.586 Td /F1 9.8 Tf  [(multiagent chemotherapy regimens may be chosen based on the drugs that are currently approved for treating metastatic CRC, )] TJ ET
BT 26.250 426.681 Td /F1 9.8 Tf  [(which include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, oxaliplatin, and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 490.652 426.681 Td /F1 9.8 Tf  [([3] [4] [5] [6])] TJ ET
0.271 0.267 0.267 rg
BT 542.152 426.681 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 414.777 Td /F1 9.8 Tf  [(Cetuximab \(Erbitux�; Imclone Systems Inc./Bristol-Myers Squibb\) and panitumumab \(Vectibix�; Amgen Inc.\) are anti-epidermal )] TJ ET
BT 26.250 402.872 Td /F1 9.8 Tf  [(growth factor receptor \(EGFR\) monoclonal antibodies that may be used for first-, second- or third-line treatment in patients with )] TJ ET
BT 26.250 390.967 Td /F1 9.8 Tf  [(metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 109.700 390.967 Td /F1 9.8 Tf  [([7] [8] [9])] TJ ET
0.271 0.267 0.267 rg
BT 147.647 390.967 Td /F1 9.8 Tf  [(. EGFR is a component of the HER/Erb-B \(human EGFR\) signaling pathway )] TJ ET
0.267 0.267 0.267 rg
BT 478.728 390.967 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 494.991 390.967 Td /F1 9.8 Tf  [(. Clinical evidence )] TJ ET
BT 26.250 379.062 Td /F1 9.8 Tf  [(suggests that benefit from the EGFR monoclonal antibody inhibitors cetuximab and panitumumab is limited to a subgroup of )] TJ ET
BT 26.250 367.158 Td /F1 9.8 Tf  [(only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 173.650 367.158 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 227.861 367.158 Td /F1 9.8 Tf  [(. Biomarkers are therefore needed to help select the patients who will benefit )] TJ ET
BT 26.250 355.253 Td /F1 9.8 Tf  [(from treatment with EGFR inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 183.917 355.253 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 194.759 355.253 Td /F1 9.8 Tf  [(. In July 2009, the presence of sequence variants in the Kirsten rat sarcoma viral )] TJ ET
BT 26.250 343.348 Td /F1 9.8 Tf  [(oncogene homolog \( )] TJ ET
BT 117.841 343.348 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 144.391 343.348 Td /F1 9.8 Tf  [( \) gene has been approved by the Food and Drug Administration \(FDA\) as a negative prognostic )] TJ ET
BT 26.250 331.443 Td /F1 9.8 Tf  [(indicator for response to treatment with cetuximab and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 325.380 331.443 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 341.643 331.443 Td /F1 9.8 Tf  [(. Another biomarker that is part of the same EGFR )] TJ ET
BT 26.250 319.539 Td /F1 9.8 Tf  [(signaling pathway as )] TJ ET
BT 119.460 319.539 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 146.009 319.539 Td /F1 9.8 Tf  [( that has been investigated for predicting response to EGFR monoclonal antibody treatment in CRC )] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(is the v-raf murine sarcoma viral oncogene homolog B, known as )] TJ ET
BT 309.107 307.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
0.267 0.267 0.267 rg
BT 337.821 307.634 Td /F1 9.8 Tf  [([14] [15])] TJ ET
0.271 0.267 0.267 rg
BT 373.058 307.634 Td /F1 9.8 Tf  [(. The )] TJ ET
BT 397.988 307.634 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 423.991 307.634 Td /F1 9.8 Tf  [( gene sequence variant )] TJ ET
BT 26.250 295.729 Td /F1 9.8 Tf  [(p.Val600Glu, often called V600E, is the main sequence variant in this gene that is associated with CRC )] TJ ET
0.267 0.267 0.267 rg
BT 473.882 295.729 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 490.145 295.729 Td /F1 9.8 Tf  [(. The frequency of )] TJ ET
BT 26.250 283.824 Td /F1 9.8 Tf  [(the )] TJ ET
BT 42.513 283.824 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 68.516 283.824 Td /F1 9.8 Tf  [( p.Val600Glu variant was 5% to 12% in CRC populations, and the presence of this variant has been found to be )] TJ ET
BT 26.250 271.920 Td /F1 9.8 Tf  [(associated with poor survival in patients with CRC in several studies in which patients were not treated with anti-EGFR )] TJ ET
BT 26.250 260.015 Td /F1 9.8 Tf  [(monoclonal antibodies )] TJ ET
0.267 0.267 0.267 rg
BT 125.963 260.015 Td /F1 9.8 Tf  [([16] [17] [18] [19] [20] [21] [22] [23])] TJ ET
0.271 0.267 0.267 rg
BT 275.041 260.015 Td /F1 9.8 Tf  [(. Furthermore, there appears to be little variation in the )] TJ ET
BT 512.941 260.015 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 26.250 248.110 Td /F1 9.8 Tf  [(p.Val600Glu status between primary and secondary tumors )] TJ ET
0.267 0.267 0.267 rg
BT 285.278 248.110 Td /F1 9.8 Tf  [([23] [24])] TJ ET
0.271 0.267 0.267 rg
BT 320.515 248.110 Td /F1 9.8 Tf  [(. As testing for the presence of )] TJ ET
BT 455.464 248.110 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 482.014 248.110 Td /F1 9.8 Tf  [( sequence variants to )] TJ ET
BT 26.250 236.205 Td /F1 9.8 Tf  [(predict response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now included in the FDA )] TJ ET
BT 26.250 224.301 Td /F1 9.8 Tf  [(prescribing information, this Knol focuses on genetic testing for )] TJ ET
BT 299.913 224.301 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 325.916 224.301 Td /F1 9.8 Tf  [( p.Val600Glu following )] TJ ET
BT 425.630 224.301 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 452.179 224.301 Td /F1 9.8 Tf  [( testing.)] TJ ET
BT 26.250 187.698 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 167.744 Td /F1 9.8 Tf  [(A number of providers have assays that can detect the )] TJ ET
BT 264.706 167.744 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 290.709 167.744 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant from formalin-fixed paraffin-)] TJ ET
BT 26.250 155.839 Td /F1 9.8 Tf  [(embedded \(FFPE\) tumor samples or slides using a variety of technologies, including polymerase chain reaction \(PCR\) with and )] TJ ET
BT 26.250 143.934 Td /F1 9.8 Tf  [(without fluorescence monitoring, dideoxy sequencing, direct sequencing, and pyrosequencing:)] TJ ET
0.271 0.267 0.267 RG
40.337 127.497 m 
40.337 127.944 40.154 128.388 39.838 128.704 c
39.522 129.020 39.078 129.204 38.631 129.204 c
38.185 129.204 37.741 129.020 37.425 128.704 c
37.109 128.388 36.925 127.944 36.925 127.497 c
36.925 127.051 37.109 126.607 37.425 126.291 c
37.741 125.975 38.185 125.791 38.631 125.791 c
39.078 125.791 39.522 125.975 39.838 126.291 c
40.154 126.607 40.337 127.051 40.337 127.497 c f
BT 45.750 124.530 Td /F1 9.8 Tf  [(ARUP Laboratories \(Salt Lake City, UT\))] TJ ET
BT 217.506 124.530 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 248.930 124.530 Td /F1 9.8 Tf  [(V600E Mutation Detection by PCR \(2002498\): This assay requires FFPE )] TJ ET
BT 45.750 112.625 Td /F1 9.8 Tf  [(tumor tissue block or at least 3 unstained 5-micrometer \(?m\) slides of tumor tissue, and uses PCR with pyrosequencing to )] TJ ET
BT 45.750 100.720 Td /F1 9.8 Tf  [(detect sequence variants in the)] TJ ET
BT 180.700 100.720 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 212.124 100.720 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 236.518 100.720 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 252.781 100.720 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 263.624 100.720 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 295.594 100.720 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can )] TJ ET
BT 45.750 88.815 Td /F1 9.8 Tf  [(also be requested by selecting the)] TJ ET
BT 193.706 88.815 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 225.677 88.815 Td /F1 9.8 Tf  [(Mutation Detection with )] TJ ET
BT 329.719 88.815 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 358.433 88.815 Td /F1 9.8 Tf  [(reflex \(2001932\) test )] TJ ET
0.267 0.267 0.267 rg
BT 450.560 88.815 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 466.823 88.815 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 76.128 m 
40.337 76.575 40.154 77.019 39.838 77.335 c
39.522 77.651 39.078 77.834 38.631 77.834 c
38.185 77.834 37.741 77.651 37.425 77.335 c
37.109 77.019 36.925 76.575 36.925 76.128 c
36.925 75.682 37.109 75.238 37.425 74.922 c
37.741 74.606 38.185 74.422 38.631 74.422 c
39.078 74.422 39.522 74.606 39.838 74.922 c
40.154 75.238 40.337 75.682 40.337 76.128 c f
BT 45.750 73.161 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) \(Burlington, NC\))] TJ ET
BT 314.499 73.161 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 345.923 73.161 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480340\): This assay )] TJ ET
BT 45.750 61.256 Td /F1 9.8 Tf  [(requires either an FFPE tissue block with ? 50% tumor or 4 unstained 5-?m slides and a single hematoxylin and eosin )] TJ ET
BT 45.750 49.351 Td /F1 9.8 Tf  [(\(H&E\)-stained 5-?m slide. The assay uses dideoxy sequencing to detect the)] TJ ET
BT 373.603 49.351 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 405.028 49.351 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 49.351 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 49.351 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 45.750 37.446 Td /F5 9.8 Tf  [(KRAS )] TJ ET
Q
q
15.000 684.354 577.500 53.646 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(BRAF p.Val600Glu \(V600E\) Testing for Assessment of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Treatment Options in Metastatic Colorectal Cancer)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(October 18, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 663.247 Td /F1 9.8 Tf  [(Andrew Lea)] TJ ET
0.271 0.267 0.267 rg
BT 78.276 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 83.697 663.247 Td /F1 9.8 Tf  [(Diane Allingham-Hawkins)] TJ ET
0.271 0.267 0.267 rg
BT 194.759 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 200.180 663.247 Td /F1 9.8 Tf  [(Susan Levine)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Lea A, Allingham-Hawkins D, Levine S. BRAF p.Val600Glu \(V600E\) Testing for Assessment of Treatment Options in Metastatic )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(Colorectal Cancer. PLOS Currents Evidence on Genomic Tests. 2010 Oct 18 . Edition 1. doi: 10.1371/currents.RRN1187.)] TJ ET
q
15.000 35.065 577.500 601.991 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Colon and rectal cancer \(CRC\) are the third most common cancer in the United States and cause approximately 50,000 deaths )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(per year. The anti-epidermal growth factor receptor \(EGFR\) monoclonal antibodies cetuximab \(Erbitux�\) and panitumumab )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(\(Vectibix�\) have been recently introduced to treat CRC. However, the response rate with these agents is low and they are )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(associated with serious adverse effects. Accordingly biomarkers that can predict those patients that will respond to treatment )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(may have clinical utility. The p.Val600Glu sequence variant \(often called V600E\) in the BRAF gene has been investigated as a )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(biomarker to predict patients that will not respond to treatment with the anti-EGFR monoclonal antibodies.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Together, colon and rectal cancer \(colorectal cancer, or CRC\) comprise the third most common cancer in the United States, )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(with an estimated 50,000 deaths caused by CRC in 2009 )] TJ ET
0.267 0.267 0.267 rg
BT 275.002 462.396 Td /F1 9.8 Tf  [([1] [2] [3] [4])] TJ ET
0.271 0.267 0.267 rg
BT 326.501 462.396 Td /F1 9.8 Tf  [(. The 5-year survival rate for the 150,000 individuals )] TJ ET
BT 26.250 450.491 Td /F1 9.8 Tf  [(diagnosed each year with CRC is 65.2% for all stages, but drops to 11.3% in those with metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 489.043 450.491 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 499.885 450.491 Td /F1 9.8 Tf  [( . Single or )] TJ ET
BT 26.250 438.586 Td /F1 9.8 Tf  [(multiagent chemotherapy regimens may be chosen based on the drugs that are currently approved for treating metastatic CRC, )] TJ ET
BT 26.250 426.681 Td /F1 9.8 Tf  [(which include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, oxaliplatin, and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 490.652 426.681 Td /F1 9.8 Tf  [([3] [4] [5] [6])] TJ ET
0.271 0.267 0.267 rg
BT 542.152 426.681 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 414.777 Td /F1 9.8 Tf  [(Cetuximab \(Erbitux�; Imclone Systems Inc./Bristol-Myers Squibb\) and panitumumab \(Vectibix�; Amgen Inc.\) are anti-epidermal )] TJ ET
BT 26.250 402.872 Td /F1 9.8 Tf  [(growth factor receptor \(EGFR\) monoclonal antibodies that may be used for first-, second- or third-line treatment in patients with )] TJ ET
BT 26.250 390.967 Td /F1 9.8 Tf  [(metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 109.700 390.967 Td /F1 9.8 Tf  [([7] [8] [9])] TJ ET
0.271 0.267 0.267 rg
BT 147.647 390.967 Td /F1 9.8 Tf  [(. EGFR is a component of the HER/Erb-B \(human EGFR\) signaling pathway )] TJ ET
0.267 0.267 0.267 rg
BT 478.728 390.967 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 494.991 390.967 Td /F1 9.8 Tf  [(. Clinical evidence )] TJ ET
BT 26.250 379.062 Td /F1 9.8 Tf  [(suggests that benefit from the EGFR monoclonal antibody inhibitors cetuximab and panitumumab is limited to a subgroup of )] TJ ET
BT 26.250 367.158 Td /F1 9.8 Tf  [(only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 173.650 367.158 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 227.861 367.158 Td /F1 9.8 Tf  [(. Biomarkers are therefore needed to help select the patients who will benefit )] TJ ET
BT 26.250 355.253 Td /F1 9.8 Tf  [(from treatment with EGFR inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 183.917 355.253 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 194.759 355.253 Td /F1 9.8 Tf  [(. In July 2009, the presence of sequence variants in the Kirsten rat sarcoma viral )] TJ ET
BT 26.250 343.348 Td /F1 9.8 Tf  [(oncogene homolog \( )] TJ ET
BT 117.841 343.348 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 144.391 343.348 Td /F1 9.8 Tf  [( \) gene has been approved by the Food and Drug Administration \(FDA\) as a negative prognostic )] TJ ET
BT 26.250 331.443 Td /F1 9.8 Tf  [(indicator for response to treatment with cetuximab and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 325.380 331.443 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 341.643 331.443 Td /F1 9.8 Tf  [(. Another biomarker that is part of the same EGFR )] TJ ET
BT 26.250 319.539 Td /F1 9.8 Tf  [(signaling pathway as )] TJ ET
BT 119.460 319.539 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 146.009 319.539 Td /F1 9.8 Tf  [( that has been investigated for predicting response to EGFR monoclonal antibody treatment in CRC )] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(is the v-raf murine sarcoma viral oncogene homolog B, known as )] TJ ET
BT 309.107 307.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
0.267 0.267 0.267 rg
BT 337.821 307.634 Td /F1 9.8 Tf  [([14] [15])] TJ ET
0.271 0.267 0.267 rg
BT 373.058 307.634 Td /F1 9.8 Tf  [(. The )] TJ ET
BT 397.988 307.634 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 423.991 307.634 Td /F1 9.8 Tf  [( gene sequence variant )] TJ ET
BT 26.250 295.729 Td /F1 9.8 Tf  [(p.Val600Glu, often called V600E, is the main sequence variant in this gene that is associated with CRC )] TJ ET
0.267 0.267 0.267 rg
BT 473.882 295.729 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 490.145 295.729 Td /F1 9.8 Tf  [(. The frequency of )] TJ ET
BT 26.250 283.824 Td /F1 9.8 Tf  [(the )] TJ ET
BT 42.513 283.824 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 68.516 283.824 Td /F1 9.8 Tf  [( p.Val600Glu variant was 5% to 12% in CRC populations, and the presence of this variant has been found to be )] TJ ET
BT 26.250 271.920 Td /F1 9.8 Tf  [(associated with poor survival in patients with CRC in several studies in which patients were not treated with anti-EGFR )] TJ ET
BT 26.250 260.015 Td /F1 9.8 Tf  [(monoclonal antibodies )] TJ ET
0.267 0.267 0.267 rg
BT 125.963 260.015 Td /F1 9.8 Tf  [([16] [17] [18] [19] [20] [21] [22] [23])] TJ ET
0.271 0.267 0.267 rg
BT 275.041 260.015 Td /F1 9.8 Tf  [(. Furthermore, there appears to be little variation in the )] TJ ET
BT 512.941 260.015 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 26.250 248.110 Td /F1 9.8 Tf  [(p.Val600Glu status between primary and secondary tumors )] TJ ET
0.267 0.267 0.267 rg
BT 285.278 248.110 Td /F1 9.8 Tf  [([23] [24])] TJ ET
0.271 0.267 0.267 rg
BT 320.515 248.110 Td /F1 9.8 Tf  [(. As testing for the presence of )] TJ ET
BT 455.464 248.110 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 482.014 248.110 Td /F1 9.8 Tf  [( sequence variants to )] TJ ET
BT 26.250 236.205 Td /F1 9.8 Tf  [(predict response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now included in the FDA )] TJ ET
BT 26.250 224.301 Td /F1 9.8 Tf  [(prescribing information, this Knol focuses on genetic testing for )] TJ ET
BT 299.913 224.301 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 325.916 224.301 Td /F1 9.8 Tf  [( p.Val600Glu following )] TJ ET
BT 425.630 224.301 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 452.179 224.301 Td /F1 9.8 Tf  [( testing.)] TJ ET
BT 26.250 187.698 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 167.744 Td /F1 9.8 Tf  [(A number of providers have assays that can detect the )] TJ ET
BT 264.706 167.744 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 290.709 167.744 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant from formalin-fixed paraffin-)] TJ ET
BT 26.250 155.839 Td /F1 9.8 Tf  [(embedded \(FFPE\) tumor samples or slides using a variety of technologies, including polymerase chain reaction \(PCR\) with and )] TJ ET
BT 26.250 143.934 Td /F1 9.8 Tf  [(without fluorescence monitoring, dideoxy sequencing, direct sequencing, and pyrosequencing:)] TJ ET
0.271 0.267 0.267 RG
40.337 127.497 m 
40.337 127.944 40.154 128.388 39.838 128.704 c
39.522 129.020 39.078 129.204 38.631 129.204 c
38.185 129.204 37.741 129.020 37.425 128.704 c
37.109 128.388 36.925 127.944 36.925 127.497 c
36.925 127.051 37.109 126.607 37.425 126.291 c
37.741 125.975 38.185 125.791 38.631 125.791 c
39.078 125.791 39.522 125.975 39.838 126.291 c
40.154 126.607 40.337 127.051 40.337 127.497 c f
BT 45.750 124.530 Td /F1 9.8 Tf  [(ARUP Laboratories \(Salt Lake City, UT\))] TJ ET
BT 217.506 124.530 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 248.930 124.530 Td /F1 9.8 Tf  [(V600E Mutation Detection by PCR \(2002498\): This assay requires FFPE )] TJ ET
BT 45.750 112.625 Td /F1 9.8 Tf  [(tumor tissue block or at least 3 unstained 5-micrometer \(?m\) slides of tumor tissue, and uses PCR with pyrosequencing to )] TJ ET
BT 45.750 100.720 Td /F1 9.8 Tf  [(detect sequence variants in the)] TJ ET
BT 180.700 100.720 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 212.124 100.720 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 236.518 100.720 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 252.781 100.720 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 263.624 100.720 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 295.594 100.720 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can )] TJ ET
BT 45.750 88.815 Td /F1 9.8 Tf  [(also be requested by selecting the)] TJ ET
BT 193.706 88.815 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 225.677 88.815 Td /F1 9.8 Tf  [(Mutation Detection with )] TJ ET
BT 329.719 88.815 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 358.433 88.815 Td /F1 9.8 Tf  [(reflex \(2001932\) test )] TJ ET
0.267 0.267 0.267 rg
BT 450.560 88.815 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 466.823 88.815 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 76.128 m 
40.337 76.575 40.154 77.019 39.838 77.335 c
39.522 77.651 39.078 77.834 38.631 77.834 c
38.185 77.834 37.741 77.651 37.425 77.335 c
37.109 77.019 36.925 76.575 36.925 76.128 c
36.925 75.682 37.109 75.238 37.425 74.922 c
37.741 74.606 38.185 74.422 38.631 74.422 c
39.078 74.422 39.522 74.606 39.838 74.922 c
40.154 75.238 40.337 75.682 40.337 76.128 c f
BT 45.750 73.161 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) \(Burlington, NC\))] TJ ET
BT 314.499 73.161 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 345.923 73.161 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480340\): This assay )] TJ ET
BT 45.750 61.256 Td /F1 9.8 Tf  [(requires either an FFPE tissue block with ? 50% tumor or 4 unstained 5-?m slides and a single hematoxylin and eosin )] TJ ET
BT 45.750 49.351 Td /F1 9.8 Tf  [(\(H&E\)-stained 5-?m slide. The assay uses dideoxy sequencing to detect the)] TJ ET
BT 373.603 49.351 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 405.028 49.351 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 49.351 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 49.351 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 45.750 37.446 Td /F5 9.8 Tf  [(KRAS )] TJ ET
Q
q
15.000 684.354 577.500 53.646 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(BRAF p.Val600Glu \(V600E\) Testing for Assessment of )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Treatment Options in Metastatic Colorectal Cancer)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(October 18, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 663.247 Td /F1 9.8 Tf  [(Andrew Lea)] TJ ET
0.271 0.267 0.267 rg
BT 78.276 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 83.697 663.247 Td /F1 9.8 Tf  [(Diane Allingham-Hawkins)] TJ ET
0.271 0.267 0.267 rg
BT 194.759 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 200.180 663.247 Td /F1 9.8 Tf  [(Susan Levine)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Lea A, Allingham-Hawkins D, Levine S. BRAF p.Val600Glu \(V600E\) Testing for Assessment of Treatment Options in Metastatic )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(Colorectal Cancer. PLOS Currents Evidence on Genomic Tests. 2010 Oct 18 . Edition 1. doi: 10.1371/currents.RRN1187.)] TJ ET
q
15.000 35.065 577.500 601.991 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Colon and rectal cancer \(CRC\) are the third most common cancer in the United States and cause approximately 50,000 deaths )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(per year. The anti-epidermal growth factor receptor \(EGFR\) monoclonal antibodies cetuximab \(Erbitux�\) and panitumumab )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(\(Vectibix�\) have been recently introduced to treat CRC. However, the response rate with these agents is low and they are )] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(associated with serious adverse effects. Accordingly biomarkers that can predict those patients that will respond to treatment )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(may have clinical utility. The p.Val600Glu sequence variant \(often called V600E\) in the BRAF gene has been investigated as a )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(biomarker to predict patients that will not respond to treatment with the anti-EGFR monoclonal antibodies.)] TJ ET
BT 26.250 494.255 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 474.300 Td /F1 9.8 Tf  [(Together, colon and rectal cancer \(colorectal cancer, or CRC\) comprise the third most common cancer in the United States, )] TJ ET
BT 26.250 462.396 Td /F1 9.8 Tf  [(with an estimated 50,000 deaths caused by CRC in 2009 )] TJ ET
0.267 0.267 0.267 rg
BT 275.002 462.396 Td /F1 9.8 Tf  [([1] [2] [3] [4])] TJ ET
0.271 0.267 0.267 rg
BT 326.501 462.396 Td /F1 9.8 Tf  [(. The 5-year survival rate for the 150,000 individuals )] TJ ET
BT 26.250 450.491 Td /F1 9.8 Tf  [(diagnosed each year with CRC is 65.2% for all stages, but drops to 11.3% in those with metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 489.043 450.491 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 499.885 450.491 Td /F1 9.8 Tf  [( . Single or )] TJ ET
BT 26.250 438.586 Td /F1 9.8 Tf  [(multiagent chemotherapy regimens may be chosen based on the drugs that are currently approved for treating metastatic CRC, )] TJ ET
BT 26.250 426.681 Td /F1 9.8 Tf  [(which include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, oxaliplatin, and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 490.652 426.681 Td /F1 9.8 Tf  [([3] [4] [5] [6])] TJ ET
0.271 0.267 0.267 rg
BT 542.152 426.681 Td /F1 9.8 Tf  [(. )] TJ ET
BT 26.250 414.777 Td /F1 9.8 Tf  [(Cetuximab \(Erbitux�; Imclone Systems Inc./Bristol-Myers Squibb\) and panitumumab \(Vectibix�; Amgen Inc.\) are anti-epidermal )] TJ ET
BT 26.250 402.872 Td /F1 9.8 Tf  [(growth factor receptor \(EGFR\) monoclonal antibodies that may be used for first-, second- or third-line treatment in patients with )] TJ ET
BT 26.250 390.967 Td /F1 9.8 Tf  [(metastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 109.700 390.967 Td /F1 9.8 Tf  [([7] [8] [9])] TJ ET
0.271 0.267 0.267 rg
BT 147.647 390.967 Td /F1 9.8 Tf  [(. EGFR is a component of the HER/Erb-B \(human EGFR\) signaling pathway )] TJ ET
0.267 0.267 0.267 rg
BT 478.728 390.967 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 494.991 390.967 Td /F1 9.8 Tf  [(. Clinical evidence )] TJ ET
BT 26.250 379.062 Td /F1 9.8 Tf  [(suggests that benefit from the EGFR monoclonal antibody inhibitors cetuximab and panitumumab is limited to a subgroup of )] TJ ET
BT 26.250 367.158 Td /F1 9.8 Tf  [(only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 173.650 367.158 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 227.861 367.158 Td /F1 9.8 Tf  [(. Biomarkers are therefore needed to help select the patients who will benefit )] TJ ET
BT 26.250 355.253 Td /F1 9.8 Tf  [(from treatment with EGFR inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 183.917 355.253 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 194.759 355.253 Td /F1 9.8 Tf  [(. In July 2009, the presence of sequence variants in the Kirsten rat sarcoma viral )] TJ ET
BT 26.250 343.348 Td /F1 9.8 Tf  [(oncogene homolog \( )] TJ ET
BT 117.841 343.348 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 144.391 343.348 Td /F1 9.8 Tf  [( \) gene has been approved by the Food and Drug Administration \(FDA\) as a negative prognostic )] TJ ET
BT 26.250 331.443 Td /F1 9.8 Tf  [(indicator for response to treatment with cetuximab and panitumumab )] TJ ET
0.267 0.267 0.267 rg
BT 325.380 331.443 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 341.643 331.443 Td /F1 9.8 Tf  [(. Another biomarker that is part of the same EGFR )] TJ ET
BT 26.250 319.539 Td /F1 9.8 Tf  [(signaling pathway as )] TJ ET
BT 119.460 319.539 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 146.009 319.539 Td /F1 9.8 Tf  [( that has been investigated for predicting response to EGFR monoclonal antibody treatment in CRC )] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(is the v-raf murine sarcoma viral oncogene homolog B, known as )] TJ ET
BT 309.107 307.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
0.267 0.267 0.267 rg
BT 337.821 307.634 Td /F1 9.8 Tf  [([14] [15])] TJ ET
0.271 0.267 0.267 rg
BT 373.058 307.634 Td /F1 9.8 Tf  [(. The )] TJ ET
BT 397.988 307.634 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 423.991 307.634 Td /F1 9.8 Tf  [( gene sequence variant )] TJ ET
BT 26.250 295.729 Td /F1 9.8 Tf  [(p.Val600Glu, often called V600E, is the main sequence variant in this gene that is associated with CRC )] TJ ET
0.267 0.267 0.267 rg
BT 473.882 295.729 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 490.145 295.729 Td /F1 9.8 Tf  [(. The frequency of )] TJ ET
BT 26.250 283.824 Td /F1 9.8 Tf  [(the )] TJ ET
BT 42.513 283.824 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 68.516 283.824 Td /F1 9.8 Tf  [( p.Val600Glu variant was 5% to 12% in CRC populations, and the presence of this variant has been found to be )] TJ ET
BT 26.250 271.920 Td /F1 9.8 Tf  [(associated with poor survival in patients with CRC in several studies in which patients were not treated with anti-EGFR )] TJ ET
BT 26.250 260.015 Td /F1 9.8 Tf  [(monoclonal antibodies )] TJ ET
0.267 0.267 0.267 rg
BT 125.963 260.015 Td /F1 9.8 Tf  [([16] [17] [18] [19] [20] [21] [22] [23])] TJ ET
0.271 0.267 0.267 rg
BT 275.041 260.015 Td /F1 9.8 Tf  [(. Furthermore, there appears to be little variation in the )] TJ ET
BT 512.941 260.015 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 26.250 248.110 Td /F1 9.8 Tf  [(p.Val600Glu status between primary and secondary tumors )] TJ ET
0.267 0.267 0.267 rg
BT 285.278 248.110 Td /F1 9.8 Tf  [([23] [24])] TJ ET
0.271 0.267 0.267 rg
BT 320.515 248.110 Td /F1 9.8 Tf  [(. As testing for the presence of )] TJ ET
BT 455.464 248.110 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 482.014 248.110 Td /F1 9.8 Tf  [( sequence variants to )] TJ ET
BT 26.250 236.205 Td /F1 9.8 Tf  [(predict response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now included in the FDA )] TJ ET
BT 26.250 224.301 Td /F1 9.8 Tf  [(prescribing information, this Knol focuses on genetic testing for )] TJ ET
BT 299.913 224.301 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 325.916 224.301 Td /F1 9.8 Tf  [( p.Val600Glu following )] TJ ET
BT 425.630 224.301 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 452.179 224.301 Td /F1 9.8 Tf  [( testing.)] TJ ET
BT 26.250 187.698 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 167.744 Td /F1 9.8 Tf  [(A number of providers have assays that can detect the )] TJ ET
BT 264.706 167.744 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 290.709 167.744 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant from formalin-fixed paraffin-)] TJ ET
BT 26.250 155.839 Td /F1 9.8 Tf  [(embedded \(FFPE\) tumor samples or slides using a variety of technologies, including polymerase chain reaction \(PCR\) with and )] TJ ET
BT 26.250 143.934 Td /F1 9.8 Tf  [(without fluorescence monitoring, dideoxy sequencing, direct sequencing, and pyrosequencing:)] TJ ET
0.271 0.267 0.267 RG
40.337 127.497 m 
40.337 127.944 40.154 128.388 39.838 128.704 c
39.522 129.020 39.078 129.204 38.631 129.204 c
38.185 129.204 37.741 129.020 37.425 128.704 c
37.109 128.388 36.925 127.944 36.925 127.497 c
36.925 127.051 37.109 126.607 37.425 126.291 c
37.741 125.975 38.185 125.791 38.631 125.791 c
39.078 125.791 39.522 125.975 39.838 126.291 c
40.154 126.607 40.337 127.051 40.337 127.497 c f
BT 45.750 124.530 Td /F1 9.8 Tf  [(ARUP Laboratories \(Salt Lake City, UT\))] TJ ET
BT 217.506 124.530 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 248.930 124.530 Td /F1 9.8 Tf  [(V600E Mutation Detection by PCR \(2002498\): This assay requires FFPE )] TJ ET
BT 45.750 112.625 Td /F1 9.8 Tf  [(tumor tissue block or at least 3 unstained 5-micrometer \(?m\) slides of tumor tissue, and uses PCR with pyrosequencing to )] TJ ET
BT 45.750 100.720 Td /F1 9.8 Tf  [(detect sequence variants in the)] TJ ET
BT 180.700 100.720 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 212.124 100.720 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 236.518 100.720 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 252.781 100.720 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 263.624 100.720 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 295.594 100.720 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can )] TJ ET
BT 45.750 88.815 Td /F1 9.8 Tf  [(also be requested by selecting the)] TJ ET
BT 193.706 88.815 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 225.677 88.815 Td /F1 9.8 Tf  [(Mutation Detection with )] TJ ET
BT 329.719 88.815 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 358.433 88.815 Td /F1 9.8 Tf  [(reflex \(2001932\) test )] TJ ET
0.267 0.267 0.267 rg
BT 450.560 88.815 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 466.823 88.815 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 76.128 m 
40.337 76.575 40.154 77.019 39.838 77.335 c
39.522 77.651 39.078 77.834 38.631 77.834 c
38.185 77.834 37.741 77.651 37.425 77.335 c
37.109 77.019 36.925 76.575 36.925 76.128 c
36.925 75.682 37.109 75.238 37.425 74.922 c
37.741 74.606 38.185 74.422 38.631 74.422 c
39.078 74.422 39.522 74.606 39.838 74.922 c
40.154 75.238 40.337 75.682 40.337 76.128 c f
BT 45.750 73.161 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) \(Burlington, NC\))] TJ ET
BT 314.499 73.161 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 345.923 73.161 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480340\): This assay )] TJ ET
BT 45.750 61.256 Td /F1 9.8 Tf  [(requires either an FFPE tissue block with ? 50% tumor or 4 unstained 5-?m slides and a single hematoxylin and eosin )] TJ ET
BT 45.750 49.351 Td /F1 9.8 Tf  [(\(H&E\)-stained 5-?m slide. The assay uses dideoxy sequencing to detect the)] TJ ET
BT 373.603 49.351 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 405.028 49.351 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 49.351 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 49.351 Td /F1 9.8 Tf  [(. If)] TJ ET
BT 45.750 37.446 Td /F5 9.8 Tf  [(KRAS )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(1)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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15.000 22.738 577.500 754.262 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can also be requested by selecting the K-ras Gene )] TJ ET
BT 534.040 767.476 Td /F1 9.8 Tf  [(Mutation )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(Detection With Reflex to)] TJ ET
BT 150.329 755.571 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 181.753 755.571 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480360\) )] TJ ET
0.267 0.267 0.267 rg
BT 355.712 755.571 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 371.975 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
0.271 0.267 0.267 RG
40.337 742.884 m 
40.337 743.331 40.154 743.775 39.838 744.091 c
39.522 744.407 39.078 744.590 38.631 744.590 c
38.185 744.590 37.741 744.407 37.425 744.091 c
37.109 743.775 36.925 743.331 36.925 742.884 c
36.925 742.438 37.109 741.994 37.425 741.678 c
37.741 741.362 38.185 741.178 38.631 741.178 c
39.078 741.178 39.522 741.362 39.838 741.678 c
40.154 741.994 40.337 742.438 40.337 742.884 c f
BT 45.750 739.917 Td /F1 9.8 Tf  [(Mayo Medical Laboratories \(Rochester, MN\))] TJ ET
BT 237.006 739.917 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 268.430 739.917 Td /F1 9.8 Tf  [(Mutation Analysis \(V600E\), Tumor \(Unit Code 87980\): The specimen )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(requirements for this assay are an FFPE tumor tissue block or a single H&E-stained 5-?m slide with 10 unstained )] TJ ET
BT 45.750 716.107 Td /F1 9.8 Tf  [(nonbaked slides with 5 slides, each with 5-?m and 10-?m-thick sections. The assay uses PCR to detect the )] TJ ET
BT 510.698 716.107 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 704.202 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 179.071 704.202 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 195.334 704.202 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 691.515 m 
40.337 691.962 40.154 692.406 39.838 692.722 c
39.522 693.038 39.078 693.221 38.631 693.221 c
38.185 693.221 37.741 693.038 37.425 692.722 c
37.109 692.406 36.925 691.962 36.925 691.515 c
36.925 691.069 37.109 690.625 37.425 690.309 c
37.741 689.993 38.185 689.809 38.631 689.809 c
39.078 689.809 39.522 689.993 39.838 690.309 c
40.154 690.625 40.337 691.069 40.337 691.515 c f
BT 45.750 688.548 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. \(Madison, NJ\) )] TJ ET
BT 209.384 688.548 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 238.098 688.548 Td /F1 9.8 Tf  [(Mutation Analysis \(16767\): This assay requires an FFPE tumor tissue block. )] TJ ET
BT 45.750 676.643 Td /F1 9.8 Tf  [(Direct sequencing is used to detect sequence variants in the )] TJ ET
BT 308.591 676.643 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 337.304 676.643 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 361.699 676.643 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 377.962 676.643 Td /F1 9.8 Tf  [(. This assay can also be requested by )] TJ ET
BT 45.750 664.738 Td /F1 9.8 Tf  [(selecting the EGFR Pathway \()] TJ ET
BT 176.341 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 205.601 664.738 Td /F1 9.8 Tf  [(with Reflex to )] TJ ET
BT 266.831 664.738 Td /F5 9.8 Tf  [(NRAS)] TJ ET
BT 293.917 664.738 Td /F1 9.8 Tf  [(,)] TJ ET
BT 296.627 664.738 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 325.341 664.738 Td /F1 9.8 Tf  [(\) \(16819\) assay if the specimen is found to be )] TJ ET
BT 525.313 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 652.833 Td /F1 9.8 Tf  [(sequence variant-negative )] TJ ET
0.267 0.267 0.267 rg
BT 162.808 652.833 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 179.071 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 640.146 m 
40.337 640.593 40.154 641.037 39.838 641.353 c
39.522 641.669 39.078 641.852 38.631 641.852 c
38.185 641.852 37.741 641.669 37.425 641.353 c
37.109 641.037 36.925 640.593 36.925 640.146 c
36.925 639.700 37.109 639.256 37.425 638.940 c
37.741 638.624 38.185 638.440 38.631 638.440 c
39.078 638.440 39.522 638.624 39.838 638.940 c
40.154 639.256 40.337 639.700 40.337 640.146 c f
BT 45.750 637.179 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories \(Chapel Hill, NC\) )] TJ ET
BT 339.401 637.179 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 368.114 637.179 Td /F1 9.8 Tf  [(Mutation Test in Colorectal Cancer: The )] TJ ET
BT 45.750 625.274 Td /F1 9.8 Tf  [(specimen preferred for this assay is an FFPE tumor tissue block containing ? 50% malignant cells or 10 5- to 10-?m slides )] TJ ET
BT 45.750 613.369 Td /F1 9.8 Tf  [(with a single H&E-stained slide. The assay uses PCR followed by pyrosequencing to detect the)] TJ ET
BT 455.971 613.369 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 487.396 613.369 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 601.464 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 601.464 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 138.970 601.464 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 588.777 m 
40.337 589.224 40.154 589.668 39.838 589.984 c
39.522 590.300 39.078 590.483 38.631 590.483 c
38.185 590.483 37.741 590.300 37.425 589.984 c
37.109 589.668 36.925 589.224 36.925 588.777 c
36.925 588.331 37.109 587.887 37.425 587.571 c
37.741 587.255 38.185 587.071 38.631 587.071 c
39.078 587.071 39.522 587.255 39.838 587.571 c
40.154 587.887 40.337 588.331 40.337 588.777 c f
BT 45.750 585.810 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services \(Nashville, TN\))] TJ ET
BT 292.288 585.810 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 323.713 585.810 Td /F1 9.8 Tf  [(\(V600E\) \(V6A\): The assay requires an FFPE tissue block )] TJ ET
BT 45.750 573.905 Td /F1 9.8 Tf  [(and uses allele-specific detection to identify the )] TJ ET
BT 252.226 573.905 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 278.229 573.905 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant. Also available is a second assay, the)] TJ ET
BT 45.750 562.000 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 71.753 562.000 Td /F1 9.8 Tf  [( \(V600E Sequencing\) \(V6S\), which uses sequencing to detect the)] TJ ET
BT 354.649 562.000 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 383.363 562.000 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 516.685 562.000 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 532.948 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 521.648 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 501.693 Td /F1 9.8 Tf  [(Available evidence indicates that the clinical benefit from treatment with EGFR monoclonal antibody inhibitors cetuximab and )] TJ ET
BT 26.250 489.789 Td /F1 9.8 Tf  [(panitumumab is limited to a subgroup of only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 349.228 489.789 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 403.438 489.789 Td /F1 9.8 Tf  [(. Accordingly, biomarkers are needed to )] TJ ET
BT 26.250 477.884 Td /F1 9.8 Tf  [(help select patients who will benefit from treatment with EGFR monoclonal antibody inhibitors and also to avoid unnecessary )] TJ ET
BT 26.250 465.979 Td /F1 9.8 Tf  [(exposure of patients to the serious adverse events associated with these agents )] TJ ET
0.267 0.267 0.267 rg
BT 374.725 465.979 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 385.567 465.979 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 429.377 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 409.422 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 390.018 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 370.613 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 351.208 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 331.803 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 312.399 Td /F1 9.8 Tf  [(If patients do not have a sequence variant in the )] TJ ET
BT 236.548 312.399 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 263.097 312.399 Td /F1 9.8 Tf  [( gene, the National Comprehensive Cancer Network \(NCCN\) guidelines )] TJ ET
BT 26.250 300.494 Td /F1 9.8 Tf  [(for patients undergoing treatment for CRC state that testing for )] TJ ET
BT 298.841 300.494 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 324.844 300.494 Td /F1 9.8 Tf  [( p.Val600Glu should be considered prior to the use of anti-)] TJ ET
BT 26.250 288.589 Td /F1 9.8 Tf  [(EGFR antibodies \(cetuximab and panitumumab\). Furthermore, these guidelines indicate that patients with a )] TJ ET
BT 492.827 288.589 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 518.830 288.589 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 26.250 276.684 Td /F1 9.8 Tf  [(variant are unlikely to respond to treatment with anti-EGFR antibodies; however, it is noted that the data are somewhat )] TJ ET
BT 26.250 264.780 Td /F1 9.8 Tf  [(inconsistent )] TJ ET
0.267 0.267 0.267 rg
BT 80.441 264.780 Td /F1 9.8 Tf  [([5] [6])] TJ ET
0.271 0.267 0.267 rg
BT 104.835 264.780 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 228.177 Td /F4 12.0 Tf  [(Search Strategy)] TJ ET
BT 26.250 208.223 Td /F1 9.8 Tf  [(Evidence evaluated for this report was obtained primarily from a search of the peer-reviewed literature in MEDLINE and )] TJ ET
BT 26.250 196.318 Td /F1 9.8 Tf  [(EMBASE databases on September 18, 2010, using the terms \( )] TJ ET
BT 299.933 196.318 Td /F5 9.8 Tf  [(V600E)] TJ ET
BT 329.202 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 349.248 196.318 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 375.251 196.318 Td /F1 9.8 Tf  [( \) AND \( )] TJ ET
BT 413.169 196.318 Td /F5 9.8 Tf  [(colon)] TJ ET
BT 436.471 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 456.517 196.318 Td /F5 9.8 Tf  [(colorectal)] TJ ET
BT 498.238 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 518.284 196.318 Td /F5 9.8 Tf  [(rectal)] TJ ET
BT 542.122 196.318 Td /F1 9.8 Tf  [( \) AND )] TJ ET
BT 26.250 184.413 Td /F5 9.8 Tf  [(cancer)] TJ ET
BT 55.510 184.413 Td /F1 9.8 Tf  [( . Limits used were English language and published since January 1, 1996.)] TJ ET
BT 26.250 147.811 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 127.857 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 127.857 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 127.857 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the presence or absence of the )] TJ ET
BT 431.587 127.857 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 457.590 127.857 Td /F1 9.8 Tf  [( p.Val600Glu sequence )] TJ ET
BT 26.250 115.952 Td /F1 9.8 Tf  [(variant \(analytic sensitivity and specificity\).)] TJ ET
BT 26.250 96.547 Td /F1 9.8 Tf  [(The analytic sensitivity and specificity of the commercially available assays are not reported on manufacturer websites )] TJ ET
0.267 0.267 0.267 rg
BT 537.774 96.547 Td /F1 9.8 Tf  [([25] [26] )] TJ ET
BT 26.250 84.642 Td /F1 9.8 Tf  [([27] [28] [29] [30] [31] [32])] TJ ET
0.271 0.267 0.267 rg
BT 137.380 84.642 Td /F1 9.8 Tf  [(. Several recent reports are available that describe studies of the analytical validity of genetic testing )] TJ ET
BT 26.250 72.738 Td /F1 9.8 Tf  [(for )] TJ ET
BT 40.339 72.738 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 66.342 72.738 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 150.884 72.738 Td /F1 9.8 Tf  [([33] [34] [35] [36] [37] [38])] TJ ET
0.271 0.267 0.267 rg
BT 262.015 72.738 Td /F1 9.8 Tf  [(. However, these reports appear to have little bearing on the )] TJ ET
BT 26.250 60.833 Td /F1 9.8 Tf  [(commercially available assays for the )] TJ ET
BT 190.421 60.833 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 216.424 60.833 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant. Two reports describe studies investigating testing )] TJ ET
BT 26.250 48.928 Td /F1 9.8 Tf  [(for multiple biomarkers, including sequence variants in the )] TJ ET
BT 279.847 48.928 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 305.851 48.928 Td /F1 9.8 Tf  [( gene, and, therefore, have no relevance to the commercially )] TJ ET
BT 26.250 37.023 Td /F1 9.8 Tf  [(available assays that detect the )] TJ ET
BT 164.993 37.023 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 190.996 37.023 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 327.028 37.023 Td /F1 9.8 Tf  [([34] [35])] TJ ET
0.271 0.267 0.267 rg
BT 362.264 37.023 Td /F1 9.8 Tf  [(. Two other reports investigate the analytical )] TJ ET
Q
q
15.000 22.738 577.500 754.262 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can also be requested by selecting the K-ras Gene )] TJ ET
BT 534.040 767.476 Td /F1 9.8 Tf  [(Mutation )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(Detection With Reflex to)] TJ ET
BT 150.329 755.571 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 181.753 755.571 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480360\) )] TJ ET
0.267 0.267 0.267 rg
BT 355.712 755.571 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 371.975 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
0.271 0.267 0.267 RG
40.337 742.884 m 
40.337 743.331 40.154 743.775 39.838 744.091 c
39.522 744.407 39.078 744.590 38.631 744.590 c
38.185 744.590 37.741 744.407 37.425 744.091 c
37.109 743.775 36.925 743.331 36.925 742.884 c
36.925 742.438 37.109 741.994 37.425 741.678 c
37.741 741.362 38.185 741.178 38.631 741.178 c
39.078 741.178 39.522 741.362 39.838 741.678 c
40.154 741.994 40.337 742.438 40.337 742.884 c f
BT 45.750 739.917 Td /F1 9.8 Tf  [(Mayo Medical Laboratories \(Rochester, MN\))] TJ ET
BT 237.006 739.917 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 268.430 739.917 Td /F1 9.8 Tf  [(Mutation Analysis \(V600E\), Tumor \(Unit Code 87980\): The specimen )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(requirements for this assay are an FFPE tumor tissue block or a single H&E-stained 5-?m slide with 10 unstained )] TJ ET
BT 45.750 716.107 Td /F1 9.8 Tf  [(nonbaked slides with 5 slides, each with 5-?m and 10-?m-thick sections. The assay uses PCR to detect the )] TJ ET
BT 510.698 716.107 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 704.202 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 179.071 704.202 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 195.334 704.202 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 691.515 m 
40.337 691.962 40.154 692.406 39.838 692.722 c
39.522 693.038 39.078 693.221 38.631 693.221 c
38.185 693.221 37.741 693.038 37.425 692.722 c
37.109 692.406 36.925 691.962 36.925 691.515 c
36.925 691.069 37.109 690.625 37.425 690.309 c
37.741 689.993 38.185 689.809 38.631 689.809 c
39.078 689.809 39.522 689.993 39.838 690.309 c
40.154 690.625 40.337 691.069 40.337 691.515 c f
BT 45.750 688.548 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. \(Madison, NJ\) )] TJ ET
BT 209.384 688.548 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 238.098 688.548 Td /F1 9.8 Tf  [(Mutation Analysis \(16767\): This assay requires an FFPE tumor tissue block. )] TJ ET
BT 45.750 676.643 Td /F1 9.8 Tf  [(Direct sequencing is used to detect sequence variants in the )] TJ ET
BT 308.591 676.643 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 337.304 676.643 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 361.699 676.643 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 377.962 676.643 Td /F1 9.8 Tf  [(. This assay can also be requested by )] TJ ET
BT 45.750 664.738 Td /F1 9.8 Tf  [(selecting the EGFR Pathway \()] TJ ET
BT 176.341 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 205.601 664.738 Td /F1 9.8 Tf  [(with Reflex to )] TJ ET
BT 266.831 664.738 Td /F5 9.8 Tf  [(NRAS)] TJ ET
BT 293.917 664.738 Td /F1 9.8 Tf  [(,)] TJ ET
BT 296.627 664.738 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 325.341 664.738 Td /F1 9.8 Tf  [(\) \(16819\) assay if the specimen is found to be )] TJ ET
BT 525.313 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 652.833 Td /F1 9.8 Tf  [(sequence variant-negative )] TJ ET
0.267 0.267 0.267 rg
BT 162.808 652.833 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 179.071 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 640.146 m 
40.337 640.593 40.154 641.037 39.838 641.353 c
39.522 641.669 39.078 641.852 38.631 641.852 c
38.185 641.852 37.741 641.669 37.425 641.353 c
37.109 641.037 36.925 640.593 36.925 640.146 c
36.925 639.700 37.109 639.256 37.425 638.940 c
37.741 638.624 38.185 638.440 38.631 638.440 c
39.078 638.440 39.522 638.624 39.838 638.940 c
40.154 639.256 40.337 639.700 40.337 640.146 c f
BT 45.750 637.179 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories \(Chapel Hill, NC\) )] TJ ET
BT 339.401 637.179 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 368.114 637.179 Td /F1 9.8 Tf  [(Mutation Test in Colorectal Cancer: The )] TJ ET
BT 45.750 625.274 Td /F1 9.8 Tf  [(specimen preferred for this assay is an FFPE tumor tissue block containing ? 50% malignant cells or 10 5- to 10-?m slides )] TJ ET
BT 45.750 613.369 Td /F1 9.8 Tf  [(with a single H&E-stained slide. The assay uses PCR followed by pyrosequencing to detect the)] TJ ET
BT 455.971 613.369 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 487.396 613.369 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 601.464 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 601.464 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 138.970 601.464 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 588.777 m 
40.337 589.224 40.154 589.668 39.838 589.984 c
39.522 590.300 39.078 590.483 38.631 590.483 c
38.185 590.483 37.741 590.300 37.425 589.984 c
37.109 589.668 36.925 589.224 36.925 588.777 c
36.925 588.331 37.109 587.887 37.425 587.571 c
37.741 587.255 38.185 587.071 38.631 587.071 c
39.078 587.071 39.522 587.255 39.838 587.571 c
40.154 587.887 40.337 588.331 40.337 588.777 c f
BT 45.750 585.810 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services \(Nashville, TN\))] TJ ET
BT 292.288 585.810 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 323.713 585.810 Td /F1 9.8 Tf  [(\(V600E\) \(V6A\): The assay requires an FFPE tissue block )] TJ ET
BT 45.750 573.905 Td /F1 9.8 Tf  [(and uses allele-specific detection to identify the )] TJ ET
BT 252.226 573.905 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 278.229 573.905 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant. Also available is a second assay, the)] TJ ET
BT 45.750 562.000 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 71.753 562.000 Td /F1 9.8 Tf  [( \(V600E Sequencing\) \(V6S\), which uses sequencing to detect the)] TJ ET
BT 354.649 562.000 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 383.363 562.000 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 516.685 562.000 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 532.948 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 521.648 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 501.693 Td /F1 9.8 Tf  [(Available evidence indicates that the clinical benefit from treatment with EGFR monoclonal antibody inhibitors cetuximab and )] TJ ET
BT 26.250 489.789 Td /F1 9.8 Tf  [(panitumumab is limited to a subgroup of only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 349.228 489.789 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 403.438 489.789 Td /F1 9.8 Tf  [(. Accordingly, biomarkers are needed to )] TJ ET
BT 26.250 477.884 Td /F1 9.8 Tf  [(help select patients who will benefit from treatment with EGFR monoclonal antibody inhibitors and also to avoid unnecessary )] TJ ET
BT 26.250 465.979 Td /F1 9.8 Tf  [(exposure of patients to the serious adverse events associated with these agents )] TJ ET
0.267 0.267 0.267 rg
BT 374.725 465.979 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 385.567 465.979 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 429.377 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 409.422 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 390.018 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 370.613 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 351.208 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 331.803 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 312.399 Td /F1 9.8 Tf  [(If patients do not have a sequence variant in the )] TJ ET
BT 236.548 312.399 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 263.097 312.399 Td /F1 9.8 Tf  [( gene, the National Comprehensive Cancer Network \(NCCN\) guidelines )] TJ ET
BT 26.250 300.494 Td /F1 9.8 Tf  [(for patients undergoing treatment for CRC state that testing for )] TJ ET
BT 298.841 300.494 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 324.844 300.494 Td /F1 9.8 Tf  [( p.Val600Glu should be considered prior to the use of anti-)] TJ ET
BT 26.250 288.589 Td /F1 9.8 Tf  [(EGFR antibodies \(cetuximab and panitumumab\). Furthermore, these guidelines indicate that patients with a )] TJ ET
BT 492.827 288.589 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 518.830 288.589 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 26.250 276.684 Td /F1 9.8 Tf  [(variant are unlikely to respond to treatment with anti-EGFR antibodies; however, it is noted that the data are somewhat )] TJ ET
BT 26.250 264.780 Td /F1 9.8 Tf  [(inconsistent )] TJ ET
0.267 0.267 0.267 rg
BT 80.441 264.780 Td /F1 9.8 Tf  [([5] [6])] TJ ET
0.271 0.267 0.267 rg
BT 104.835 264.780 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 228.177 Td /F4 12.0 Tf  [(Search Strategy)] TJ ET
BT 26.250 208.223 Td /F1 9.8 Tf  [(Evidence evaluated for this report was obtained primarily from a search of the peer-reviewed literature in MEDLINE and )] TJ ET
BT 26.250 196.318 Td /F1 9.8 Tf  [(EMBASE databases on September 18, 2010, using the terms \( )] TJ ET
BT 299.933 196.318 Td /F5 9.8 Tf  [(V600E)] TJ ET
BT 329.202 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 349.248 196.318 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 375.251 196.318 Td /F1 9.8 Tf  [( \) AND \( )] TJ ET
BT 413.169 196.318 Td /F5 9.8 Tf  [(colon)] TJ ET
BT 436.471 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 456.517 196.318 Td /F5 9.8 Tf  [(colorectal)] TJ ET
BT 498.238 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
BT 518.284 196.318 Td /F5 9.8 Tf  [(rectal)] TJ ET
BT 542.122 196.318 Td /F1 9.8 Tf  [( \) AND )] TJ ET
BT 26.250 184.413 Td /F5 9.8 Tf  [(cancer)] TJ ET
BT 55.510 184.413 Td /F1 9.8 Tf  [( . Limits used were English language and published since January 1, 1996.)] TJ ET
BT 26.250 147.811 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 127.857 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 127.857 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 127.857 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the presence or absence of the )] TJ ET
BT 431.587 127.857 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 457.590 127.857 Td /F1 9.8 Tf  [( p.Val600Glu sequence )] TJ ET
BT 26.250 115.952 Td /F1 9.8 Tf  [(variant \(analytic sensitivity and specificity\).)] TJ ET
BT 26.250 96.547 Td /F1 9.8 Tf  [(The analytic sensitivity and specificity of the commercially available assays are not reported on manufacturer websites )] TJ ET
0.267 0.267 0.267 rg
BT 537.774 96.547 Td /F1 9.8 Tf  [([25] [26] )] TJ ET
BT 26.250 84.642 Td /F1 9.8 Tf  [([27] [28] [29] [30] [31] [32])] TJ ET
0.271 0.267 0.267 rg
BT 137.380 84.642 Td /F1 9.8 Tf  [(. Several recent reports are available that describe studies of the analytical validity of genetic testing )] TJ ET
BT 26.250 72.738 Td /F1 9.8 Tf  [(for )] TJ ET
BT 40.339 72.738 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 66.342 72.738 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 150.884 72.738 Td /F1 9.8 Tf  [([33] [34] [35] [36] [37] [38])] TJ ET
0.271 0.267 0.267 rg
BT 262.015 72.738 Td /F1 9.8 Tf  [(. However, these reports appear to have little bearing on the )] TJ ET
BT 26.250 60.833 Td /F1 9.8 Tf  [(commercially available assays for the )] TJ ET
BT 190.421 60.833 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 216.424 60.833 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant. Two reports describe studies investigating testing )] TJ ET
BT 26.250 48.928 Td /F1 9.8 Tf  [(for multiple biomarkers, including sequence variants in the )] TJ ET
BT 279.847 48.928 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 305.851 48.928 Td /F1 9.8 Tf  [( gene, and, therefore, have no relevance to the commercially )] TJ ET
BT 26.250 37.023 Td /F1 9.8 Tf  [(available assays that detect the )] TJ ET
BT 164.993 37.023 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 190.996 37.023 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 327.028 37.023 Td /F1 9.8 Tf  [([34] [35])] TJ ET
0.271 0.267 0.267 rg
BT 362.264 37.023 Td /F1 9.8 Tf  [(. Two other reports investigate the analytical )] TJ ET
Q
q
15.000 22.738 577.500 754.262 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(sequence variants are not detected in a specimen, this assay can also be requested by selecting the K-ras Gene )] TJ ET
BT 534.040 767.476 Td /F1 9.8 Tf  [(Mutation )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(Detection With Reflex to)] TJ ET
BT 150.329 755.571 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 181.753 755.571 Td /F1 9.8 Tf  [(Gene Mutation Detection Test \(480360\) )] TJ ET
0.267 0.267 0.267 rg
BT 355.712 755.571 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 371.975 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
0.271 0.267 0.267 RG
40.337 742.884 m 
40.337 743.331 40.154 743.775 39.838 744.091 c
39.522 744.407 39.078 744.590 38.631 744.590 c
38.185 744.590 37.741 744.407 37.425 744.091 c
37.109 743.775 36.925 743.331 36.925 742.884 c
36.925 742.438 37.109 741.994 37.425 741.678 c
37.741 741.362 38.185 741.178 38.631 741.178 c
39.078 741.178 39.522 741.362 39.838 741.678 c
40.154 741.994 40.337 742.438 40.337 742.884 c f
BT 45.750 739.917 Td /F1 9.8 Tf  [(Mayo Medical Laboratories \(Rochester, MN\))] TJ ET
BT 237.006 739.917 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 268.430 739.917 Td /F1 9.8 Tf  [(Mutation Analysis \(V600E\), Tumor \(Unit Code 87980\): The specimen )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(requirements for this assay are an FFPE tumor tissue block or a single H&E-stained 5-?m slide with 10 unstained )] TJ ET
BT 45.750 716.107 Td /F1 9.8 Tf  [(nonbaked slides with 5 slides, each with 5-?m and 10-?m-thick sections. The assay uses PCR to detect the )] TJ ET
BT 510.698 716.107 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 704.202 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 179.071 704.202 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 195.334 704.202 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 691.515 m 
40.337 691.962 40.154 692.406 39.838 692.722 c
39.522 693.038 39.078 693.221 38.631 693.221 c
38.185 693.221 37.741 693.038 37.425 692.722 c
37.109 692.406 36.925 691.962 36.925 691.515 c
36.925 691.069 37.109 690.625 37.425 690.309 c
37.741 689.993 38.185 689.809 38.631 689.809 c
39.078 689.809 39.522 689.993 39.838 690.309 c
40.154 690.625 40.337 691.069 40.337 691.515 c f
BT 45.750 688.548 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. \(Madison, NJ\) )] TJ ET
BT 209.384 688.548 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 238.098 688.548 Td /F1 9.8 Tf  [(Mutation Analysis \(16767\): This assay requires an FFPE tumor tissue block. )] TJ ET
BT 45.750 676.643 Td /F1 9.8 Tf  [(Direct sequencing is used to detect sequence variants in the )] TJ ET
BT 308.591 676.643 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 337.304 676.643 Td /F1 9.8 Tf  [(gene )] TJ ET
0.267 0.267 0.267 rg
BT 361.699 676.643 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 377.962 676.643 Td /F1 9.8 Tf  [(. This assay can also be requested by )] TJ ET
BT 45.750 664.738 Td /F1 9.8 Tf  [(selecting the EGFR Pathway \()] TJ ET
BT 176.341 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 205.601 664.738 Td /F1 9.8 Tf  [(with Reflex to )] TJ ET
BT 266.831 664.738 Td /F5 9.8 Tf  [(NRAS)] TJ ET
BT 293.917 664.738 Td /F1 9.8 Tf  [(,)] TJ ET
BT 296.627 664.738 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 325.341 664.738 Td /F1 9.8 Tf  [(\) \(16819\) assay if the specimen is found to be )] TJ ET
BT 525.313 664.738 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 652.833 Td /F1 9.8 Tf  [(sequence variant-negative )] TJ ET
0.267 0.267 0.267 rg
BT 162.808 652.833 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 179.071 652.833 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 640.146 m 
40.337 640.593 40.154 641.037 39.838 641.353 c
39.522 641.669 39.078 641.852 38.631 641.852 c
38.185 641.852 37.741 641.669 37.425 641.353 c
37.109 641.037 36.925 640.593 36.925 640.146 c
36.925 639.700 37.109 639.256 37.425 638.940 c
37.741 638.624 38.185 638.440 38.631 638.440 c
39.078 638.440 39.522 638.624 39.838 638.940 c
40.154 639.256 40.337 639.700 40.337 640.146 c f
BT 45.750 637.179 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories \(Chapel Hill, NC\) )] TJ ET
BT 339.401 637.179 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 368.114 637.179 Td /F1 9.8 Tf  [(Mutation Test in Colorectal Cancer: The )] TJ ET
BT 45.750 625.274 Td /F1 9.8 Tf  [(specimen preferred for this assay is an FFPE tumor tissue block containing ? 50% malignant cells or 10 5- to 10-?m slides )] TJ ET
BT 45.750 613.369 Td /F1 9.8 Tf  [(with a single H&E-stained slide. The assay uses PCR followed by pyrosequencing to detect the)] TJ ET
BT 455.971 613.369 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 487.396 613.369 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 601.464 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 601.464 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 138.970 601.464 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 588.777 m 
40.337 589.224 40.154 589.668 39.838 589.984 c
39.522 590.300 39.078 590.483 38.631 590.483 c
38.185 590.483 37.741 590.300 37.425 589.984 c
37.109 589.668 36.925 589.224 36.925 588.777 c
36.925 588.331 37.109 587.887 37.425 587.571 c
37.741 587.255 38.185 587.071 38.631 587.071 c
39.078 587.071 39.522 587.255 39.838 587.571 c
40.154 587.887 40.337 588.331 40.337 588.777 c f
BT 45.750 585.810 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services \(Nashville, TN\))] TJ ET
BT 292.288 585.810 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 323.713 585.810 Td /F1 9.8 Tf  [(\(V600E\) \(V6A\): The assay requires an FFPE tissue block )] TJ ET
BT 45.750 573.905 Td /F1 9.8 Tf  [(and uses allele-specific detection to identify the )] TJ ET
BT 252.226 573.905 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 278.229 573.905 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant. Also available is a second assay, the)] TJ ET
BT 45.750 562.000 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 71.753 562.000 Td /F1 9.8 Tf  [( \(V600E Sequencing\) \(V6S\), which uses sequencing to detect the)] TJ ET
BT 354.649 562.000 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 383.363 562.000 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 516.685 562.000 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 532.948 562.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 521.648 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 501.693 Td /F1 9.8 Tf  [(Available evidence indicates that the clinical benefit from treatment with EGFR monoclonal antibody inhibitors cetuximab and )] TJ ET
BT 26.250 489.789 Td /F1 9.8 Tf  [(panitumumab is limited to a subgroup of only 10% to 30% of CRC patients )] TJ ET
0.267 0.267 0.267 rg
BT 349.228 489.789 Td /F1 9.8 Tf  [([11] [12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 403.438 489.789 Td /F1 9.8 Tf  [(. Accordingly, biomarkers are needed to )] TJ ET
BT 26.250 477.884 Td /F1 9.8 Tf  [(help select patients who will benefit from treatment with EGFR monoclonal antibody inhibitors and also to avoid unnecessary )] TJ ET
BT 26.250 465.979 Td /F1 9.8 Tf  [(exposure of patients to the serious adverse events associated with these agents )] TJ ET
0.267 0.267 0.267 rg
BT 374.725 465.979 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 385.567 465.979 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 429.377 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 409.422 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 390.018 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 370.613 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 351.208 Td /F1 9.8 Tf  [(None identified.)] TJ ET
BT 26.250 331.803 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 312.399 Td /F1 9.8 Tf  [(If patients do not have a sequence variant in the )] TJ ET
BT 236.548 312.399 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 263.097 312.399 Td /F1 9.8 Tf  [( gene, the National Comprehensive Cancer Network \(NCCN\) guidelines )] TJ ET
BT 26.250 300.494 Td /F1 9.8 Tf  [(for patients undergoing treatment for CRC state that testing for )] TJ ET
BT 298.841 300.494 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 324.844 300.494 Td /F1 9.8 Tf  [( p.Val600Glu should be considered prior to the use of anti-)] TJ ET
BT 26.250 288.589 Td /F1 9.8 Tf  [(EGFR antibodies \(cetuximab and panitumumab\). Furthermore, these guidelines indicate that patients with a )] TJ ET
BT 492.827 288.589 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 518.830 288.589 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 26.250 276.684 Td /F1 9.8 Tf  [(variant are unlikely to respond to treatment with anti-EGFR antibodies; however, it is noted that the data are somewhat )] TJ ET
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BT 26.250 228.177 Td /F4 12.0 Tf  [(Search Strategy)] TJ ET
BT 26.250 208.223 Td /F1 9.8 Tf  [(Evidence evaluated for this report was obtained primarily from a search of the peer-reviewed literature in MEDLINE and )] TJ ET
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BT 329.202 196.318 Td /F1 9.8 Tf  [( OR )] TJ ET
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BT 26.250 115.952 Td /F1 9.8 Tf  [(variant \(analytic sensitivity and specificity\).)] TJ ET
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BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(accuracy of the technique of pyrosequencing )] TJ ET
0.267 0.267 0.267 rg
BT 222.440 767.476 Td /F1 9.8 Tf  [([33] [36])] TJ ET
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BT 257.676 767.476 Td /F1 9.8 Tf  [(, a technology that is used only by UNC Health Care McLendon Clinical )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Laboratories. The report by Tan and colleagues \(2008\) suggests that pyrosequencing was able to detect the )] TJ ET
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BT 26.250 743.667 Td /F1 9.8 Tf  [(sequence variant at a tenfold lower variant-to-normal ratio than dideoxy sequencing, as well as being quicker and less costly to )] TJ ET
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BT 62.549 731.762 Td /F1 9.8 Tf  [([33])] TJ ET
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BT 78.812 731.762 Td /F1 9.8 Tf  [(. Packham and colleagues \(2009\) found that pyrosequencing had a sensitivity of 94.9% and a specificity of 100% in )] TJ ET
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BT 384.982 719.857 Td /F1 9.8 Tf  [([36])] TJ ET
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0.267 0.267 0.267 rg
283.469 452.661 157.203 0.750 re f
283.469 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 288.719 442.806 Td /F4 9.8 Tf  [(Results for)] TJ ET
BT 339.643 442.806 Td /F6 9.8 Tf  [(KRAS)] TJ ET
BT 367.265 442.806 Td /F4 9.8 Tf  [( and)] TJ ET
BT 387.311 442.806 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 288.719 435.175 Td /F4 9.8 Tf  [(analyzes)] TJ ET
0.267 0.267 0.267 rg
439.922 452.661 147.993 0.750 re f
439.922 429.148 0.750 24.263 re f
587.165 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 445.172 442.806 Td /F4 9.8 Tf  [(Comments)] TJ ET
0.267 0.267 0.267 rg
26.625 429.148 98.949 0.750 re f
26.625 112.684 98.949 0.750 re f
26.625 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
BT 31.875 419.293 Td /F1 9.8 Tf  [(De Roock and )] TJ ET
BT 31.875 411.662 Td /F1 9.8 Tf  [(colleagues \(2010\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 404.031 Td /F1 9.8 Tf  [([46])] TJ ET
124.824 429.148 159.395 0.750 re f
124.824 112.684 159.395 0.750 re f
124.824 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 422.592 m 
144.161 423.039 143.977 423.483 143.661 423.799 c
143.346 424.115 142.902 424.298 142.455 424.298 c
142.008 424.298 141.564 424.115 141.248 423.799 c
140.933 423.483 140.749 423.039 140.749 422.592 c
140.749 422.146 140.933 421.702 141.248 421.386 c
141.564 421.070 142.008 420.886 142.455 420.886 c
142.902 420.886 143.346 421.070 143.661 421.386 c
143.977 421.702 144.161 422.146 144.161 422.592 c f
BT 149.574 419.625 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 407.720 Td /F1 9.8 Tf  [(treated with cetuximab in )] TJ ET
BT 149.574 395.815 Td /F1 9.8 Tf  [(combination with )] TJ ET
BT 149.574 383.910 Td /F1 9.8 Tf  [(chemotherapy at 11 )] TJ ET
BT 149.574 372.006 Td /F1 9.8 Tf  [(European centers between )] TJ ET
BT 149.574 360.101 Td /F1 9.8 Tf  [(2001 and 2008.)] TJ ET
144.161 347.414 m 
144.161 347.860 143.977 348.304 143.661 348.620 c
143.346 348.936 142.902 349.120 142.455 349.120 c
142.008 349.120 141.564 348.936 141.248 348.620 c
140.933 348.304 140.749 347.860 140.749 347.414 c
140.749 346.967 140.933 346.523 141.248 346.207 c
141.564 345.891 142.008 345.707 142.455 345.707 c
142.902 345.707 143.346 345.891 143.661 346.207 c
143.977 346.523 144.161 346.967 144.161 347.414 c f
BT 149.574 344.446 Td /F1 9.8 Tf  [(The primary endpoint was )] TJ ET
BT 149.574 332.541 Td /F1 9.8 Tf  [(objective response, with PFS )] TJ ET
BT 149.574 320.637 Td /F1 9.8 Tf  [(as a secondary endpoint.)] TJ ET
144.161 307.949 m 
144.161 308.396 143.977 308.840 143.661 309.156 c
143.346 309.472 142.902 309.656 142.455 309.656 c
142.008 309.656 141.564 309.472 141.248 309.156 c
140.933 308.840 140.749 308.396 140.749 307.949 c
140.749 307.503 140.933 307.059 141.248 306.743 c
141.564 306.427 142.008 306.243 142.455 306.243 c
142.902 306.243 143.346 306.427 143.661 306.743 c
143.977 307.059 144.161 307.503 144.161 307.949 c f
BT 149.574 304.982 Td /F1 9.8 Tf  [(Sequence variants in the )] TJ ET
BT 149.574 293.077 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 176.123 293.077 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.807 293.077 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 223.810 293.077 Td /F1 9.8 Tf  [( genes )] TJ ET
BT 149.574 281.172 Td /F1 9.8 Tf  [(were identified using multiple )] TJ ET
BT 149.574 269.268 Td /F1 9.8 Tf  [(PCR with MALDI-TOF )] TJ ET
BT 149.574 257.363 Td /F1 9.8 Tf  [(MassARRAY Type 4 )] TJ ET
BT 149.574 245.458 Td /F1 9.8 Tf  [(Analyzer \(Sequenom Inc., )] TJ ET
BT 149.574 233.553 Td /F1 9.8 Tf  [(San Diego\).)] TJ ET
0.267 0.267 0.267 rg
283.469 429.148 157.203 0.750 re f
283.469 112.684 157.203 0.750 re f
283.469 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
302.806 422.592 m 
302.806 423.039 302.623 423.483 302.307 423.799 c
301.991 424.115 301.547 424.298 301.100 424.298 c
300.653 424.298 300.210 424.115 299.894 423.799 c
299.578 423.483 299.394 423.039 299.394 422.592 c
299.394 422.146 299.578 421.702 299.894 421.386 c
300.210 421.070 300.653 420.886 301.100 420.886 c
301.547 420.886 301.991 421.070 302.307 421.386 c
302.623 421.702 302.806 422.146 302.806 422.592 c f
BT 308.219 419.625 Td /F5 9.8 Tf  [(KRAS and BRAF)] TJ ET
BT 382.455 419.625 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 407.720 Td /F1 9.8 Tf  [(variants were found in 299 )] TJ ET
BT 308.219 395.815 Td /F1 9.8 Tf  [(of 747 \(40.0%\) and 35 of )] TJ ET
BT 308.219 383.910 Td /F1 9.8 Tf  [(761 \(4.7%\) evaluable pts, )] TJ ET
BT 308.219 372.006 Td /F1 9.8 Tf  [(respectively.)] TJ ET
302.806 359.318 m 
302.806 359.765 302.623 360.209 302.307 360.525 c
301.991 360.841 301.547 361.025 301.100 361.025 c
300.653 361.025 300.210 360.841 299.894 360.525 c
299.578 360.209 299.394 359.765 299.394 359.318 c
299.394 358.872 299.578 358.428 299.894 358.112 c
300.210 357.796 300.653 357.612 301.100 357.612 c
301.547 357.612 301.991 357.796 302.307 358.112 c
302.623 358.428 302.806 358.872 302.806 359.318 c f
BT 308.219 356.351 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 356.351 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 344.446 Td /F1 9.8 Tf  [(occurred only in pts without )] TJ ET
BT 308.219 332.541 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 332.541 Td /F1 9.8 Tf  [( sequence variants.)] TJ ET
302.806 319.854 m 
302.806 320.301 302.623 320.745 302.307 321.061 c
301.991 321.377 301.547 321.560 301.100 321.560 c
300.653 321.560 300.210 321.377 299.894 321.061 c
299.578 320.745 299.394 320.301 299.394 319.854 c
299.394 319.408 299.578 318.964 299.894 318.648 c
300.210 318.332 300.653 318.148 301.100 318.148 c
301.547 318.148 301.991 318.332 302.307 318.648 c
302.623 318.964 302.806 319.408 302.806 319.854 c f
BT 308.219 316.887 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 316.887 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 308.219 304.982 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
0.39 w 1 J 1 j
322.306 292.295 m 
322.306 292.741 322.123 293.185 321.807 293.501 c
321.491 293.817 321.047 294.001 320.600 294.001 c
320.153 294.001 319.710 293.817 319.394 293.501 c
319.078 293.185 318.894 292.741 318.894 292.295 c
318.894 291.848 319.078 291.404 319.394 291.088 c
319.710 290.772 320.153 290.588 320.600 290.588 c
321.047 290.588 321.491 290.772 321.807 291.088 c
322.123 291.404 322.306 291.848 322.306 292.295 c s
BT 327.719 289.327 Td /F1 9.8 Tf  [(Response to treatment )] TJ ET
BT 327.719 277.422 Td /F1 9.8 Tf  [(was lower in pts with )] TJ ET
BT 327.719 265.518 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 265.518 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 253.613 Td /F1 9.8 Tf  [(variants than without )] TJ ET
BT 327.719 241.708 Td /F1 9.8 Tf  [(\(8.3% versus 38.0%; )] TJ ET
BT 327.719 229.803 Td /F1 9.8 Tf  [(OR 0.15; 95% CI, 0.02-)] TJ ET
BT 327.719 217.899 Td /F1 9.8 Tf  [(0.51; P=0.0012\))] TJ ET
0.39 w 1 J 1 j
322.306 205.211 m 
322.306 205.658 322.123 206.102 321.807 206.418 c
321.491 206.734 321.047 206.918 320.600 206.918 c
320.153 206.918 319.710 206.734 319.394 206.418 c
319.078 206.102 318.894 205.658 318.894 205.211 c
318.894 204.765 319.078 204.321 319.394 204.005 c
319.710 203.689 320.153 203.505 320.600 203.505 c
321.047 203.505 321.491 203.689 321.807 204.005 c
322.123 204.321 322.306 204.765 322.306 205.211 c s
BT 327.719 202.244 Td /F1 9.8 Tf  [(Median PFS was )] TJ ET
BT 327.719 190.339 Td /F1 9.8 Tf  [(shorter in pts with )] TJ ET
BT 406.830 190.339 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 178.434 Td /F1 9.8 Tf  [(sequence variants than )] TJ ET
BT 327.719 166.530 Td /F1 9.8 Tf  [(without \(8 wks versus )] TJ ET
BT 327.719 154.625 Td /F1 9.8 Tf  [(26 wks; HR, 3.74; 95% )] TJ ET
BT 327.719 142.720 Td /F1 9.8 Tf  [(CI, 2.44-5.75; )] TJ ET
BT 327.719 130.815 Td /F1 9.8 Tf  [(P<0.0001\).)] TJ ET
0.267 0.267 0.267 rg
439.922 429.148 147.993 0.750 re f
439.922 112.684 147.993 0.750 re f
439.922 112.684 0.750 317.214 re f
587.165 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
459.259 422.592 m 
459.259 423.039 459.076 423.483 458.760 423.799 c
458.444 424.115 458.000 424.298 457.553 424.298 c
457.107 424.298 456.663 424.115 456.347 423.799 c
456.031 423.483 455.847 423.039 455.847 422.592 c
455.847 422.146 456.031 421.702 456.347 421.386 c
456.663 421.070 457.107 420.886 457.553 420.886 c
458.000 420.886 458.444 421.070 458.760 421.386 c
459.076 421.702 459.259 422.146 459.259 422.592 c f
BT 464.672 419.625 Td /F1 9.8 Tf  [(Approximately one third of )] TJ ET
BT 464.672 407.720 Td /F1 9.8 Tf  [(pts included in this study )] TJ ET
BT 464.672 395.815 Td /F1 9.8 Tf  [(had been included in )] TJ ET
BT 464.672 383.910 Td /F1 9.8 Tf  [(previous reports.)] TJ ET
459.259 371.223 m 
459.259 371.670 459.076 372.114 458.760 372.430 c
458.444 372.746 458.000 372.929 457.553 372.929 c
457.107 372.929 456.663 372.746 456.347 372.430 c
456.031 372.114 455.847 371.670 455.847 371.223 c
455.847 370.777 456.031 370.333 456.347 370.017 c
456.663 369.701 457.107 369.517 457.553 369.517 c
458.000 369.517 458.444 369.701 458.760 370.017 c
459.076 370.333 459.259 370.777 459.259 371.223 c f
BT 464.672 368.256 Td /F1 9.8 Tf  [(Of the 2 pts that )] TJ ET
BT 464.672 356.351 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 464.672 344.446 Td /F1 9.8 Tf  [(with )] TJ ET
BT 484.718 344.446 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 510.721 344.446 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 332.541 Td /F1 9.8 Tf  [(variants, 1 had a )] TJ ET
BT 464.672 320.637 Td /F1 9.8 Tf  [(p.Asp549Gly variant and )] TJ ET
BT 464.672 308.732 Td /F1 9.8 Tf  [(the other had the )] TJ ET
BT 464.672 296.827 Td /F1 9.8 Tf  [(p.Val600Glu variant, but )] TJ ET
BT 464.672 284.922 Td /F1 9.8 Tf  [(at a low copy number in )] TJ ET
BT 464.672 273.018 Td /F1 9.8 Tf  [(the tumor sample.)] TJ ET
Q
q
15.000 112.309 577.500 664.691 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(accuracy of the technique of pyrosequencing )] TJ ET
0.267 0.267 0.267 rg
BT 222.440 767.476 Td /F1 9.8 Tf  [([33] [36])] TJ ET
0.271 0.267 0.267 rg
BT 257.676 767.476 Td /F1 9.8 Tf  [(, a technology that is used only by UNC Health Care McLendon Clinical )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Laboratories. The report by Tan and colleagues \(2008\) suggests that pyrosequencing was able to detect the )] TJ ET
BT 495.040 755.571 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 521.043 755.571 Td /F1 9.8 Tf  [( p.Val600Glu )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(sequence variant at a tenfold lower variant-to-normal ratio than dideoxy sequencing, as well as being quicker and less costly to )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(perform )] TJ ET
0.267 0.267 0.267 rg
BT 62.549 731.762 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 78.812 731.762 Td /F1 9.8 Tf  [(. Packham and colleagues \(2009\) found that pyrosequencing had a sensitivity of 94.9% and a specificity of 100% in )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(comparison to real-time PCR in detecting the )] TJ ET
BT 222.946 719.857 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 248.950 719.857 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 384.982 719.857 Td /F1 9.8 Tf  [([36])] TJ ET
0.271 0.267 0.267 rg
BT 401.245 719.857 Td /F1 9.8 Tf  [(. Jakubauskas and colleagues \(2010\) )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(investigated the possibility of using multiplex PCR followed by dideoxy-termination sequencing to simultaneously detect )] TJ ET
BT 542.668 707.952 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 26.250 696.048 Td /F1 9.8 Tf  [(sequence variants and the )] TJ ET
BT 143.318 696.048 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 169.322 696.048 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 305.354 696.048 Td /F1 9.8 Tf  [([38])] TJ ET
0.271 0.267 0.267 rg
BT 321.617 696.048 Td /F1 9.8 Tf  [(, a technique not used in any of the commercially available )] TJ ET
BT 26.250 684.143 Td /F1 9.8 Tf  [(assays. The final report compared the use of PCR followed by high-resolution melting \(HRM\) analysis, with the more traditional )] TJ ET
BT 26.250 672.238 Td /F1 9.8 Tf  [(techniques of PCR followed by denaturing high-performance liquid chromatography \(dHPLC\), conventional PCR followed by )] TJ ET
BT 26.250 660.333 Td /F1 9.8 Tf  [(direct sequencing, and real-time allele-specific PCR \(RT-PCR\) )] TJ ET
0.267 0.267 0.267 rg
BT 298.226 660.333 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 314.489 660.333 Td /F1 9.8 Tf  [(. Although the complete results of this study were not clearly )] TJ ET
BT 26.250 648.429 Td /F1 9.8 Tf  [(presented, the authors concluded that, for the detection of )] TJ ET
BT 278.824 648.429 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 304.827 648.429 Td /F1 9.8 Tf  [( p.Val600Glu sequence variants, HRM was more sensitive than )] TJ ET
BT 26.250 636.524 Td /F1 9.8 Tf  [(both DNA sequencing and dHPLC, and similar to RT-PCR )] TJ ET
0.267 0.267 0.267 rg
BT 279.838 636.524 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 296.101 636.524 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 617.119 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 617.119 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 617.119 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying patients that will respond to treatment with EGFR monoclonal )] TJ ET
BT 26.250 605.214 Td /F1 9.8 Tf  [(antibody inhibitors \(predictive value\).)] TJ ET
BT 26.250 585.810 Td /F1 9.8 Tf  [(Published studies of the clinical validity of )] TJ ET
BT 207.785 585.810 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 233.788 585.810 Td /F1 9.8 Tf  [( p.Val600Glu testing were retrospective analyses of patients treated with )] TJ ET
BT 26.250 573.905 Td /F1 9.8 Tf  [(cetuximab or panitumumab at cancer treatment centers )] TJ ET
0.267 0.267 0.267 rg
BT 267.933 573.905 Td /F1 9.8 Tf  [([19] [39] [40] [41] [42] [43])] TJ ET
0.271 0.267 0.267 rg
BT 379.063 573.905 Td /F1 9.8 Tf  [( or a cohort of patients that had been in one of )] TJ ET
BT 26.250 562.000 Td /F1 9.8 Tf  [(three clinical trials )] TJ ET
0.267 0.267 0.267 rg
BT 106.434 562.000 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 122.697 562.000 Td /F1 9.8 Tf  [( \(see Table 1\). Response to treatment was generally defined using the Response Evaluation Criteria in )] TJ ET
BT 26.250 550.095 Td /F1 9.8 Tf  [(Solid Tumors \(RECIST\) system, which classifies patients as having complete response \(CR\), partial response \(PR\), stable )] TJ ET
BT 26.250 538.191 Td /F1 9.8 Tf  [(disease \(SD\), or progressive disease \(PD\) )] TJ ET
0.267 0.267 0.267 rg
BT 211.549 538.191 Td /F1 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 227.812 538.191 Td /F1 9.8 Tf  [(. Patients are defined as having responded to treatment if they have either CR or )] TJ ET
BT 26.250 526.286 Td /F1 9.8 Tf  [(PR. Other endpoints commonly used were progression-free survival and overall survival.)] TJ ET
BT 26.250 506.881 Td /F4 9.8 Tf  [(Table 1. Overview of studies that examined the clinical validity of testing for)] TJ ET
BT 377.367 506.881 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 404.443 506.881 Td /F4 9.8 Tf  [( p.Val600Glu for assessment of )] TJ ET
BT 26.250 494.976 Td /F4 9.8 Tf  [(treatment options for colorectal cancer \(CRC\). Response to treatment was measured using the RECIST criteria)] TJ ET
0.267 0.267 0.267 rg
BT 538.242 494.976 Td /F4 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 555.577 494.976 Td /F4 9.8 Tf  [(.)] TJ ET
BT 26.250 475.572 Td /F4 9.8 Tf  [(Key:)] TJ ET
BT 47.378 475.572 Td /F1 9.8 Tf  [( CI, confidence interval; FOLFIRI, folinic acid, fluorouracil, and irinotecan; IR, irinotecan; OR, odds ratio; OS, overall )] TJ ET
BT 26.250 463.667 Td /F1 9.8 Tf  [(survival; PCR, polymerase chain reaction; PFS, progression free survival; pt\(s\), patient\(s\).)] TJ ET
1.000 1.000 1.000 rg
26.250 112.309 555.000 341.477 re f
0.267 0.267 0.267 rg
26.625 452.661 98.949 0.750 re f
26.625 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 442.806 Td /F4 9.8 Tf  [(Study)] TJ ET
0.267 0.267 0.267 rg
124.824 452.661 159.395 0.750 re f
124.824 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 130.074 442.806 Td /F4 9.8 Tf  [(Protocol and Methods)] TJ ET
0.267 0.267 0.267 rg
283.469 452.661 157.203 0.750 re f
283.469 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 288.719 442.806 Td /F4 9.8 Tf  [(Results for)] TJ ET
BT 339.643 442.806 Td /F6 9.8 Tf  [(KRAS)] TJ ET
BT 367.265 442.806 Td /F4 9.8 Tf  [( and)] TJ ET
BT 387.311 442.806 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 288.719 435.175 Td /F4 9.8 Tf  [(analyzes)] TJ ET
0.267 0.267 0.267 rg
439.922 452.661 147.993 0.750 re f
439.922 429.148 0.750 24.263 re f
587.165 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 445.172 442.806 Td /F4 9.8 Tf  [(Comments)] TJ ET
0.267 0.267 0.267 rg
26.625 429.148 98.949 0.750 re f
26.625 112.684 98.949 0.750 re f
26.625 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
BT 31.875 419.293 Td /F1 9.8 Tf  [(De Roock and )] TJ ET
BT 31.875 411.662 Td /F1 9.8 Tf  [(colleagues \(2010\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 404.031 Td /F1 9.8 Tf  [([46])] TJ ET
124.824 429.148 159.395 0.750 re f
124.824 112.684 159.395 0.750 re f
124.824 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 422.592 m 
144.161 423.039 143.977 423.483 143.661 423.799 c
143.346 424.115 142.902 424.298 142.455 424.298 c
142.008 424.298 141.564 424.115 141.248 423.799 c
140.933 423.483 140.749 423.039 140.749 422.592 c
140.749 422.146 140.933 421.702 141.248 421.386 c
141.564 421.070 142.008 420.886 142.455 420.886 c
142.902 420.886 143.346 421.070 143.661 421.386 c
143.977 421.702 144.161 422.146 144.161 422.592 c f
BT 149.574 419.625 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 407.720 Td /F1 9.8 Tf  [(treated with cetuximab in )] TJ ET
BT 149.574 395.815 Td /F1 9.8 Tf  [(combination with )] TJ ET
BT 149.574 383.910 Td /F1 9.8 Tf  [(chemotherapy at 11 )] TJ ET
BT 149.574 372.006 Td /F1 9.8 Tf  [(European centers between )] TJ ET
BT 149.574 360.101 Td /F1 9.8 Tf  [(2001 and 2008.)] TJ ET
144.161 347.414 m 
144.161 347.860 143.977 348.304 143.661 348.620 c
143.346 348.936 142.902 349.120 142.455 349.120 c
142.008 349.120 141.564 348.936 141.248 348.620 c
140.933 348.304 140.749 347.860 140.749 347.414 c
140.749 346.967 140.933 346.523 141.248 346.207 c
141.564 345.891 142.008 345.707 142.455 345.707 c
142.902 345.707 143.346 345.891 143.661 346.207 c
143.977 346.523 144.161 346.967 144.161 347.414 c f
BT 149.574 344.446 Td /F1 9.8 Tf  [(The primary endpoint was )] TJ ET
BT 149.574 332.541 Td /F1 9.8 Tf  [(objective response, with PFS )] TJ ET
BT 149.574 320.637 Td /F1 9.8 Tf  [(as a secondary endpoint.)] TJ ET
144.161 307.949 m 
144.161 308.396 143.977 308.840 143.661 309.156 c
143.346 309.472 142.902 309.656 142.455 309.656 c
142.008 309.656 141.564 309.472 141.248 309.156 c
140.933 308.840 140.749 308.396 140.749 307.949 c
140.749 307.503 140.933 307.059 141.248 306.743 c
141.564 306.427 142.008 306.243 142.455 306.243 c
142.902 306.243 143.346 306.427 143.661 306.743 c
143.977 307.059 144.161 307.503 144.161 307.949 c f
BT 149.574 304.982 Td /F1 9.8 Tf  [(Sequence variants in the )] TJ ET
BT 149.574 293.077 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 176.123 293.077 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.807 293.077 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 223.810 293.077 Td /F1 9.8 Tf  [( genes )] TJ ET
BT 149.574 281.172 Td /F1 9.8 Tf  [(were identified using multiple )] TJ ET
BT 149.574 269.268 Td /F1 9.8 Tf  [(PCR with MALDI-TOF )] TJ ET
BT 149.574 257.363 Td /F1 9.8 Tf  [(MassARRAY Type 4 )] TJ ET
BT 149.574 245.458 Td /F1 9.8 Tf  [(Analyzer \(Sequenom Inc., )] TJ ET
BT 149.574 233.553 Td /F1 9.8 Tf  [(San Diego\).)] TJ ET
0.267 0.267 0.267 rg
283.469 429.148 157.203 0.750 re f
283.469 112.684 157.203 0.750 re f
283.469 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
302.806 422.592 m 
302.806 423.039 302.623 423.483 302.307 423.799 c
301.991 424.115 301.547 424.298 301.100 424.298 c
300.653 424.298 300.210 424.115 299.894 423.799 c
299.578 423.483 299.394 423.039 299.394 422.592 c
299.394 422.146 299.578 421.702 299.894 421.386 c
300.210 421.070 300.653 420.886 301.100 420.886 c
301.547 420.886 301.991 421.070 302.307 421.386 c
302.623 421.702 302.806 422.146 302.806 422.592 c f
BT 308.219 419.625 Td /F5 9.8 Tf  [(KRAS and BRAF)] TJ ET
BT 382.455 419.625 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 407.720 Td /F1 9.8 Tf  [(variants were found in 299 )] TJ ET
BT 308.219 395.815 Td /F1 9.8 Tf  [(of 747 \(40.0%\) and 35 of )] TJ ET
BT 308.219 383.910 Td /F1 9.8 Tf  [(761 \(4.7%\) evaluable pts, )] TJ ET
BT 308.219 372.006 Td /F1 9.8 Tf  [(respectively.)] TJ ET
302.806 359.318 m 
302.806 359.765 302.623 360.209 302.307 360.525 c
301.991 360.841 301.547 361.025 301.100 361.025 c
300.653 361.025 300.210 360.841 299.894 360.525 c
299.578 360.209 299.394 359.765 299.394 359.318 c
299.394 358.872 299.578 358.428 299.894 358.112 c
300.210 357.796 300.653 357.612 301.100 357.612 c
301.547 357.612 301.991 357.796 302.307 358.112 c
302.623 358.428 302.806 358.872 302.806 359.318 c f
BT 308.219 356.351 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 356.351 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 344.446 Td /F1 9.8 Tf  [(occurred only in pts without )] TJ ET
BT 308.219 332.541 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 332.541 Td /F1 9.8 Tf  [( sequence variants.)] TJ ET
302.806 319.854 m 
302.806 320.301 302.623 320.745 302.307 321.061 c
301.991 321.377 301.547 321.560 301.100 321.560 c
300.653 321.560 300.210 321.377 299.894 321.061 c
299.578 320.745 299.394 320.301 299.394 319.854 c
299.394 319.408 299.578 318.964 299.894 318.648 c
300.210 318.332 300.653 318.148 301.100 318.148 c
301.547 318.148 301.991 318.332 302.307 318.648 c
302.623 318.964 302.806 319.408 302.806 319.854 c f
BT 308.219 316.887 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 316.887 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 308.219 304.982 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
0.39 w 1 J 1 j
322.306 292.295 m 
322.306 292.741 322.123 293.185 321.807 293.501 c
321.491 293.817 321.047 294.001 320.600 294.001 c
320.153 294.001 319.710 293.817 319.394 293.501 c
319.078 293.185 318.894 292.741 318.894 292.295 c
318.894 291.848 319.078 291.404 319.394 291.088 c
319.710 290.772 320.153 290.588 320.600 290.588 c
321.047 290.588 321.491 290.772 321.807 291.088 c
322.123 291.404 322.306 291.848 322.306 292.295 c s
BT 327.719 289.327 Td /F1 9.8 Tf  [(Response to treatment )] TJ ET
BT 327.719 277.422 Td /F1 9.8 Tf  [(was lower in pts with )] TJ ET
BT 327.719 265.518 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 265.518 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 253.613 Td /F1 9.8 Tf  [(variants than without )] TJ ET
BT 327.719 241.708 Td /F1 9.8 Tf  [(\(8.3% versus 38.0%; )] TJ ET
BT 327.719 229.803 Td /F1 9.8 Tf  [(OR 0.15; 95% CI, 0.02-)] TJ ET
BT 327.719 217.899 Td /F1 9.8 Tf  [(0.51; P=0.0012\))] TJ ET
0.39 w 1 J 1 j
322.306 205.211 m 
322.306 205.658 322.123 206.102 321.807 206.418 c
321.491 206.734 321.047 206.918 320.600 206.918 c
320.153 206.918 319.710 206.734 319.394 206.418 c
319.078 206.102 318.894 205.658 318.894 205.211 c
318.894 204.765 319.078 204.321 319.394 204.005 c
319.710 203.689 320.153 203.505 320.600 203.505 c
321.047 203.505 321.491 203.689 321.807 204.005 c
322.123 204.321 322.306 204.765 322.306 205.211 c s
BT 327.719 202.244 Td /F1 9.8 Tf  [(Median PFS was )] TJ ET
BT 327.719 190.339 Td /F1 9.8 Tf  [(shorter in pts with )] TJ ET
BT 406.830 190.339 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 178.434 Td /F1 9.8 Tf  [(sequence variants than )] TJ ET
BT 327.719 166.530 Td /F1 9.8 Tf  [(without \(8 wks versus )] TJ ET
BT 327.719 154.625 Td /F1 9.8 Tf  [(26 wks; HR, 3.74; 95% )] TJ ET
BT 327.719 142.720 Td /F1 9.8 Tf  [(CI, 2.44-5.75; )] TJ ET
BT 327.719 130.815 Td /F1 9.8 Tf  [(P<0.0001\).)] TJ ET
0.267 0.267 0.267 rg
439.922 429.148 147.993 0.750 re f
439.922 112.684 147.993 0.750 re f
439.922 112.684 0.750 317.214 re f
587.165 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
459.259 422.592 m 
459.259 423.039 459.076 423.483 458.760 423.799 c
458.444 424.115 458.000 424.298 457.553 424.298 c
457.107 424.298 456.663 424.115 456.347 423.799 c
456.031 423.483 455.847 423.039 455.847 422.592 c
455.847 422.146 456.031 421.702 456.347 421.386 c
456.663 421.070 457.107 420.886 457.553 420.886 c
458.000 420.886 458.444 421.070 458.760 421.386 c
459.076 421.702 459.259 422.146 459.259 422.592 c f
BT 464.672 419.625 Td /F1 9.8 Tf  [(Approximately one third of )] TJ ET
BT 464.672 407.720 Td /F1 9.8 Tf  [(pts included in this study )] TJ ET
BT 464.672 395.815 Td /F1 9.8 Tf  [(had been included in )] TJ ET
BT 464.672 383.910 Td /F1 9.8 Tf  [(previous reports.)] TJ ET
459.259 371.223 m 
459.259 371.670 459.076 372.114 458.760 372.430 c
458.444 372.746 458.000 372.929 457.553 372.929 c
457.107 372.929 456.663 372.746 456.347 372.430 c
456.031 372.114 455.847 371.670 455.847 371.223 c
455.847 370.777 456.031 370.333 456.347 370.017 c
456.663 369.701 457.107 369.517 457.553 369.517 c
458.000 369.517 458.444 369.701 458.760 370.017 c
459.076 370.333 459.259 370.777 459.259 371.223 c f
BT 464.672 368.256 Td /F1 9.8 Tf  [(Of the 2 pts that )] TJ ET
BT 464.672 356.351 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 464.672 344.446 Td /F1 9.8 Tf  [(with )] TJ ET
BT 484.718 344.446 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 510.721 344.446 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 332.541 Td /F1 9.8 Tf  [(variants, 1 had a )] TJ ET
BT 464.672 320.637 Td /F1 9.8 Tf  [(p.Asp549Gly variant and )] TJ ET
BT 464.672 308.732 Td /F1 9.8 Tf  [(the other had the )] TJ ET
BT 464.672 296.827 Td /F1 9.8 Tf  [(p.Val600Glu variant, but )] TJ ET
BT 464.672 284.922 Td /F1 9.8 Tf  [(at a low copy number in )] TJ ET
BT 464.672 273.018 Td /F1 9.8 Tf  [(the tumor sample.)] TJ ET
Q
q
15.000 112.309 577.500 664.691 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(accuracy of the technique of pyrosequencing )] TJ ET
0.267 0.267 0.267 rg
BT 222.440 767.476 Td /F1 9.8 Tf  [([33] [36])] TJ ET
0.271 0.267 0.267 rg
BT 257.676 767.476 Td /F1 9.8 Tf  [(, a technology that is used only by UNC Health Care McLendon Clinical )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(Laboratories. The report by Tan and colleagues \(2008\) suggests that pyrosequencing was able to detect the )] TJ ET
BT 495.040 755.571 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 521.043 755.571 Td /F1 9.8 Tf  [( p.Val600Glu )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(sequence variant at a tenfold lower variant-to-normal ratio than dideoxy sequencing, as well as being quicker and less costly to )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(perform )] TJ ET
0.267 0.267 0.267 rg
BT 62.549 731.762 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 78.812 731.762 Td /F1 9.8 Tf  [(. Packham and colleagues \(2009\) found that pyrosequencing had a sensitivity of 94.9% and a specificity of 100% in )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(comparison to real-time PCR in detecting the )] TJ ET
BT 222.946 719.857 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 248.950 719.857 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 384.982 719.857 Td /F1 9.8 Tf  [([36])] TJ ET
0.271 0.267 0.267 rg
BT 401.245 719.857 Td /F1 9.8 Tf  [(. Jakubauskas and colleagues \(2010\) )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(investigated the possibility of using multiplex PCR followed by dideoxy-termination sequencing to simultaneously detect )] TJ ET
BT 542.668 707.952 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 26.250 696.048 Td /F1 9.8 Tf  [(sequence variants and the )] TJ ET
BT 143.318 696.048 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 169.322 696.048 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 305.354 696.048 Td /F1 9.8 Tf  [([38])] TJ ET
0.271 0.267 0.267 rg
BT 321.617 696.048 Td /F1 9.8 Tf  [(, a technique not used in any of the commercially available )] TJ ET
BT 26.250 684.143 Td /F1 9.8 Tf  [(assays. The final report compared the use of PCR followed by high-resolution melting \(HRM\) analysis, with the more traditional )] TJ ET
BT 26.250 672.238 Td /F1 9.8 Tf  [(techniques of PCR followed by denaturing high-performance liquid chromatography \(dHPLC\), conventional PCR followed by )] TJ ET
BT 26.250 660.333 Td /F1 9.8 Tf  [(direct sequencing, and real-time allele-specific PCR \(RT-PCR\) )] TJ ET
0.267 0.267 0.267 rg
BT 298.226 660.333 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 314.489 660.333 Td /F1 9.8 Tf  [(. Although the complete results of this study were not clearly )] TJ ET
BT 26.250 648.429 Td /F1 9.8 Tf  [(presented, the authors concluded that, for the detection of )] TJ ET
BT 278.824 648.429 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 304.827 648.429 Td /F1 9.8 Tf  [( p.Val600Glu sequence variants, HRM was more sensitive than )] TJ ET
BT 26.250 636.524 Td /F1 9.8 Tf  [(both DNA sequencing and dHPLC, and similar to RT-PCR )] TJ ET
0.267 0.267 0.267 rg
BT 279.838 636.524 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 296.101 636.524 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 617.119 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 617.119 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 617.119 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying patients that will respond to treatment with EGFR monoclonal )] TJ ET
BT 26.250 605.214 Td /F1 9.8 Tf  [(antibody inhibitors \(predictive value\).)] TJ ET
BT 26.250 585.810 Td /F1 9.8 Tf  [(Published studies of the clinical validity of )] TJ ET
BT 207.785 585.810 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 233.788 585.810 Td /F1 9.8 Tf  [( p.Val600Glu testing were retrospective analyses of patients treated with )] TJ ET
BT 26.250 573.905 Td /F1 9.8 Tf  [(cetuximab or panitumumab at cancer treatment centers )] TJ ET
0.267 0.267 0.267 rg
BT 267.933 573.905 Td /F1 9.8 Tf  [([19] [39] [40] [41] [42] [43])] TJ ET
0.271 0.267 0.267 rg
BT 379.063 573.905 Td /F1 9.8 Tf  [( or a cohort of patients that had been in one of )] TJ ET
BT 26.250 562.000 Td /F1 9.8 Tf  [(three clinical trials )] TJ ET
0.267 0.267 0.267 rg
BT 106.434 562.000 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 122.697 562.000 Td /F1 9.8 Tf  [( \(see Table 1\). Response to treatment was generally defined using the Response Evaluation Criteria in )] TJ ET
BT 26.250 550.095 Td /F1 9.8 Tf  [(Solid Tumors \(RECIST\) system, which classifies patients as having complete response \(CR\), partial response \(PR\), stable )] TJ ET
BT 26.250 538.191 Td /F1 9.8 Tf  [(disease \(SD\), or progressive disease \(PD\) )] TJ ET
0.267 0.267 0.267 rg
BT 211.549 538.191 Td /F1 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 227.812 538.191 Td /F1 9.8 Tf  [(. Patients are defined as having responded to treatment if they have either CR or )] TJ ET
BT 26.250 526.286 Td /F1 9.8 Tf  [(PR. Other endpoints commonly used were progression-free survival and overall survival.)] TJ ET
BT 26.250 506.881 Td /F4 9.8 Tf  [(Table 1. Overview of studies that examined the clinical validity of testing for)] TJ ET
BT 377.367 506.881 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 404.443 506.881 Td /F4 9.8 Tf  [( p.Val600Glu for assessment of )] TJ ET
BT 26.250 494.976 Td /F4 9.8 Tf  [(treatment options for colorectal cancer \(CRC\). Response to treatment was measured using the RECIST criteria)] TJ ET
0.267 0.267 0.267 rg
BT 538.242 494.976 Td /F4 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 555.577 494.976 Td /F4 9.8 Tf  [(.)] TJ ET
BT 26.250 475.572 Td /F4 9.8 Tf  [(Key:)] TJ ET
BT 47.378 475.572 Td /F1 9.8 Tf  [( CI, confidence interval; FOLFIRI, folinic acid, fluorouracil, and irinotecan; IR, irinotecan; OR, odds ratio; OS, overall )] TJ ET
BT 26.250 463.667 Td /F1 9.8 Tf  [(survival; PCR, polymerase chain reaction; PFS, progression free survival; pt\(s\), patient\(s\).)] TJ ET
1.000 1.000 1.000 rg
26.250 112.309 555.000 341.477 re f
0.267 0.267 0.267 rg
26.625 452.661 98.949 0.750 re f
26.625 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 31.875 442.806 Td /F4 9.8 Tf  [(Study)] TJ ET
0.267 0.267 0.267 rg
124.824 452.661 159.395 0.750 re f
124.824 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 130.074 442.806 Td /F4 9.8 Tf  [(Protocol and Methods)] TJ ET
0.267 0.267 0.267 rg
283.469 452.661 157.203 0.750 re f
283.469 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 288.719 442.806 Td /F4 9.8 Tf  [(Results for)] TJ ET
BT 339.643 442.806 Td /F6 9.8 Tf  [(KRAS)] TJ ET
BT 367.265 442.806 Td /F4 9.8 Tf  [( and)] TJ ET
BT 387.311 442.806 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 288.719 435.175 Td /F4 9.8 Tf  [(analyzes)] TJ ET
0.267 0.267 0.267 rg
439.922 452.661 147.993 0.750 re f
439.922 429.148 0.750 24.263 re f
587.165 429.148 0.750 24.263 re f
0.271 0.267 0.267 rg
BT 445.172 442.806 Td /F4 9.8 Tf  [(Comments)] TJ ET
0.267 0.267 0.267 rg
26.625 429.148 98.949 0.750 re f
26.625 112.684 98.949 0.750 re f
26.625 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
BT 31.875 419.293 Td /F1 9.8 Tf  [(De Roock and )] TJ ET
BT 31.875 411.662 Td /F1 9.8 Tf  [(colleagues \(2010\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 404.031 Td /F1 9.8 Tf  [([46])] TJ ET
124.824 429.148 159.395 0.750 re f
124.824 112.684 159.395 0.750 re f
124.824 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 422.592 m 
144.161 423.039 143.977 423.483 143.661 423.799 c
143.346 424.115 142.902 424.298 142.455 424.298 c
142.008 424.298 141.564 424.115 141.248 423.799 c
140.933 423.483 140.749 423.039 140.749 422.592 c
140.749 422.146 140.933 421.702 141.248 421.386 c
141.564 421.070 142.008 420.886 142.455 420.886 c
142.902 420.886 143.346 421.070 143.661 421.386 c
143.977 421.702 144.161 422.146 144.161 422.592 c f
BT 149.574 419.625 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 407.720 Td /F1 9.8 Tf  [(treated with cetuximab in )] TJ ET
BT 149.574 395.815 Td /F1 9.8 Tf  [(combination with )] TJ ET
BT 149.574 383.910 Td /F1 9.8 Tf  [(chemotherapy at 11 )] TJ ET
BT 149.574 372.006 Td /F1 9.8 Tf  [(European centers between )] TJ ET
BT 149.574 360.101 Td /F1 9.8 Tf  [(2001 and 2008.)] TJ ET
144.161 347.414 m 
144.161 347.860 143.977 348.304 143.661 348.620 c
143.346 348.936 142.902 349.120 142.455 349.120 c
142.008 349.120 141.564 348.936 141.248 348.620 c
140.933 348.304 140.749 347.860 140.749 347.414 c
140.749 346.967 140.933 346.523 141.248 346.207 c
141.564 345.891 142.008 345.707 142.455 345.707 c
142.902 345.707 143.346 345.891 143.661 346.207 c
143.977 346.523 144.161 346.967 144.161 347.414 c f
BT 149.574 344.446 Td /F1 9.8 Tf  [(The primary endpoint was )] TJ ET
BT 149.574 332.541 Td /F1 9.8 Tf  [(objective response, with PFS )] TJ ET
BT 149.574 320.637 Td /F1 9.8 Tf  [(as a secondary endpoint.)] TJ ET
144.161 307.949 m 
144.161 308.396 143.977 308.840 143.661 309.156 c
143.346 309.472 142.902 309.656 142.455 309.656 c
142.008 309.656 141.564 309.472 141.248 309.156 c
140.933 308.840 140.749 308.396 140.749 307.949 c
140.749 307.503 140.933 307.059 141.248 306.743 c
141.564 306.427 142.008 306.243 142.455 306.243 c
142.902 306.243 143.346 306.427 143.661 306.743 c
143.977 307.059 144.161 307.503 144.161 307.949 c f
BT 149.574 304.982 Td /F1 9.8 Tf  [(Sequence variants in the )] TJ ET
BT 149.574 293.077 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 176.123 293.077 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.807 293.077 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 223.810 293.077 Td /F1 9.8 Tf  [( genes )] TJ ET
BT 149.574 281.172 Td /F1 9.8 Tf  [(were identified using multiple )] TJ ET
BT 149.574 269.268 Td /F1 9.8 Tf  [(PCR with MALDI-TOF )] TJ ET
BT 149.574 257.363 Td /F1 9.8 Tf  [(MassARRAY Type 4 )] TJ ET
BT 149.574 245.458 Td /F1 9.8 Tf  [(Analyzer \(Sequenom Inc., )] TJ ET
BT 149.574 233.553 Td /F1 9.8 Tf  [(San Diego\).)] TJ ET
0.267 0.267 0.267 rg
283.469 429.148 157.203 0.750 re f
283.469 112.684 157.203 0.750 re f
283.469 112.684 0.750 317.214 re f
0.271 0.267 0.267 rg
302.806 422.592 m 
302.806 423.039 302.623 423.483 302.307 423.799 c
301.991 424.115 301.547 424.298 301.100 424.298 c
300.653 424.298 300.210 424.115 299.894 423.799 c
299.578 423.483 299.394 423.039 299.394 422.592 c
299.394 422.146 299.578 421.702 299.894 421.386 c
300.210 421.070 300.653 420.886 301.100 420.886 c
301.547 420.886 301.991 421.070 302.307 421.386 c
302.623 421.702 302.806 422.146 302.806 422.592 c f
BT 308.219 419.625 Td /F5 9.8 Tf  [(KRAS and BRAF)] TJ ET
BT 382.455 419.625 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 407.720 Td /F1 9.8 Tf  [(variants were found in 299 )] TJ ET
BT 308.219 395.815 Td /F1 9.8 Tf  [(of 747 \(40.0%\) and 35 of )] TJ ET
BT 308.219 383.910 Td /F1 9.8 Tf  [(761 \(4.7%\) evaluable pts, )] TJ ET
BT 308.219 372.006 Td /F1 9.8 Tf  [(respectively.)] TJ ET
302.806 359.318 m 
302.806 359.765 302.623 360.209 302.307 360.525 c
301.991 360.841 301.547 361.025 301.100 361.025 c
300.653 361.025 300.210 360.841 299.894 360.525 c
299.578 360.209 299.394 359.765 299.394 359.318 c
299.394 358.872 299.578 358.428 299.894 358.112 c
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301.547 357.612 301.991 357.796 302.307 358.112 c
302.623 358.428 302.806 358.872 302.806 359.318 c f
BT 308.219 356.351 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 356.351 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 344.446 Td /F1 9.8 Tf  [(occurred only in pts without )] TJ ET
BT 308.219 332.541 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 332.541 Td /F1 9.8 Tf  [( sequence variants.)] TJ ET
302.806 319.854 m 
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301.991 321.377 301.547 321.560 301.100 321.560 c
300.653 321.560 300.210 321.377 299.894 321.061 c
299.578 320.745 299.394 320.301 299.394 319.854 c
299.394 319.408 299.578 318.964 299.894 318.648 c
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301.547 318.148 301.991 318.332 302.307 318.648 c
302.623 318.964 302.806 319.408 302.806 319.854 c f
BT 308.219 316.887 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 316.887 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 308.219 304.982 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
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322.306 292.295 m 
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321.491 293.817 321.047 294.001 320.600 294.001 c
320.153 294.001 319.710 293.817 319.394 293.501 c
319.078 293.185 318.894 292.741 318.894 292.295 c
318.894 291.848 319.078 291.404 319.394 291.088 c
319.710 290.772 320.153 290.588 320.600 290.588 c
321.047 290.588 321.491 290.772 321.807 291.088 c
322.123 291.404 322.306 291.848 322.306 292.295 c s
BT 327.719 289.327 Td /F1 9.8 Tf  [(Response to treatment )] TJ ET
BT 327.719 277.422 Td /F1 9.8 Tf  [(was lower in pts with )] TJ ET
BT 327.719 265.518 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 265.518 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 253.613 Td /F1 9.8 Tf  [(variants than without )] TJ ET
BT 327.719 241.708 Td /F1 9.8 Tf  [(\(8.3% versus 38.0%; )] TJ ET
BT 327.719 229.803 Td /F1 9.8 Tf  [(OR 0.15; 95% CI, 0.02-)] TJ ET
BT 327.719 217.899 Td /F1 9.8 Tf  [(0.51; P=0.0012\))] TJ ET
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322.306 205.211 m 
322.306 205.658 322.123 206.102 321.807 206.418 c
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320.153 206.918 319.710 206.734 319.394 206.418 c
319.078 206.102 318.894 205.658 318.894 205.211 c
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319.710 203.689 320.153 203.505 320.600 203.505 c
321.047 203.505 321.491 203.689 321.807 204.005 c
322.123 204.321 322.306 204.765 322.306 205.211 c s
BT 327.719 202.244 Td /F1 9.8 Tf  [(Median PFS was )] TJ ET
BT 327.719 190.339 Td /F1 9.8 Tf  [(shorter in pts with )] TJ ET
BT 406.830 190.339 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 178.434 Td /F1 9.8 Tf  [(sequence variants than )] TJ ET
BT 327.719 166.530 Td /F1 9.8 Tf  [(without \(8 wks versus )] TJ ET
BT 327.719 154.625 Td /F1 9.8 Tf  [(26 wks; HR, 3.74; 95% )] TJ ET
BT 327.719 142.720 Td /F1 9.8 Tf  [(CI, 2.44-5.75; )] TJ ET
BT 327.719 130.815 Td /F1 9.8 Tf  [(P<0.0001\).)] TJ ET
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459.259 422.592 m 
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BT 464.672 419.625 Td /F1 9.8 Tf  [(Approximately one third of )] TJ ET
BT 464.672 407.720 Td /F1 9.8 Tf  [(pts included in this study )] TJ ET
BT 464.672 395.815 Td /F1 9.8 Tf  [(had been included in )] TJ ET
BT 464.672 383.910 Td /F1 9.8 Tf  [(previous reports.)] TJ ET
459.259 371.223 m 
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BT 464.672 368.256 Td /F1 9.8 Tf  [(Of the 2 pts that )] TJ ET
BT 464.672 356.351 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 464.672 344.446 Td /F1 9.8 Tf  [(with )] TJ ET
BT 484.718 344.446 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 510.721 344.446 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 332.541 Td /F1 9.8 Tf  [(variants, 1 had a )] TJ ET
BT 464.672 320.637 Td /F1 9.8 Tf  [(p.Asp549Gly variant and )] TJ ET
BT 464.672 308.732 Td /F1 9.8 Tf  [(the other had the )] TJ ET
BT 464.672 296.827 Td /F1 9.8 Tf  [(p.Val600Glu variant, but )] TJ ET
BT 464.672 284.922 Td /F1 9.8 Tf  [(at a low copy number in )] TJ ET
BT 464.672 273.018 Td /F1 9.8 Tf  [(the tumor sample.)] TJ ET
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BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(IR or FOLFIRI at 6 French )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(hospitals.)] TJ ET
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144.161 691.140 m 
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BT 308.219 743.292 Td /F1 9.8 Tf  [(\(31.4%\) pts.)] TJ ET
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BT 410.633 703.827 Td /F1 9.8 Tf  [( -)] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(negative pts.)] TJ ET
302.806 679.236 m 
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300.210 677.713 300.653 677.529 301.100 677.529 c
301.547 677.529 301.991 677.713 302.307 678.029 c
302.623 678.345 302.806 678.789 302.806 679.236 c f
BT 308.219 676.268 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 664.363 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
0.39 w 1 J 1 j
322.306 651.676 m 
322.306 652.123 322.123 652.567 321.807 652.883 c
321.491 653.198 321.047 653.382 320.600 653.382 c
320.153 653.382 319.710 653.198 319.394 652.883 c
319.078 652.567 318.894 652.123 318.894 651.676 c
318.894 651.229 319.078 650.785 319.394 650.469 c
319.710 650.154 320.153 649.970 320.600 649.970 c
321.047 649.970 321.491 650.154 321.807 650.469 c
322.123 650.785 322.306 651.229 322.306 651.676 c s
BT 327.719 648.708 Td /F1 9.8 Tf  [(No pts with )] TJ ET
BT 378.653 648.708 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 636.804 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
BT 327.719 624.899 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 327.719 612.994 Td /F1 9.8 Tf  [(compared with 51 of )] TJ ET
BT 327.719 601.089 Td /F1 9.8 Tf  [(110 \(46.4%\) without )] TJ ET
BT 327.719 589.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 589.185 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 577.280 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.39 w 1 J 1 j
322.306 564.593 m 
322.306 565.039 322.123 565.483 321.807 565.799 c
321.491 566.115 321.047 566.299 320.600 566.299 c
320.153 566.299 319.710 566.115 319.394 565.799 c
319.078 565.483 318.894 565.039 318.894 564.593 c
318.894 564.146 319.078 563.702 319.394 563.386 c
319.710 563.070 320.153 562.886 320.600 562.886 c
321.047 562.886 321.491 563.070 321.807 563.386 c
322.123 563.702 322.306 564.146 322.306 564.593 c s
BT 327.719 561.625 Td /F1 9.8 Tf  [(PFS was shorter in pts )] TJ ET
BT 327.719 549.720 Td /F1 9.8 Tf  [(with than without )] TJ ET
BT 403.047 549.720 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 537.816 Td /F1 9.8 Tf  [(sequence variants \(8.0 )] TJ ET
BT 327.719 525.911 Td /F1 9.8 Tf  [(wks versus 31.4 wks; )] TJ ET
BT 327.719 514.006 Td /F1 9.8 Tf  [(P<0.001\). OS was also )] TJ ET
BT 327.719 502.101 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 327.719 490.197 Td /F1 9.8 Tf  [(without )] TJ ET
BT 361.317 490.197 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 387.321 490.197 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 478.292 Td /F1 9.8 Tf  [(variants \(6.5 mos )] TJ ET
BT 327.719 466.387 Td /F1 9.8 Tf  [(versus 14.8 mos; )] TJ ET
BT 327.719 454.482 Td /F1 9.8 Tf  [(P<0.001\).)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 436.352 0.750 341.023 re f
587.165 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(In this study, the presence )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(of )] TJ ET
BT 475.514 755.196 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 502.063 755.196 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(variants was found to be a )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(significant predictor of )] TJ ET
BT 464.672 719.482 Td /F1 9.8 Tf  [(response to treatment, )] TJ ET
BT 464.672 707.577 Td /F1 9.8 Tf  [(PFS and OS.)] TJ ET
0.267 0.267 0.267 rg
26.625 436.352 98.949 0.750 re f
26.625 175.007 98.949 0.750 re f
26.625 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
BT 31.875 426.497 Td /F1 9.8 Tf  [(Loupakis and )] TJ ET
BT 31.875 418.865 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 411.234 Td /F1 9.8 Tf  [([39])] TJ ET
124.824 436.352 159.395 0.750 re f
124.824 175.007 159.395 0.750 re f
124.824 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
144.161 429.795 m 
144.161 430.242 143.977 430.686 143.661 431.002 c
143.346 431.318 142.902 431.502 142.455 431.502 c
142.008 431.502 141.564 431.318 141.248 431.002 c
140.933 430.686 140.749 430.242 140.749 429.795 c
140.749 429.349 140.933 428.905 141.248 428.589 c
141.564 428.273 142.008 428.089 142.455 428.089 c
142.902 428.089 143.346 428.273 143.661 428.589 c
143.977 428.905 144.161 429.349 144.161 429.795 c f
BT 149.574 426.828 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 414.923 Td /F1 9.8 Tf  [(treated at cancer treatment )] TJ ET
BT 149.574 403.018 Td /F1 9.8 Tf  [(centers with cetuximab plus )] TJ ET
BT 149.574 391.113 Td /F1 9.8 Tf  [(IR who had previously tested )] TJ ET
BT 149.574 379.209 Td /F1 9.8 Tf  [(negative for )] TJ ET
BT 203.228 379.209 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 229.777 379.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 367.304 Td /F1 9.8 Tf  [(variants.)] TJ ET
144.161 354.617 m 
144.161 355.063 143.977 355.507 143.661 355.823 c
143.346 356.139 142.902 356.323 142.455 356.323 c
142.008 356.323 141.564 356.139 141.248 355.823 c
140.933 355.507 140.749 355.063 140.749 354.617 c
140.749 354.170 140.933 353.726 141.248 353.410 c
141.564 353.094 142.008 352.911 142.455 352.911 c
142.902 352.911 143.346 353.094 143.661 353.410 c
143.977 353.726 144.161 354.170 144.161 354.617 c f
BT 149.574 351.649 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 339.744 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 327.057 m 
144.161 327.504 143.977 327.948 143.661 328.264 c
143.346 328.580 142.902 328.764 142.455 328.764 c
142.008 328.764 141.564 328.580 141.248 328.264 c
140.933 327.948 140.749 327.504 140.749 327.057 c
140.749 326.611 140.933 326.167 141.248 325.851 c
141.564 325.535 142.008 325.351 142.455 325.351 c
142.902 325.351 143.346 325.535 143.661 325.851 c
143.977 326.167 144.161 326.611 144.161 327.057 c f
BT 149.574 324.090 Td /F1 9.8 Tf  [(PCR with pyrosequencing )] TJ ET
BT 149.574 312.185 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 312.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 300.280 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 436.352 157.203 0.750 re f
283.469 175.007 157.203 0.750 re f
283.469 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
302.806 429.795 m 
302.806 430.242 302.623 430.686 302.307 431.002 c
301.991 431.318 301.547 431.502 301.100 431.502 c
300.653 431.502 300.210 431.318 299.894 431.002 c
299.578 430.686 299.394 430.242 299.394 429.795 c
299.394 429.349 299.578 428.905 299.894 428.589 c
300.210 428.273 300.653 428.089 301.100 428.089 c
301.547 428.089 301.991 428.273 302.307 428.589 c
302.623 428.905 302.806 429.349 302.806 429.795 c f
BT 308.219 426.828 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 426.828 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 414.923 Td /F1 9.8 Tf  [(were found in 13 of 87 )] TJ ET
BT 308.219 403.018 Td /F1 9.8 Tf  [(\(14.9%\) pts without )] TJ ET
BT 394.380 403.018 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 391.113 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 378.426 m 
302.806 378.873 302.623 379.317 302.307 379.633 c
301.991 379.949 301.547 380.132 301.100 380.132 c
300.653 380.132 300.210 379.949 299.894 379.633 c
299.578 379.317 299.394 378.873 299.394 378.426 c
299.394 377.980 299.578 377.536 299.894 377.220 c
300.210 376.904 300.653 376.720 301.100 376.720 c
301.547 376.720 301.991 376.904 302.307 377.220 c
302.623 377.536 302.806 377.980 302.806 378.426 c f
BT 308.219 375.459 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 363.554 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 351.649 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 351.649 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 351.649 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 339.744 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 327.840 Td /F1 9.8 Tf  [(27.6%; P=0.016\).)] TJ ET
302.806 315.153 m 
302.806 315.599 302.623 316.043 302.307 316.359 c
301.991 316.675 301.547 316.859 301.100 316.859 c
300.653 316.859 300.210 316.675 299.894 316.359 c
299.578 316.043 299.394 315.599 299.394 315.153 c
299.394 314.706 299.578 314.262 299.894 313.946 c
300.210 313.630 300.653 313.446 301.100 313.446 c
301.547 313.446 301.991 313.630 302.307 313.946 c
302.623 314.262 302.806 314.706 302.806 315.153 c f
BT 308.219 312.185 Td /F1 9.8 Tf  [(Median PFS was shorter in )] TJ ET
BT 308.219 300.280 Td /F1 9.8 Tf  [(pts with than without )] TJ ET
BT 399.264 300.280 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 288.375 Td /F1 9.8 Tf  [(sequence variants, but not )] TJ ET
BT 308.219 276.471 Td /F1 9.8 Tf  [(significantly \(2.6 mos versus )] TJ ET
BT 308.219 264.566 Td /F1 9.8 Tf  [(4.4 mos; P=0.073\).)] TJ ET
302.806 251.879 m 
302.806 252.325 302.623 252.769 302.307 253.085 c
301.991 253.401 301.547 253.585 301.100 253.585 c
300.653 253.585 300.210 253.401 299.894 253.085 c
299.578 252.769 299.394 252.325 299.394 251.879 c
299.394 251.432 299.578 250.988 299.894 250.672 c
300.210 250.356 300.653 250.173 301.100 250.173 c
301.547 250.173 301.991 250.356 302.307 250.672 c
302.623 250.988 302.806 251.432 302.806 251.879 c f
BT 308.219 248.911 Td /F1 9.8 Tf  [(Median OS was significantly )] TJ ET
BT 308.219 237.006 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 308.219 225.102 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 225.102 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 225.102 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 213.197 Td /F1 9.8 Tf  [(variants \(4.1 mos versus )] TJ ET
BT 308.219 201.292 Td /F1 9.8 Tf  [(13.9 mos; HR 0.51; 95% CI, )] TJ ET
BT 308.219 189.387 Td /F1 9.8 Tf  [(0.18-0.95; P=0.037\).)] TJ ET
0.267 0.267 0.267 rg
439.922 436.352 147.993 0.750 re f
439.922 175.007 147.993 0.750 re f
439.922 175.007 0.750 262.095 re f
587.165 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
459.259 429.795 m 
459.259 430.242 459.076 430.686 458.760 431.002 c
458.444 431.318 458.000 431.502 457.553 431.502 c
457.107 431.502 456.663 431.318 456.347 431.002 c
456.031 430.686 455.847 430.242 455.847 429.795 c
455.847 429.349 456.031 428.905 456.347 428.589 c
456.663 428.273 457.107 428.089 457.553 428.089 c
458.000 428.089 458.444 428.273 458.760 428.589 c
459.076 428.905 459.259 429.349 459.259 429.795 c f
BT 464.672 426.828 Td /F1 9.8 Tf  [(By the time of this )] TJ ET
BT 464.672 414.923 Td /F1 9.8 Tf  [(analysis, 93% of pts had )] TJ ET
BT 464.672 403.018 Td /F1 9.8 Tf  [(experienced disease )] TJ ET
BT 464.672 391.113 Td /F1 9.8 Tf  [(progression and 72% had )] TJ ET
BT 464.672 379.209 Td /F1 9.8 Tf  [(died.)] TJ ET
Q
q
15.000 174.632 577.500 602.368 re W n
1.000 1.000 1.000 rg
26.250 174.632 555.000 602.368 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Laurent-Puig and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([43])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(IR or FOLFIRI at 6 French )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(hospitals.)] TJ ET
144.161 718.700 m 
144.161 719.146 143.977 719.590 143.661 719.906 c
143.346 720.222 142.902 720.406 142.455 720.406 c
142.008 720.406 141.564 720.222 141.248 719.906 c
140.933 719.590 140.749 719.146 140.749 718.700 c
140.749 718.253 140.933 717.809 141.248 717.493 c
141.564 717.177 142.008 716.994 142.455 716.994 c
142.902 716.994 143.346 717.177 143.661 717.493 c
143.977 717.809 144.161 718.253 144.161 718.700 c f
BT 149.574 715.732 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 703.827 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 691.140 m 
144.161 691.587 143.977 692.031 143.661 692.347 c
143.346 692.663 142.902 692.846 142.455 692.846 c
142.008 692.846 141.564 692.663 141.248 692.347 c
140.933 692.031 140.749 691.587 140.749 691.140 c
140.749 690.694 140.933 690.250 141.248 689.934 c
141.564 689.618 142.008 689.434 142.455 689.434 c
142.902 689.434 143.346 689.618 143.661 689.934 c
143.977 690.250 144.161 690.694 144.161 691.140 c f
BT 149.574 688.173 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 176.123 688.173 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.807 688.173 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 223.810 688.173 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 676.268 Td /F1 9.8 Tf  [(variants were identified using )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(allelic discrimination with )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(TaqMan probes.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were found in 53 of 169 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(31.4%\) pts.)] TJ ET
302.806 730.605 m 
302.806 731.051 302.623 731.495 302.307 731.811 c
301.991 732.127 301.547 732.311 301.100 732.311 c
300.653 732.311 300.210 732.127 299.894 731.811 c
299.578 731.495 299.394 731.051 299.394 730.605 c
299.394 730.158 299.578 729.714 299.894 729.398 c
300.210 729.082 300.653 728.898 301.100 728.898 c
301.547 728.898 301.991 729.082 302.307 729.398 c
302.623 729.714 302.806 730.158 302.806 730.605 c f
BT 308.219 727.637 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 727.637 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 715.732 Td /F1 9.8 Tf  [(were identified in 5 of 115 )] TJ ET
BT 308.219 703.827 Td /F1 9.8 Tf  [(\(4.3%\) evaluable )] TJ ET
BT 384.084 703.827 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 410.633 703.827 Td /F1 9.8 Tf  [( -)] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(negative pts.)] TJ ET
302.806 679.236 m 
302.806 679.682 302.623 680.126 302.307 680.442 c
301.991 680.758 301.547 680.942 301.100 680.942 c
300.653 680.942 300.210 680.758 299.894 680.442 c
299.578 680.126 299.394 679.682 299.394 679.236 c
299.394 678.789 299.578 678.345 299.894 678.029 c
300.210 677.713 300.653 677.529 301.100 677.529 c
301.547 677.529 301.991 677.713 302.307 678.029 c
302.623 678.345 302.806 678.789 302.806 679.236 c f
BT 308.219 676.268 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 664.363 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
0.39 w 1 J 1 j
322.306 651.676 m 
322.306 652.123 322.123 652.567 321.807 652.883 c
321.491 653.198 321.047 653.382 320.600 653.382 c
320.153 653.382 319.710 653.198 319.394 652.883 c
319.078 652.567 318.894 652.123 318.894 651.676 c
318.894 651.229 319.078 650.785 319.394 650.469 c
319.710 650.154 320.153 649.970 320.600 649.970 c
321.047 649.970 321.491 650.154 321.807 650.469 c
322.123 650.785 322.306 651.229 322.306 651.676 c s
BT 327.719 648.708 Td /F1 9.8 Tf  [(No pts with )] TJ ET
BT 378.653 648.708 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 636.804 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
BT 327.719 624.899 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 327.719 612.994 Td /F1 9.8 Tf  [(compared with 51 of )] TJ ET
BT 327.719 601.089 Td /F1 9.8 Tf  [(110 \(46.4%\) without )] TJ ET
BT 327.719 589.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 589.185 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 577.280 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.39 w 1 J 1 j
322.306 564.593 m 
322.306 565.039 322.123 565.483 321.807 565.799 c
321.491 566.115 321.047 566.299 320.600 566.299 c
320.153 566.299 319.710 566.115 319.394 565.799 c
319.078 565.483 318.894 565.039 318.894 564.593 c
318.894 564.146 319.078 563.702 319.394 563.386 c
319.710 563.070 320.153 562.886 320.600 562.886 c
321.047 562.886 321.491 563.070 321.807 563.386 c
322.123 563.702 322.306 564.146 322.306 564.593 c s
BT 327.719 561.625 Td /F1 9.8 Tf  [(PFS was shorter in pts )] TJ ET
BT 327.719 549.720 Td /F1 9.8 Tf  [(with than without )] TJ ET
BT 403.047 549.720 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 537.816 Td /F1 9.8 Tf  [(sequence variants \(8.0 )] TJ ET
BT 327.719 525.911 Td /F1 9.8 Tf  [(wks versus 31.4 wks; )] TJ ET
BT 327.719 514.006 Td /F1 9.8 Tf  [(P<0.001\). OS was also )] TJ ET
BT 327.719 502.101 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 327.719 490.197 Td /F1 9.8 Tf  [(without )] TJ ET
BT 361.317 490.197 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 387.321 490.197 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 478.292 Td /F1 9.8 Tf  [(variants \(6.5 mos )] TJ ET
BT 327.719 466.387 Td /F1 9.8 Tf  [(versus 14.8 mos; )] TJ ET
BT 327.719 454.482 Td /F1 9.8 Tf  [(P<0.001\).)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 436.352 0.750 341.023 re f
587.165 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(In this study, the presence )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(of )] TJ ET
BT 475.514 755.196 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 502.063 755.196 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(variants was found to be a )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(significant predictor of )] TJ ET
BT 464.672 719.482 Td /F1 9.8 Tf  [(response to treatment, )] TJ ET
BT 464.672 707.577 Td /F1 9.8 Tf  [(PFS and OS.)] TJ ET
0.267 0.267 0.267 rg
26.625 436.352 98.949 0.750 re f
26.625 175.007 98.949 0.750 re f
26.625 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
BT 31.875 426.497 Td /F1 9.8 Tf  [(Loupakis and )] TJ ET
BT 31.875 418.865 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 411.234 Td /F1 9.8 Tf  [([39])] TJ ET
124.824 436.352 159.395 0.750 re f
124.824 175.007 159.395 0.750 re f
124.824 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
144.161 429.795 m 
144.161 430.242 143.977 430.686 143.661 431.002 c
143.346 431.318 142.902 431.502 142.455 431.502 c
142.008 431.502 141.564 431.318 141.248 431.002 c
140.933 430.686 140.749 430.242 140.749 429.795 c
140.749 429.349 140.933 428.905 141.248 428.589 c
141.564 428.273 142.008 428.089 142.455 428.089 c
142.902 428.089 143.346 428.273 143.661 428.589 c
143.977 428.905 144.161 429.349 144.161 429.795 c f
BT 149.574 426.828 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 414.923 Td /F1 9.8 Tf  [(treated at cancer treatment )] TJ ET
BT 149.574 403.018 Td /F1 9.8 Tf  [(centers with cetuximab plus )] TJ ET
BT 149.574 391.113 Td /F1 9.8 Tf  [(IR who had previously tested )] TJ ET
BT 149.574 379.209 Td /F1 9.8 Tf  [(negative for )] TJ ET
BT 203.228 379.209 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 229.777 379.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 367.304 Td /F1 9.8 Tf  [(variants.)] TJ ET
144.161 354.617 m 
144.161 355.063 143.977 355.507 143.661 355.823 c
143.346 356.139 142.902 356.323 142.455 356.323 c
142.008 356.323 141.564 356.139 141.248 355.823 c
140.933 355.507 140.749 355.063 140.749 354.617 c
140.749 354.170 140.933 353.726 141.248 353.410 c
141.564 353.094 142.008 352.911 142.455 352.911 c
142.902 352.911 143.346 353.094 143.661 353.410 c
143.977 353.726 144.161 354.170 144.161 354.617 c f
BT 149.574 351.649 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 339.744 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 327.057 m 
144.161 327.504 143.977 327.948 143.661 328.264 c
143.346 328.580 142.902 328.764 142.455 328.764 c
142.008 328.764 141.564 328.580 141.248 328.264 c
140.933 327.948 140.749 327.504 140.749 327.057 c
140.749 326.611 140.933 326.167 141.248 325.851 c
141.564 325.535 142.008 325.351 142.455 325.351 c
142.902 325.351 143.346 325.535 143.661 325.851 c
143.977 326.167 144.161 326.611 144.161 327.057 c f
BT 149.574 324.090 Td /F1 9.8 Tf  [(PCR with pyrosequencing )] TJ ET
BT 149.574 312.185 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 312.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 300.280 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 436.352 157.203 0.750 re f
283.469 175.007 157.203 0.750 re f
283.469 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
302.806 429.795 m 
302.806 430.242 302.623 430.686 302.307 431.002 c
301.991 431.318 301.547 431.502 301.100 431.502 c
300.653 431.502 300.210 431.318 299.894 431.002 c
299.578 430.686 299.394 430.242 299.394 429.795 c
299.394 429.349 299.578 428.905 299.894 428.589 c
300.210 428.273 300.653 428.089 301.100 428.089 c
301.547 428.089 301.991 428.273 302.307 428.589 c
302.623 428.905 302.806 429.349 302.806 429.795 c f
BT 308.219 426.828 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 426.828 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 414.923 Td /F1 9.8 Tf  [(were found in 13 of 87 )] TJ ET
BT 308.219 403.018 Td /F1 9.8 Tf  [(\(14.9%\) pts without )] TJ ET
BT 394.380 403.018 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 391.113 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 378.426 m 
302.806 378.873 302.623 379.317 302.307 379.633 c
301.991 379.949 301.547 380.132 301.100 380.132 c
300.653 380.132 300.210 379.949 299.894 379.633 c
299.578 379.317 299.394 378.873 299.394 378.426 c
299.394 377.980 299.578 377.536 299.894 377.220 c
300.210 376.904 300.653 376.720 301.100 376.720 c
301.547 376.720 301.991 376.904 302.307 377.220 c
302.623 377.536 302.806 377.980 302.806 378.426 c f
BT 308.219 375.459 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 363.554 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 351.649 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 351.649 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 351.649 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 339.744 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 327.840 Td /F1 9.8 Tf  [(27.6%; P=0.016\).)] TJ ET
302.806 315.153 m 
302.806 315.599 302.623 316.043 302.307 316.359 c
301.991 316.675 301.547 316.859 301.100 316.859 c
300.653 316.859 300.210 316.675 299.894 316.359 c
299.578 316.043 299.394 315.599 299.394 315.153 c
299.394 314.706 299.578 314.262 299.894 313.946 c
300.210 313.630 300.653 313.446 301.100 313.446 c
301.547 313.446 301.991 313.630 302.307 313.946 c
302.623 314.262 302.806 314.706 302.806 315.153 c f
BT 308.219 312.185 Td /F1 9.8 Tf  [(Median PFS was shorter in )] TJ ET
BT 308.219 300.280 Td /F1 9.8 Tf  [(pts with than without )] TJ ET
BT 399.264 300.280 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 288.375 Td /F1 9.8 Tf  [(sequence variants, but not )] TJ ET
BT 308.219 276.471 Td /F1 9.8 Tf  [(significantly \(2.6 mos versus )] TJ ET
BT 308.219 264.566 Td /F1 9.8 Tf  [(4.4 mos; P=0.073\).)] TJ ET
302.806 251.879 m 
302.806 252.325 302.623 252.769 302.307 253.085 c
301.991 253.401 301.547 253.585 301.100 253.585 c
300.653 253.585 300.210 253.401 299.894 253.085 c
299.578 252.769 299.394 252.325 299.394 251.879 c
299.394 251.432 299.578 250.988 299.894 250.672 c
300.210 250.356 300.653 250.173 301.100 250.173 c
301.547 250.173 301.991 250.356 302.307 250.672 c
302.623 250.988 302.806 251.432 302.806 251.879 c f
BT 308.219 248.911 Td /F1 9.8 Tf  [(Median OS was significantly )] TJ ET
BT 308.219 237.006 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 308.219 225.102 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 225.102 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 225.102 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 213.197 Td /F1 9.8 Tf  [(variants \(4.1 mos versus )] TJ ET
BT 308.219 201.292 Td /F1 9.8 Tf  [(13.9 mos; HR 0.51; 95% CI, )] TJ ET
BT 308.219 189.387 Td /F1 9.8 Tf  [(0.18-0.95; P=0.037\).)] TJ ET
0.267 0.267 0.267 rg
439.922 436.352 147.993 0.750 re f
439.922 175.007 147.993 0.750 re f
439.922 175.007 0.750 262.095 re f
587.165 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
459.259 429.795 m 
459.259 430.242 459.076 430.686 458.760 431.002 c
458.444 431.318 458.000 431.502 457.553 431.502 c
457.107 431.502 456.663 431.318 456.347 431.002 c
456.031 430.686 455.847 430.242 455.847 429.795 c
455.847 429.349 456.031 428.905 456.347 428.589 c
456.663 428.273 457.107 428.089 457.553 428.089 c
458.000 428.089 458.444 428.273 458.760 428.589 c
459.076 428.905 459.259 429.349 459.259 429.795 c f
BT 464.672 426.828 Td /F1 9.8 Tf  [(By the time of this )] TJ ET
BT 464.672 414.923 Td /F1 9.8 Tf  [(analysis, 93% of pts had )] TJ ET
BT 464.672 403.018 Td /F1 9.8 Tf  [(experienced disease )] TJ ET
BT 464.672 391.113 Td /F1 9.8 Tf  [(progression and 72% had )] TJ ET
BT 464.672 379.209 Td /F1 9.8 Tf  [(died.)] TJ ET
Q
q
15.000 174.632 577.500 602.368 re W n
1.000 1.000 1.000 rg
26.250 174.632 555.000 602.368 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Laurent-Puig and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([43])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(IR or FOLFIRI at 6 French )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(hospitals.)] TJ ET
144.161 718.700 m 
144.161 719.146 143.977 719.590 143.661 719.906 c
143.346 720.222 142.902 720.406 142.455 720.406 c
142.008 720.406 141.564 720.222 141.248 719.906 c
140.933 719.590 140.749 719.146 140.749 718.700 c
140.749 718.253 140.933 717.809 141.248 717.493 c
141.564 717.177 142.008 716.994 142.455 716.994 c
142.902 716.994 143.346 717.177 143.661 717.493 c
143.977 717.809 144.161 718.253 144.161 718.700 c f
BT 149.574 715.732 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 703.827 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 691.140 m 
144.161 691.587 143.977 692.031 143.661 692.347 c
143.346 692.663 142.902 692.846 142.455 692.846 c
142.008 692.846 141.564 692.663 141.248 692.347 c
140.933 692.031 140.749 691.587 140.749 691.140 c
140.749 690.694 140.933 690.250 141.248 689.934 c
141.564 689.618 142.008 689.434 142.455 689.434 c
142.902 689.434 143.346 689.618 143.661 689.934 c
143.977 690.250 144.161 690.694 144.161 691.140 c f
BT 149.574 688.173 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 176.123 688.173 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.807 688.173 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 223.810 688.173 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 676.268 Td /F1 9.8 Tf  [(variants were identified using )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(allelic discrimination with )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(TaqMan probes.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were found in 53 of 169 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(31.4%\) pts.)] TJ ET
302.806 730.605 m 
302.806 731.051 302.623 731.495 302.307 731.811 c
301.991 732.127 301.547 732.311 301.100 732.311 c
300.653 732.311 300.210 732.127 299.894 731.811 c
299.578 731.495 299.394 731.051 299.394 730.605 c
299.394 730.158 299.578 729.714 299.894 729.398 c
300.210 729.082 300.653 728.898 301.100 728.898 c
301.547 728.898 301.991 729.082 302.307 729.398 c
302.623 729.714 302.806 730.158 302.806 730.605 c f
BT 308.219 727.637 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 727.637 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 715.732 Td /F1 9.8 Tf  [(were identified in 5 of 115 )] TJ ET
BT 308.219 703.827 Td /F1 9.8 Tf  [(\(4.3%\) evaluable )] TJ ET
BT 384.084 703.827 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 410.633 703.827 Td /F1 9.8 Tf  [( -)] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(negative pts.)] TJ ET
302.806 679.236 m 
302.806 679.682 302.623 680.126 302.307 680.442 c
301.991 680.758 301.547 680.942 301.100 680.942 c
300.653 680.942 300.210 680.758 299.894 680.442 c
299.578 680.126 299.394 679.682 299.394 679.236 c
299.394 678.789 299.578 678.345 299.894 678.029 c
300.210 677.713 300.653 677.529 301.100 677.529 c
301.547 677.529 301.991 677.713 302.307 678.029 c
302.623 678.345 302.806 678.789 302.806 679.236 c f
BT 308.219 676.268 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 664.363 Td /F1 9.8 Tf  [(sequence variants: )] TJ ET
0.39 w 1 J 1 j
322.306 651.676 m 
322.306 652.123 322.123 652.567 321.807 652.883 c
321.491 653.198 321.047 653.382 320.600 653.382 c
320.153 653.382 319.710 653.198 319.394 652.883 c
319.078 652.567 318.894 652.123 318.894 651.676 c
318.894 651.229 319.078 650.785 319.394 650.469 c
319.710 650.154 320.153 649.970 320.600 649.970 c
321.047 649.970 321.491 650.154 321.807 650.469 c
322.123 650.785 322.306 651.229 322.306 651.676 c s
BT 327.719 648.708 Td /F1 9.8 Tf  [(No pts with )] TJ ET
BT 378.653 648.708 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 636.804 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
BT 327.719 624.899 Td /F1 9.8 Tf  [(responded to treatment )] TJ ET
BT 327.719 612.994 Td /F1 9.8 Tf  [(compared with 51 of )] TJ ET
BT 327.719 601.089 Td /F1 9.8 Tf  [(110 \(46.4%\) without )] TJ ET
BT 327.719 589.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.722 589.185 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 577.280 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.39 w 1 J 1 j
322.306 564.593 m 
322.306 565.039 322.123 565.483 321.807 565.799 c
321.491 566.115 321.047 566.299 320.600 566.299 c
320.153 566.299 319.710 566.115 319.394 565.799 c
319.078 565.483 318.894 565.039 318.894 564.593 c
318.894 564.146 319.078 563.702 319.394 563.386 c
319.710 563.070 320.153 562.886 320.600 562.886 c
321.047 562.886 321.491 563.070 321.807 563.386 c
322.123 563.702 322.306 564.146 322.306 564.593 c s
BT 327.719 561.625 Td /F1 9.8 Tf  [(PFS was shorter in pts )] TJ ET
BT 327.719 549.720 Td /F1 9.8 Tf  [(with than without )] TJ ET
BT 403.047 549.720 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 327.719 537.816 Td /F1 9.8 Tf  [(sequence variants \(8.0 )] TJ ET
BT 327.719 525.911 Td /F1 9.8 Tf  [(wks versus 31.4 wks; )] TJ ET
BT 327.719 514.006 Td /F1 9.8 Tf  [(P<0.001\). OS was also )] TJ ET
BT 327.719 502.101 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 327.719 490.197 Td /F1 9.8 Tf  [(without )] TJ ET
BT 361.317 490.197 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 387.321 490.197 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 327.719 478.292 Td /F1 9.8 Tf  [(variants \(6.5 mos )] TJ ET
BT 327.719 466.387 Td /F1 9.8 Tf  [(versus 14.8 mos; )] TJ ET
BT 327.719 454.482 Td /F1 9.8 Tf  [(P<0.001\).)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 436.352 0.750 341.023 re f
587.165 436.352 0.750 341.023 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(In this study, the presence )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(of )] TJ ET
BT 475.514 755.196 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 502.063 755.196 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(variants was found to be a )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(significant predictor of )] TJ ET
BT 464.672 719.482 Td /F1 9.8 Tf  [(response to treatment, )] TJ ET
BT 464.672 707.577 Td /F1 9.8 Tf  [(PFS and OS.)] TJ ET
0.267 0.267 0.267 rg
26.625 436.352 98.949 0.750 re f
26.625 175.007 98.949 0.750 re f
26.625 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
BT 31.875 426.497 Td /F1 9.8 Tf  [(Loupakis and )] TJ ET
BT 31.875 418.865 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 411.234 Td /F1 9.8 Tf  [([39])] TJ ET
124.824 436.352 159.395 0.750 re f
124.824 175.007 159.395 0.750 re f
124.824 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
144.161 429.795 m 
144.161 430.242 143.977 430.686 143.661 431.002 c
143.346 431.318 142.902 431.502 142.455 431.502 c
142.008 431.502 141.564 431.318 141.248 431.002 c
140.933 430.686 140.749 430.242 140.749 429.795 c
140.749 429.349 140.933 428.905 141.248 428.589 c
141.564 428.273 142.008 428.089 142.455 428.089 c
142.902 428.089 143.346 428.273 143.661 428.589 c
143.977 428.905 144.161 429.349 144.161 429.795 c f
BT 149.574 426.828 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 414.923 Td /F1 9.8 Tf  [(treated at cancer treatment )] TJ ET
BT 149.574 403.018 Td /F1 9.8 Tf  [(centers with cetuximab plus )] TJ ET
BT 149.574 391.113 Td /F1 9.8 Tf  [(IR who had previously tested )] TJ ET
BT 149.574 379.209 Td /F1 9.8 Tf  [(negative for )] TJ ET
BT 203.228 379.209 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 229.777 379.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 367.304 Td /F1 9.8 Tf  [(variants.)] TJ ET
144.161 354.617 m 
144.161 355.063 143.977 355.507 143.661 355.823 c
143.346 356.139 142.902 356.323 142.455 356.323 c
142.008 356.323 141.564 356.139 141.248 355.823 c
140.933 355.507 140.749 355.063 140.749 354.617 c
140.749 354.170 140.933 353.726 141.248 353.410 c
141.564 353.094 142.008 352.911 142.455 352.911 c
142.902 352.911 143.346 353.094 143.661 353.410 c
143.977 353.726 144.161 354.170 144.161 354.617 c f
BT 149.574 351.649 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 339.744 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 327.057 m 
144.161 327.504 143.977 327.948 143.661 328.264 c
143.346 328.580 142.902 328.764 142.455 328.764 c
142.008 328.764 141.564 328.580 141.248 328.264 c
140.933 327.948 140.749 327.504 140.749 327.057 c
140.749 326.611 140.933 326.167 141.248 325.851 c
141.564 325.535 142.008 325.351 142.455 325.351 c
142.902 325.351 143.346 325.535 143.661 325.851 c
143.977 326.167 144.161 326.611 144.161 327.057 c f
BT 149.574 324.090 Td /F1 9.8 Tf  [(PCR with pyrosequencing )] TJ ET
BT 149.574 312.185 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 312.185 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 300.280 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 436.352 157.203 0.750 re f
283.469 175.007 157.203 0.750 re f
283.469 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
302.806 429.795 m 
302.806 430.242 302.623 430.686 302.307 431.002 c
301.991 431.318 301.547 431.502 301.100 431.502 c
300.653 431.502 300.210 431.318 299.894 431.002 c
299.578 430.686 299.394 430.242 299.394 429.795 c
299.394 429.349 299.578 428.905 299.894 428.589 c
300.210 428.273 300.653 428.089 301.100 428.089 c
301.547 428.089 301.991 428.273 302.307 428.589 c
302.623 428.905 302.806 429.349 302.806 429.795 c f
BT 308.219 426.828 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 426.828 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 414.923 Td /F1 9.8 Tf  [(were found in 13 of 87 )] TJ ET
BT 308.219 403.018 Td /F1 9.8 Tf  [(\(14.9%\) pts without )] TJ ET
BT 394.380 403.018 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 391.113 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 378.426 m 
302.806 378.873 302.623 379.317 302.307 379.633 c
301.991 379.949 301.547 380.132 301.100 380.132 c
300.653 380.132 300.210 379.949 299.894 379.633 c
299.578 379.317 299.394 378.873 299.394 378.426 c
299.394 377.980 299.578 377.536 299.894 377.220 c
300.210 376.904 300.653 376.720 301.100 376.720 c
301.547 376.720 301.991 376.904 302.307 377.220 c
302.623 377.536 302.806 377.980 302.806 378.426 c f
BT 308.219 375.459 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 363.554 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 351.649 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 351.649 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 351.649 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 339.744 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 327.840 Td /F1 9.8 Tf  [(27.6%; P=0.016\).)] TJ ET
302.806 315.153 m 
302.806 315.599 302.623 316.043 302.307 316.359 c
301.991 316.675 301.547 316.859 301.100 316.859 c
300.653 316.859 300.210 316.675 299.894 316.359 c
299.578 316.043 299.394 315.599 299.394 315.153 c
299.394 314.706 299.578 314.262 299.894 313.946 c
300.210 313.630 300.653 313.446 301.100 313.446 c
301.547 313.446 301.991 313.630 302.307 313.946 c
302.623 314.262 302.806 314.706 302.806 315.153 c f
BT 308.219 312.185 Td /F1 9.8 Tf  [(Median PFS was shorter in )] TJ ET
BT 308.219 300.280 Td /F1 9.8 Tf  [(pts with than without )] TJ ET
BT 399.264 300.280 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 288.375 Td /F1 9.8 Tf  [(sequence variants, but not )] TJ ET
BT 308.219 276.471 Td /F1 9.8 Tf  [(significantly \(2.6 mos versus )] TJ ET
BT 308.219 264.566 Td /F1 9.8 Tf  [(4.4 mos; P=0.073\).)] TJ ET
302.806 251.879 m 
302.806 252.325 302.623 252.769 302.307 253.085 c
301.991 253.401 301.547 253.585 301.100 253.585 c
300.653 253.585 300.210 253.401 299.894 253.085 c
299.578 252.769 299.394 252.325 299.394 251.879 c
299.394 251.432 299.578 250.988 299.894 250.672 c
300.210 250.356 300.653 250.173 301.100 250.173 c
301.547 250.173 301.991 250.356 302.307 250.672 c
302.623 250.988 302.806 251.432 302.806 251.879 c f
BT 308.219 248.911 Td /F1 9.8 Tf  [(Median OS was significantly )] TJ ET
BT 308.219 237.006 Td /F1 9.8 Tf  [(shorter in pts with than )] TJ ET
BT 308.219 225.102 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 225.102 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 225.102 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 213.197 Td /F1 9.8 Tf  [(variants \(4.1 mos versus )] TJ ET
BT 308.219 201.292 Td /F1 9.8 Tf  [(13.9 mos; HR 0.51; 95% CI, )] TJ ET
BT 308.219 189.387 Td /F1 9.8 Tf  [(0.18-0.95; P=0.037\).)] TJ ET
0.267 0.267 0.267 rg
439.922 436.352 147.993 0.750 re f
439.922 175.007 147.993 0.750 re f
439.922 175.007 0.750 262.095 re f
587.165 175.007 0.750 262.095 re f
0.271 0.267 0.267 rg
459.259 429.795 m 
459.259 430.242 459.076 430.686 458.760 431.002 c
458.444 431.318 458.000 431.502 457.553 431.502 c
457.107 431.502 456.663 431.318 456.347 431.002 c
456.031 430.686 455.847 430.242 455.847 429.795 c
455.847 429.349 456.031 428.905 456.347 428.589 c
456.663 428.273 457.107 428.089 457.553 428.089 c
458.000 428.089 458.444 428.273 458.760 428.589 c
459.076 428.905 459.259 429.349 459.259 429.795 c f
BT 464.672 426.828 Td /F1 9.8 Tf  [(By the time of this )] TJ ET
BT 464.672 414.923 Td /F1 9.8 Tf  [(analysis, 93% of pts had )] TJ ET
BT 464.672 403.018 Td /F1 9.8 Tf  [(experienced disease )] TJ ET
BT 464.672 391.113 Td /F1 9.8 Tf  [(progression and 72% had )] TJ ET
BT 464.672 379.209 Td /F1 9.8 Tf  [(died.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(4)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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0.271 0.267 0.267 RG
0.39 w 1 J 1 j
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1.000 1.000 1.000 rg
26.250 67.953 555.000 709.047 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Perrone and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([42])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis at a )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(single Italian center of pts )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(that were refractory to IR and )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 719.482 Td /F1 9.8 Tf  [(IR.)] TJ ET
144.161 706.795 m 
144.161 707.242 143.977 707.686 143.661 708.002 c
143.346 708.317 142.902 708.501 142.455 708.501 c
142.008 708.501 141.564 708.317 141.248 708.002 c
140.933 707.686 140.749 707.242 140.749 706.795 c
140.749 706.348 140.933 705.904 141.248 705.588 c
141.564 705.273 142.008 705.089 142.455 705.089 c
142.902 705.089 143.346 705.273 143.661 705.588 c
143.977 705.904 144.161 706.348 144.161 706.795 c f
BT 149.574 703.827 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 691.923 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 679.236 m 
144.161 679.682 143.977 680.126 143.661 680.442 c
143.346 680.758 142.902 680.942 142.455 680.942 c
142.008 680.942 141.564 680.758 141.248 680.442 c
140.933 680.126 140.749 679.682 140.749 679.236 c
140.749 678.789 140.933 678.345 141.248 678.029 c
141.564 677.713 142.008 677.529 142.455 677.529 c
142.902 677.529 143.346 677.713 143.661 678.029 c
143.977 678.345 144.161 678.789 144.161 679.236 c f
BT 149.574 676.268 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 676.268 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 676.268 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(variants were identified using )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(specific primers with PCR )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(amplification.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were identified in 7 of 29 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(24.1%\) of pts.)] TJ ET
302.806 730.605 m 
302.806 731.051 302.623 731.495 302.307 731.811 c
301.991 732.127 301.547 732.311 301.100 732.311 c
300.653 732.311 300.210 732.127 299.894 731.811 c
299.578 731.495 299.394 731.051 299.394 730.605 c
299.394 730.158 299.578 729.714 299.894 729.398 c
300.210 729.082 300.653 728.898 301.100 728.898 c
301.547 728.898 301.991 729.082 302.307 729.398 c
302.623 729.714 302.806 730.158 302.806 730.605 c f
BT 308.219 727.637 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 727.637 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 715.732 Td /F1 9.8 Tf  [(were found in 2 of 31 \(6.4%\) )] TJ ET
BT 308.219 703.827 Td /F1 9.8 Tf  [(pts of which 1 pt responded )] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(to treatment and the other )] TJ ET
BT 308.219 680.018 Td /F1 9.8 Tf  [(did not.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 595.423 0.750 181.952 re f
587.165 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(treatment with cetuximab )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(was experienced by 10 of )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(32 \(31.2%\) pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 595.423 98.949 0.750 re f
26.625 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
BT 31.875 585.568 Td /F1 9.8 Tf  [(Sartore-Bianchi )] TJ ET
BT 31.875 577.937 Td /F1 9.8 Tf  [(and colleagues )] TJ ET
BT 31.875 570.305 Td /F1 9.8 Tf  [(\(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 62.763 570.305 Td /F1 9.8 Tf  [([40])] TJ ET
124.824 595.423 159.395 0.750 re f
124.824 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
144.161 588.867 m 
144.161 589.313 143.977 589.757 143.661 590.073 c
143.346 590.389 142.902 590.573 142.455 590.573 c
142.008 590.573 141.564 590.389 141.248 590.073 c
140.933 589.757 140.749 589.313 140.749 588.867 c
140.749 588.420 140.933 587.976 141.248 587.660 c
141.564 587.344 142.008 587.160 142.455 587.160 c
142.902 587.160 143.346 587.344 143.661 587.660 c
143.977 587.976 144.161 588.420 144.161 588.867 c f
BT 149.574 585.899 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 573.994 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 562.089 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 550.185 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 537.498 m 
144.161 537.944 143.977 538.388 143.661 538.704 c
143.346 539.020 142.902 539.204 142.455 539.204 c
142.008 539.204 141.564 539.020 141.248 538.704 c
140.933 538.388 140.749 537.944 140.749 537.498 c
140.749 537.051 140.933 536.607 141.248 536.291 c
141.564 535.975 142.008 535.791 142.455 535.791 c
142.902 535.791 143.346 535.975 143.661 536.291 c
143.977 536.607 144.161 537.051 144.161 537.498 c f
BT 149.574 534.530 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 522.625 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 509.938 m 
144.161 510.385 143.977 510.829 143.661 511.145 c
143.346 511.460 142.902 511.644 142.455 511.644 c
142.008 511.644 141.564 511.460 141.248 511.145 c
140.933 510.829 140.749 510.385 140.749 509.938 c
140.749 509.491 140.933 509.047 141.248 508.731 c
141.564 508.416 142.008 508.232 142.455 508.232 c
142.902 508.232 143.346 508.416 143.661 508.731 c
143.977 509.047 144.161 509.491 144.161 509.938 c f
BT 149.574 506.970 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 495.066 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 483.161 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 471.256 Td /F1 9.8 Tf  [(ABI PRISM 3730 \(Applied )] TJ ET
BT 149.574 459.351 Td /F1 9.8 Tf  [(Biosystems, Foster City, CA\) )] TJ ET
BT 149.574 447.447 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 447.447 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 435.542 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 435.542 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 435.542 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 423.637 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 595.423 157.203 0.750 re f
283.469 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
302.806 588.867 m 
302.806 589.313 302.623 589.757 302.307 590.073 c
301.991 590.389 301.547 590.573 301.100 590.573 c
300.653 590.573 300.210 590.389 299.894 590.073 c
299.578 589.757 299.394 589.313 299.394 588.867 c
299.394 588.420 299.578 587.976 299.894 587.660 c
300.210 587.344 300.653 587.160 301.100 587.160 c
301.547 587.160 301.991 587.344 302.307 587.660 c
302.623 587.976 302.806 588.420 302.806 588.867 c f
BT 308.219 585.899 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 585.899 Td /F1 9.8 Tf  [( and )] TJ ET
BT 356.452 585.899 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 382.455 585.899 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 573.994 Td /F1 9.8 Tf  [(variants were identified in 35 )] TJ ET
BT 308.219 562.089 Td /F1 9.8 Tf  [(of 132 \(26.5%\) and 11 of )] TJ ET
BT 308.219 550.185 Td /F1 9.8 Tf  [(132 \(8.3%\) of pts )] TJ ET
BT 308.219 538.280 Td /F1 9.8 Tf  [(respectively. No pts had )] TJ ET
BT 308.219 526.375 Td /F1 9.8 Tf  [(both )] TJ ET
BT 329.903 526.375 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 356.452 526.375 Td /F1 9.8 Tf  [( and )] TJ ET
BT 378.136 526.375 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 514.470 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 501.783 m 
302.806 502.230 302.623 502.674 302.307 502.990 c
301.991 503.306 301.547 503.489 301.100 503.489 c
300.653 503.489 300.210 503.306 299.894 502.990 c
299.578 502.674 299.394 502.230 299.394 501.783 c
299.394 501.337 299.578 500.893 299.894 500.577 c
300.210 500.261 300.653 500.077 301.100 500.077 c
301.547 500.077 301.991 500.261 302.307 500.577 c
302.623 500.893 302.806 501.337 302.806 501.783 c f
BT 308.219 498.816 Td /F1 9.8 Tf  [(The relationship between )] TJ ET
BT 308.219 486.911 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 486.911 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 475.006 Td /F1 9.8 Tf  [(and response to treatment in )] TJ ET
BT 308.219 463.101 Td /F1 9.8 Tf  [(pts without )] TJ ET
BT 357.534 463.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 384.084 463.101 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 451.197 Td /F1 9.8 Tf  [(variants was not significant )] TJ ET
BT 308.219 439.292 Td /F1 9.8 Tf  [(\(OR, 0.24; 95% CI, 0.00-)] TJ ET
BT 308.219 427.387 Td /F1 9.8 Tf  [(3.09; P=0.265\).)] TJ ET
302.806 414.700 m 
302.806 415.147 302.623 415.591 302.307 415.907 c
301.991 416.222 301.547 416.406 301.100 416.406 c
300.653 416.406 300.210 416.222 299.894 415.907 c
299.578 415.591 299.394 415.147 299.394 414.700 c
299.394 414.253 299.578 413.809 299.894 413.493 c
300.210 413.178 300.653 412.994 301.100 412.994 c
301.547 412.994 301.991 413.178 302.307 413.493 c
302.623 413.809 302.806 414.253 302.806 414.700 c f
BT 308.219 411.732 Td /F1 9.8 Tf  [(PFS was not significantly )] TJ ET
BT 308.219 399.828 Td /F1 9.8 Tf  [(different between those with )] TJ ET
BT 308.219 387.923 Td /F1 9.8 Tf  [(and without )] TJ ET
BT 360.791 387.923 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 386.794 387.923 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 376.018 Td /F1 9.8 Tf  [(variants \(P=0.22\), however, )] TJ ET
BT 308.219 364.113 Td /F1 9.8 Tf  [(OS was longer in pts without )] TJ ET
BT 308.219 352.209 Td /F1 9.8 Tf  [(than with )] TJ ET
BT 349.949 352.209 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 375.952 352.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 340.304 Td /F1 9.8 Tf  [(variants \(HR 3.75; 95% CI, )] TJ ET
BT 308.219 328.399 Td /F1 9.8 Tf  [(1.29-10.90; P=0.015\).)] TJ ET
0.267 0.267 0.267 rg
439.922 595.423 147.993 0.750 re f
439.922 314.018 0.750 282.155 re f
587.165 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
459.259 588.867 m 
459.259 589.313 459.076 589.757 458.760 590.073 c
458.444 590.389 458.000 590.573 457.553 590.573 c
457.107 590.573 456.663 590.389 456.347 590.073 c
456.031 589.757 455.847 589.313 455.847 588.867 c
455.847 588.420 456.031 587.976 456.347 587.660 c
456.663 587.344 457.107 587.160 457.553 587.160 c
458.000 587.160 458.444 587.344 458.760 587.660 c
459.076 587.976 459.259 588.420 459.259 588.867 c f
BT 464.672 585.899 Td /F1 9.8 Tf  [(109 pts received )] TJ ET
BT 464.672 573.994 Td /F1 9.8 Tf  [(cetuximab, with 23 pts )] TJ ET
BT 464.672 562.089 Td /F1 9.8 Tf  [(receiving panitumumab.)] TJ ET
459.259 549.402 m 
459.259 549.849 459.076 550.293 458.760 550.609 c
458.444 550.925 458.000 551.109 457.553 551.109 c
457.107 551.109 456.663 550.925 456.347 550.609 c
456.031 550.293 455.847 549.849 455.847 549.402 c
455.847 548.956 456.031 548.512 456.347 548.196 c
456.663 547.880 457.107 547.696 457.553 547.696 c
458.000 547.696 458.444 547.880 458.760 548.196 c
459.076 548.512 459.259 548.956 459.259 549.402 c f
BT 464.672 546.435 Td /F1 9.8 Tf  [(This report came from the )] TJ ET
BT 464.672 534.530 Td /F1 9.8 Tf  [(same research group as )] TJ ET
BT 464.672 522.625 Td /F1 9.8 Tf  [(the report by Di )] TJ ET
BT 464.672 510.720 Td /F1 9.8 Tf  [(Nicolantonio and )] TJ ET
BT 464.672 498.816 Td /F1 9.8 Tf  [(colleagues )] TJ ET
0.267 0.267 0.267 rg
BT 513.987 498.816 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 530.250 498.816 Td /F1 9.8 Tf  [( and may )] TJ ET
BT 464.672 486.911 Td /F1 9.8 Tf  [(have included some of the )] TJ ET
BT 464.672 475.006 Td /F1 9.8 Tf  [(same pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 314.018 98.949 0.750 re f
26.625 68.328 98.949 0.750 re f
26.625 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
BT 31.875 304.163 Td /F1 9.8 Tf  [(Souglakos and )] TJ ET
BT 31.875 296.532 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 288.901 Td /F1 9.8 Tf  [([19])] TJ ET
124.824 314.018 159.395 0.750 re f
124.824 68.328 159.395 0.750 re f
124.824 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
144.161 307.462 m 
144.161 307.909 143.977 308.353 143.661 308.669 c
143.346 308.984 142.902 309.168 142.455 309.168 c
142.008 309.168 141.564 308.984 141.248 308.669 c
140.933 308.353 140.749 307.909 140.749 307.462 c
140.749 307.015 140.933 306.571 141.248 306.255 c
141.564 305.940 142.008 305.756 142.455 305.756 c
142.902 305.756 143.346 305.940 143.661 306.255 c
143.977 306.571 144.161 307.015 144.161 307.462 c f
BT 149.574 304.494 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 292.590 Td /F1 9.8 Tf  [(treated at 2 cancer centers in )] TJ ET
BT 149.574 280.685 Td /F1 9.8 Tf  [(the United States and )] TJ ET
BT 149.574 268.780 Td /F1 9.8 Tf  [(Greece; 100 pts received a )] TJ ET
BT 149.574 256.875 Td /F1 9.8 Tf  [(variety of chemotherapy )] TJ ET
BT 149.574 244.971 Td /F1 9.8 Tf  [(regimen that included )] TJ ET
BT 149.574 233.066 Td /F1 9.8 Tf  [(cetuximab.)] TJ ET
144.161 220.379 m 
144.161 220.825 143.977 221.269 143.661 221.585 c
143.346 221.901 142.902 222.085 142.455 222.085 c
142.008 222.085 141.564 221.901 141.248 221.585 c
140.933 221.269 140.749 220.825 140.749 220.379 c
140.749 219.932 140.933 219.488 141.248 219.172 c
141.564 218.856 142.008 218.672 142.455 218.672 c
142.902 218.672 143.346 218.856 143.661 219.172 c
143.977 219.488 144.161 219.932 144.161 220.379 c f
BT 149.574 217.411 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 205.506 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 192.819 m 
144.161 193.266 143.977 193.710 143.661 194.026 c
143.346 194.342 142.902 194.526 142.455 194.526 c
142.008 194.526 141.564 194.342 141.248 194.026 c
140.933 193.710 140.749 193.266 140.749 192.819 c
140.749 192.373 140.933 191.929 141.248 191.613 c
141.564 191.297 142.008 191.113 142.455 191.113 c
142.902 191.113 143.346 191.297 143.661 191.613 c
143.977 191.929 144.161 192.373 144.161 192.819 c f
BT 149.574 189.852 Td /F1 9.8 Tf  [(Sequence variants in )] TJ ET
BT 243.330 189.852 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 177.947 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 177.947 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 177.947 Td /F1 9.8 Tf  [( were identified )] TJ ET
BT 149.574 166.042 Td /F1 9.8 Tf  [(using PCR followed by mass-)] TJ ET
BT 149.574 154.137 Td /F1 9.8 Tf  [(spectrometric genotyping or )] TJ ET
BT 149.574 142.233 Td /F1 9.8 Tf  [(Sanger sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 314.018 157.203 0.750 re f
283.469 68.328 157.203 0.750 re f
283.469 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
302.806 307.462 m 
302.806 307.909 302.623 308.353 302.307 308.669 c
301.991 308.984 301.547 309.168 301.100 309.168 c
300.653 309.168 300.210 308.984 299.894 308.669 c
299.578 308.353 299.394 307.909 299.394 307.462 c
299.394 307.015 299.578 306.571 299.894 306.255 c
300.210 305.940 300.653 305.756 301.100 305.756 c
301.547 305.756 301.991 305.940 302.307 306.255 c
302.623 306.571 302.806 307.015 302.806 307.462 c f
BT 308.219 304.494 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 304.494 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 292.590 Td /F1 9.8 Tf  [(were found in 32 of 92 )] TJ ET
BT 308.219 280.685 Td /F1 9.8 Tf  [(\(34.8%\) of pts.)] TJ ET
302.806 267.998 m 
302.806 268.444 302.623 268.888 302.307 269.204 c
301.991 269.520 301.547 269.704 301.100 269.704 c
300.653 269.704 300.210 269.520 299.894 269.204 c
299.578 268.888 299.394 268.444 299.394 267.998 c
299.394 267.551 299.578 267.107 299.894 266.791 c
300.210 266.475 300.653 266.291 301.100 266.291 c
301.547 266.291 301.991 266.475 302.307 266.791 c
302.623 267.107 302.806 267.551 302.806 267.998 c f
BT 308.219 265.030 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 265.030 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 253.125 Td /F1 9.8 Tf  [(were identified in 9 of 92 )] TJ ET
BT 308.219 241.221 Td /F1 9.8 Tf  [(\(9.8%\) of pts. No pts that )] TJ ET
BT 308.219 229.316 Td /F1 9.8 Tf  [(had )] TJ ET
BT 327.192 229.316 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.196 229.316 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 217.411 Td /F1 9.8 Tf  [(variants responded to )] TJ ET
BT 308.219 205.506 Td /F1 9.8 Tf  [(treatment compared to 14 of )] TJ ET
BT 308.219 193.602 Td /F1 9.8 Tf  [(83 \(16.9%\) without )] TJ ET
BT 392.215 193.602 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 181.697 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 169.010 m 
302.806 169.456 302.623 169.900 302.307 170.216 c
301.991 170.532 301.547 170.716 301.100 170.716 c
300.653 170.716 300.210 170.532 299.894 170.216 c
299.578 169.900 299.394 169.456 299.394 169.010 c
299.394 168.563 299.578 168.119 299.894 167.803 c
300.210 167.487 300.653 167.304 301.100 167.304 c
301.547 167.304 301.991 167.487 302.307 167.803 c
302.623 168.119 302.806 168.563 302.806 169.010 c f
BT 308.219 166.042 Td /F1 9.8 Tf  [(PFS was significantly )] TJ ET
BT 308.219 154.137 Td /F1 9.8 Tf  [(shorter in those with than )] TJ ET
BT 308.219 142.233 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 142.233 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 142.233 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 130.328 Td /F1 9.8 Tf  [(variants that were treated )] TJ ET
BT 308.219 118.423 Td /F1 9.8 Tf  [(with first-line cetuximab )] TJ ET
BT 308.219 106.518 Td /F1 9.8 Tf  [(regimens \(2.0 mos versus )] TJ ET
BT 308.219 94.614 Td /F1 9.8 Tf  [(3.9 mos; HR 3.6; 95% CI )] TJ ET
BT 308.219 82.709 Td /F1 9.8 Tf  [(1.8-7.4\).)] TJ ET
0.267 0.267 0.267 rg
439.922 314.018 147.993 0.750 re f
439.922 68.328 147.993 0.750 re f
439.922 68.328 0.750 246.440 re f
587.165 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
459.259 307.462 m 
459.259 307.909 459.076 308.353 458.760 308.669 c
458.444 308.984 458.000 309.168 457.553 309.168 c
457.107 309.168 456.663 308.984 456.347 308.669 c
456.031 308.353 455.847 307.909 455.847 307.462 c
455.847 307.015 456.031 306.571 456.347 306.255 c
456.663 305.940 457.107 305.756 457.553 305.756 c
458.000 305.756 458.444 305.940 458.760 306.255 c
459.076 306.571 459.259 307.015 459.259 307.462 c f
BT 464.672 304.494 Td /F1 9.8 Tf  [(Of the 100 pts that )] TJ ET
BT 464.672 292.590 Td /F1 9.8 Tf  [(received cetuximab, it was )] TJ ET
BT 464.672 280.685 Td /F1 9.8 Tf  [(as first-line \(n=8\), second-)] TJ ET
BT 464.672 268.780 Td /F1 9.8 Tf  [(line \(n=37\) or third-line or )] TJ ET
BT 464.672 256.875 Td /F1 9.8 Tf  [(higher therapy \(n=55\).)] TJ ET
Q
q
15.000 67.953 577.500 709.047 re W n
1.000 1.000 1.000 rg
26.250 67.953 555.000 709.047 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Perrone and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([42])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis at a )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(single Italian center of pts )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(that were refractory to IR and )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 719.482 Td /F1 9.8 Tf  [(IR.)] TJ ET
144.161 706.795 m 
144.161 707.242 143.977 707.686 143.661 708.002 c
143.346 708.317 142.902 708.501 142.455 708.501 c
142.008 708.501 141.564 708.317 141.248 708.002 c
140.933 707.686 140.749 707.242 140.749 706.795 c
140.749 706.348 140.933 705.904 141.248 705.588 c
141.564 705.273 142.008 705.089 142.455 705.089 c
142.902 705.089 143.346 705.273 143.661 705.588 c
143.977 705.904 144.161 706.348 144.161 706.795 c f
BT 149.574 703.827 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 691.923 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 679.236 m 
144.161 679.682 143.977 680.126 143.661 680.442 c
143.346 680.758 142.902 680.942 142.455 680.942 c
142.008 680.942 141.564 680.758 141.248 680.442 c
140.933 680.126 140.749 679.682 140.749 679.236 c
140.749 678.789 140.933 678.345 141.248 678.029 c
141.564 677.713 142.008 677.529 142.455 677.529 c
142.902 677.529 143.346 677.713 143.661 678.029 c
143.977 678.345 144.161 678.789 144.161 679.236 c f
BT 149.574 676.268 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 676.268 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 676.268 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(variants were identified using )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(specific primers with PCR )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(amplification.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were identified in 7 of 29 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(24.1%\) of pts.)] TJ ET
302.806 730.605 m 
302.806 731.051 302.623 731.495 302.307 731.811 c
301.991 732.127 301.547 732.311 301.100 732.311 c
300.653 732.311 300.210 732.127 299.894 731.811 c
299.578 731.495 299.394 731.051 299.394 730.605 c
299.394 730.158 299.578 729.714 299.894 729.398 c
300.210 729.082 300.653 728.898 301.100 728.898 c
301.547 728.898 301.991 729.082 302.307 729.398 c
302.623 729.714 302.806 730.158 302.806 730.605 c f
BT 308.219 727.637 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 727.637 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 715.732 Td /F1 9.8 Tf  [(were found in 2 of 31 \(6.4%\) )] TJ ET
BT 308.219 703.827 Td /F1 9.8 Tf  [(pts of which 1 pt responded )] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(to treatment and the other )] TJ ET
BT 308.219 680.018 Td /F1 9.8 Tf  [(did not.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 595.423 0.750 181.952 re f
587.165 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(treatment with cetuximab )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(was experienced by 10 of )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(32 \(31.2%\) pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 595.423 98.949 0.750 re f
26.625 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
BT 31.875 585.568 Td /F1 9.8 Tf  [(Sartore-Bianchi )] TJ ET
BT 31.875 577.937 Td /F1 9.8 Tf  [(and colleagues )] TJ ET
BT 31.875 570.305 Td /F1 9.8 Tf  [(\(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 62.763 570.305 Td /F1 9.8 Tf  [([40])] TJ ET
124.824 595.423 159.395 0.750 re f
124.824 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
144.161 588.867 m 
144.161 589.313 143.977 589.757 143.661 590.073 c
143.346 590.389 142.902 590.573 142.455 590.573 c
142.008 590.573 141.564 590.389 141.248 590.073 c
140.933 589.757 140.749 589.313 140.749 588.867 c
140.749 588.420 140.933 587.976 141.248 587.660 c
141.564 587.344 142.008 587.160 142.455 587.160 c
142.902 587.160 143.346 587.344 143.661 587.660 c
143.977 587.976 144.161 588.420 144.161 588.867 c f
BT 149.574 585.899 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 573.994 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 562.089 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 550.185 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 537.498 m 
144.161 537.944 143.977 538.388 143.661 538.704 c
143.346 539.020 142.902 539.204 142.455 539.204 c
142.008 539.204 141.564 539.020 141.248 538.704 c
140.933 538.388 140.749 537.944 140.749 537.498 c
140.749 537.051 140.933 536.607 141.248 536.291 c
141.564 535.975 142.008 535.791 142.455 535.791 c
142.902 535.791 143.346 535.975 143.661 536.291 c
143.977 536.607 144.161 537.051 144.161 537.498 c f
BT 149.574 534.530 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 522.625 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 509.938 m 
144.161 510.385 143.977 510.829 143.661 511.145 c
143.346 511.460 142.902 511.644 142.455 511.644 c
142.008 511.644 141.564 511.460 141.248 511.145 c
140.933 510.829 140.749 510.385 140.749 509.938 c
140.749 509.491 140.933 509.047 141.248 508.731 c
141.564 508.416 142.008 508.232 142.455 508.232 c
142.902 508.232 143.346 508.416 143.661 508.731 c
143.977 509.047 144.161 509.491 144.161 509.938 c f
BT 149.574 506.970 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 495.066 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 483.161 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 471.256 Td /F1 9.8 Tf  [(ABI PRISM 3730 \(Applied )] TJ ET
BT 149.574 459.351 Td /F1 9.8 Tf  [(Biosystems, Foster City, CA\) )] TJ ET
BT 149.574 447.447 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 447.447 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 435.542 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 435.542 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 435.542 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 423.637 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 595.423 157.203 0.750 re f
283.469 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
302.806 588.867 m 
302.806 589.313 302.623 589.757 302.307 590.073 c
301.991 590.389 301.547 590.573 301.100 590.573 c
300.653 590.573 300.210 590.389 299.894 590.073 c
299.578 589.757 299.394 589.313 299.394 588.867 c
299.394 588.420 299.578 587.976 299.894 587.660 c
300.210 587.344 300.653 587.160 301.100 587.160 c
301.547 587.160 301.991 587.344 302.307 587.660 c
302.623 587.976 302.806 588.420 302.806 588.867 c f
BT 308.219 585.899 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 585.899 Td /F1 9.8 Tf  [( and )] TJ ET
BT 356.452 585.899 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 382.455 585.899 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 573.994 Td /F1 9.8 Tf  [(variants were identified in 35 )] TJ ET
BT 308.219 562.089 Td /F1 9.8 Tf  [(of 132 \(26.5%\) and 11 of )] TJ ET
BT 308.219 550.185 Td /F1 9.8 Tf  [(132 \(8.3%\) of pts )] TJ ET
BT 308.219 538.280 Td /F1 9.8 Tf  [(respectively. No pts had )] TJ ET
BT 308.219 526.375 Td /F1 9.8 Tf  [(both )] TJ ET
BT 329.903 526.375 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 356.452 526.375 Td /F1 9.8 Tf  [( and )] TJ ET
BT 378.136 526.375 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 514.470 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 501.783 m 
302.806 502.230 302.623 502.674 302.307 502.990 c
301.991 503.306 301.547 503.489 301.100 503.489 c
300.653 503.489 300.210 503.306 299.894 502.990 c
299.578 502.674 299.394 502.230 299.394 501.783 c
299.394 501.337 299.578 500.893 299.894 500.577 c
300.210 500.261 300.653 500.077 301.100 500.077 c
301.547 500.077 301.991 500.261 302.307 500.577 c
302.623 500.893 302.806 501.337 302.806 501.783 c f
BT 308.219 498.816 Td /F1 9.8 Tf  [(The relationship between )] TJ ET
BT 308.219 486.911 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 486.911 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 475.006 Td /F1 9.8 Tf  [(and response to treatment in )] TJ ET
BT 308.219 463.101 Td /F1 9.8 Tf  [(pts without )] TJ ET
BT 357.534 463.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 384.084 463.101 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 451.197 Td /F1 9.8 Tf  [(variants was not significant )] TJ ET
BT 308.219 439.292 Td /F1 9.8 Tf  [(\(OR, 0.24; 95% CI, 0.00-)] TJ ET
BT 308.219 427.387 Td /F1 9.8 Tf  [(3.09; P=0.265\).)] TJ ET
302.806 414.700 m 
302.806 415.147 302.623 415.591 302.307 415.907 c
301.991 416.222 301.547 416.406 301.100 416.406 c
300.653 416.406 300.210 416.222 299.894 415.907 c
299.578 415.591 299.394 415.147 299.394 414.700 c
299.394 414.253 299.578 413.809 299.894 413.493 c
300.210 413.178 300.653 412.994 301.100 412.994 c
301.547 412.994 301.991 413.178 302.307 413.493 c
302.623 413.809 302.806 414.253 302.806 414.700 c f
BT 308.219 411.732 Td /F1 9.8 Tf  [(PFS was not significantly )] TJ ET
BT 308.219 399.828 Td /F1 9.8 Tf  [(different between those with )] TJ ET
BT 308.219 387.923 Td /F1 9.8 Tf  [(and without )] TJ ET
BT 360.791 387.923 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 386.794 387.923 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 376.018 Td /F1 9.8 Tf  [(variants \(P=0.22\), however, )] TJ ET
BT 308.219 364.113 Td /F1 9.8 Tf  [(OS was longer in pts without )] TJ ET
BT 308.219 352.209 Td /F1 9.8 Tf  [(than with )] TJ ET
BT 349.949 352.209 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 375.952 352.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 340.304 Td /F1 9.8 Tf  [(variants \(HR 3.75; 95% CI, )] TJ ET
BT 308.219 328.399 Td /F1 9.8 Tf  [(1.29-10.90; P=0.015\).)] TJ ET
0.267 0.267 0.267 rg
439.922 595.423 147.993 0.750 re f
439.922 314.018 0.750 282.155 re f
587.165 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
459.259 588.867 m 
459.259 589.313 459.076 589.757 458.760 590.073 c
458.444 590.389 458.000 590.573 457.553 590.573 c
457.107 590.573 456.663 590.389 456.347 590.073 c
456.031 589.757 455.847 589.313 455.847 588.867 c
455.847 588.420 456.031 587.976 456.347 587.660 c
456.663 587.344 457.107 587.160 457.553 587.160 c
458.000 587.160 458.444 587.344 458.760 587.660 c
459.076 587.976 459.259 588.420 459.259 588.867 c f
BT 464.672 585.899 Td /F1 9.8 Tf  [(109 pts received )] TJ ET
BT 464.672 573.994 Td /F1 9.8 Tf  [(cetuximab, with 23 pts )] TJ ET
BT 464.672 562.089 Td /F1 9.8 Tf  [(receiving panitumumab.)] TJ ET
459.259 549.402 m 
459.259 549.849 459.076 550.293 458.760 550.609 c
458.444 550.925 458.000 551.109 457.553 551.109 c
457.107 551.109 456.663 550.925 456.347 550.609 c
456.031 550.293 455.847 549.849 455.847 549.402 c
455.847 548.956 456.031 548.512 456.347 548.196 c
456.663 547.880 457.107 547.696 457.553 547.696 c
458.000 547.696 458.444 547.880 458.760 548.196 c
459.076 548.512 459.259 548.956 459.259 549.402 c f
BT 464.672 546.435 Td /F1 9.8 Tf  [(This report came from the )] TJ ET
BT 464.672 534.530 Td /F1 9.8 Tf  [(same research group as )] TJ ET
BT 464.672 522.625 Td /F1 9.8 Tf  [(the report by Di )] TJ ET
BT 464.672 510.720 Td /F1 9.8 Tf  [(Nicolantonio and )] TJ ET
BT 464.672 498.816 Td /F1 9.8 Tf  [(colleagues )] TJ ET
0.267 0.267 0.267 rg
BT 513.987 498.816 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 530.250 498.816 Td /F1 9.8 Tf  [( and may )] TJ ET
BT 464.672 486.911 Td /F1 9.8 Tf  [(have included some of the )] TJ ET
BT 464.672 475.006 Td /F1 9.8 Tf  [(same pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 314.018 98.949 0.750 re f
26.625 68.328 98.949 0.750 re f
26.625 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
BT 31.875 304.163 Td /F1 9.8 Tf  [(Souglakos and )] TJ ET
BT 31.875 296.532 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 288.901 Td /F1 9.8 Tf  [([19])] TJ ET
124.824 314.018 159.395 0.750 re f
124.824 68.328 159.395 0.750 re f
124.824 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
144.161 307.462 m 
144.161 307.909 143.977 308.353 143.661 308.669 c
143.346 308.984 142.902 309.168 142.455 309.168 c
142.008 309.168 141.564 308.984 141.248 308.669 c
140.933 308.353 140.749 307.909 140.749 307.462 c
140.749 307.015 140.933 306.571 141.248 306.255 c
141.564 305.940 142.008 305.756 142.455 305.756 c
142.902 305.756 143.346 305.940 143.661 306.255 c
143.977 306.571 144.161 307.015 144.161 307.462 c f
BT 149.574 304.494 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 292.590 Td /F1 9.8 Tf  [(treated at 2 cancer centers in )] TJ ET
BT 149.574 280.685 Td /F1 9.8 Tf  [(the United States and )] TJ ET
BT 149.574 268.780 Td /F1 9.8 Tf  [(Greece; 100 pts received a )] TJ ET
BT 149.574 256.875 Td /F1 9.8 Tf  [(variety of chemotherapy )] TJ ET
BT 149.574 244.971 Td /F1 9.8 Tf  [(regimen that included )] TJ ET
BT 149.574 233.066 Td /F1 9.8 Tf  [(cetuximab.)] TJ ET
144.161 220.379 m 
144.161 220.825 143.977 221.269 143.661 221.585 c
143.346 221.901 142.902 222.085 142.455 222.085 c
142.008 222.085 141.564 221.901 141.248 221.585 c
140.933 221.269 140.749 220.825 140.749 220.379 c
140.749 219.932 140.933 219.488 141.248 219.172 c
141.564 218.856 142.008 218.672 142.455 218.672 c
142.902 218.672 143.346 218.856 143.661 219.172 c
143.977 219.488 144.161 219.932 144.161 220.379 c f
BT 149.574 217.411 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 205.506 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 192.819 m 
144.161 193.266 143.977 193.710 143.661 194.026 c
143.346 194.342 142.902 194.526 142.455 194.526 c
142.008 194.526 141.564 194.342 141.248 194.026 c
140.933 193.710 140.749 193.266 140.749 192.819 c
140.749 192.373 140.933 191.929 141.248 191.613 c
141.564 191.297 142.008 191.113 142.455 191.113 c
142.902 191.113 143.346 191.297 143.661 191.613 c
143.977 191.929 144.161 192.373 144.161 192.819 c f
BT 149.574 189.852 Td /F1 9.8 Tf  [(Sequence variants in )] TJ ET
BT 243.330 189.852 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 177.947 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 177.947 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 177.947 Td /F1 9.8 Tf  [( were identified )] TJ ET
BT 149.574 166.042 Td /F1 9.8 Tf  [(using PCR followed by mass-)] TJ ET
BT 149.574 154.137 Td /F1 9.8 Tf  [(spectrometric genotyping or )] TJ ET
BT 149.574 142.233 Td /F1 9.8 Tf  [(Sanger sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 314.018 157.203 0.750 re f
283.469 68.328 157.203 0.750 re f
283.469 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
302.806 307.462 m 
302.806 307.909 302.623 308.353 302.307 308.669 c
301.991 308.984 301.547 309.168 301.100 309.168 c
300.653 309.168 300.210 308.984 299.894 308.669 c
299.578 308.353 299.394 307.909 299.394 307.462 c
299.394 307.015 299.578 306.571 299.894 306.255 c
300.210 305.940 300.653 305.756 301.100 305.756 c
301.547 305.756 301.991 305.940 302.307 306.255 c
302.623 306.571 302.806 307.015 302.806 307.462 c f
BT 308.219 304.494 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 304.494 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 292.590 Td /F1 9.8 Tf  [(were found in 32 of 92 )] TJ ET
BT 308.219 280.685 Td /F1 9.8 Tf  [(\(34.8%\) of pts.)] TJ ET
302.806 267.998 m 
302.806 268.444 302.623 268.888 302.307 269.204 c
301.991 269.520 301.547 269.704 301.100 269.704 c
300.653 269.704 300.210 269.520 299.894 269.204 c
299.578 268.888 299.394 268.444 299.394 267.998 c
299.394 267.551 299.578 267.107 299.894 266.791 c
300.210 266.475 300.653 266.291 301.100 266.291 c
301.547 266.291 301.991 266.475 302.307 266.791 c
302.623 267.107 302.806 267.551 302.806 267.998 c f
BT 308.219 265.030 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 265.030 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 253.125 Td /F1 9.8 Tf  [(were identified in 9 of 92 )] TJ ET
BT 308.219 241.221 Td /F1 9.8 Tf  [(\(9.8%\) of pts. No pts that )] TJ ET
BT 308.219 229.316 Td /F1 9.8 Tf  [(had )] TJ ET
BT 327.192 229.316 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.196 229.316 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 217.411 Td /F1 9.8 Tf  [(variants responded to )] TJ ET
BT 308.219 205.506 Td /F1 9.8 Tf  [(treatment compared to 14 of )] TJ ET
BT 308.219 193.602 Td /F1 9.8 Tf  [(83 \(16.9%\) without )] TJ ET
BT 392.215 193.602 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 181.697 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 169.010 m 
302.806 169.456 302.623 169.900 302.307 170.216 c
301.991 170.532 301.547 170.716 301.100 170.716 c
300.653 170.716 300.210 170.532 299.894 170.216 c
299.578 169.900 299.394 169.456 299.394 169.010 c
299.394 168.563 299.578 168.119 299.894 167.803 c
300.210 167.487 300.653 167.304 301.100 167.304 c
301.547 167.304 301.991 167.487 302.307 167.803 c
302.623 168.119 302.806 168.563 302.806 169.010 c f
BT 308.219 166.042 Td /F1 9.8 Tf  [(PFS was significantly )] TJ ET
BT 308.219 154.137 Td /F1 9.8 Tf  [(shorter in those with than )] TJ ET
BT 308.219 142.233 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 142.233 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 142.233 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 130.328 Td /F1 9.8 Tf  [(variants that were treated )] TJ ET
BT 308.219 118.423 Td /F1 9.8 Tf  [(with first-line cetuximab )] TJ ET
BT 308.219 106.518 Td /F1 9.8 Tf  [(regimens \(2.0 mos versus )] TJ ET
BT 308.219 94.614 Td /F1 9.8 Tf  [(3.9 mos; HR 3.6; 95% CI )] TJ ET
BT 308.219 82.709 Td /F1 9.8 Tf  [(1.8-7.4\).)] TJ ET
0.267 0.267 0.267 rg
439.922 314.018 147.993 0.750 re f
439.922 68.328 147.993 0.750 re f
439.922 68.328 0.750 246.440 re f
587.165 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
459.259 307.462 m 
459.259 307.909 459.076 308.353 458.760 308.669 c
458.444 308.984 458.000 309.168 457.553 309.168 c
457.107 309.168 456.663 308.984 456.347 308.669 c
456.031 308.353 455.847 307.909 455.847 307.462 c
455.847 307.015 456.031 306.571 456.347 306.255 c
456.663 305.940 457.107 305.756 457.553 305.756 c
458.000 305.756 458.444 305.940 458.760 306.255 c
459.076 306.571 459.259 307.015 459.259 307.462 c f
BT 464.672 304.494 Td /F1 9.8 Tf  [(Of the 100 pts that )] TJ ET
BT 464.672 292.590 Td /F1 9.8 Tf  [(received cetuximab, it was )] TJ ET
BT 464.672 280.685 Td /F1 9.8 Tf  [(as first-line \(n=8\), second-)] TJ ET
BT 464.672 268.780 Td /F1 9.8 Tf  [(line \(n=37\) or third-line or )] TJ ET
BT 464.672 256.875 Td /F1 9.8 Tf  [(higher therapy \(n=55\).)] TJ ET
Q
q
15.000 67.953 577.500 709.047 re W n
1.000 1.000 1.000 rg
26.250 67.953 555.000 709.047 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Perrone and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([42])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis at a )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(single Italian center of pts )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(that were refractory to IR and )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(treated with cetuximab plus )] TJ ET
BT 149.574 719.482 Td /F1 9.8 Tf  [(IR.)] TJ ET
144.161 706.795 m 
144.161 707.242 143.977 707.686 143.661 708.002 c
143.346 708.317 142.902 708.501 142.455 708.501 c
142.008 708.501 141.564 708.317 141.248 708.002 c
140.933 707.686 140.749 707.242 140.749 706.795 c
140.749 706.348 140.933 705.904 141.248 705.588 c
141.564 705.273 142.008 705.089 142.455 705.089 c
142.902 705.089 143.346 705.273 143.661 705.588 c
143.977 705.904 144.161 706.348 144.161 706.795 c f
BT 149.574 703.827 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 691.923 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 679.236 m 
144.161 679.682 143.977 680.126 143.661 680.442 c
143.346 680.758 142.902 680.942 142.455 680.942 c
142.008 680.942 141.564 680.758 141.248 680.442 c
140.933 680.126 140.749 679.682 140.749 679.236 c
140.749 678.789 140.933 678.345 141.248 678.029 c
141.564 677.713 142.008 677.529 142.455 677.529 c
142.902 677.529 143.346 677.713 143.661 678.029 c
143.977 678.345 144.161 678.789 144.161 679.236 c f
BT 149.574 676.268 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 676.268 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 676.268 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 676.268 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(variants were identified using )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(specific primers with PCR )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(amplification.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were identified in 7 of 29 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(24.1%\) of pts.)] TJ ET
302.806 730.605 m 
302.806 731.051 302.623 731.495 302.307 731.811 c
301.991 732.127 301.547 732.311 301.100 732.311 c
300.653 732.311 300.210 732.127 299.894 731.811 c
299.578 731.495 299.394 731.051 299.394 730.605 c
299.394 730.158 299.578 729.714 299.894 729.398 c
300.210 729.082 300.653 728.898 301.100 728.898 c
301.547 728.898 301.991 729.082 302.307 729.398 c
302.623 729.714 302.806 730.158 302.806 730.605 c f
BT 308.219 727.637 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 727.637 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 715.732 Td /F1 9.8 Tf  [(were found in 2 of 31 \(6.4%\) )] TJ ET
BT 308.219 703.827 Td /F1 9.8 Tf  [(pts of which 1 pt responded )] TJ ET
BT 308.219 691.923 Td /F1 9.8 Tf  [(to treatment and the other )] TJ ET
BT 308.219 680.018 Td /F1 9.8 Tf  [(did not.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 595.423 0.750 181.952 re f
587.165 595.423 0.750 181.952 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(treatment with cetuximab )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(was experienced by 10 of )] TJ ET
BT 464.672 731.387 Td /F1 9.8 Tf  [(32 \(31.2%\) pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 595.423 98.949 0.750 re f
26.625 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
BT 31.875 585.568 Td /F1 9.8 Tf  [(Sartore-Bianchi )] TJ ET
BT 31.875 577.937 Td /F1 9.8 Tf  [(and colleagues )] TJ ET
BT 31.875 570.305 Td /F1 9.8 Tf  [(\(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 62.763 570.305 Td /F1 9.8 Tf  [([40])] TJ ET
124.824 595.423 159.395 0.750 re f
124.824 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
144.161 588.867 m 
144.161 589.313 143.977 589.757 143.661 590.073 c
143.346 590.389 142.902 590.573 142.455 590.573 c
142.008 590.573 141.564 590.389 141.248 590.073 c
140.933 589.757 140.749 589.313 140.749 588.867 c
140.749 588.420 140.933 587.976 141.248 587.660 c
141.564 587.344 142.008 587.160 142.455 587.160 c
142.902 587.160 143.346 587.344 143.661 587.660 c
143.977 587.976 144.161 588.420 144.161 588.867 c f
BT 149.574 585.899 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 573.994 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 562.089 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 550.185 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 537.498 m 
144.161 537.944 143.977 538.388 143.661 538.704 c
143.346 539.020 142.902 539.204 142.455 539.204 c
142.008 539.204 141.564 539.020 141.248 538.704 c
140.933 538.388 140.749 537.944 140.749 537.498 c
140.749 537.051 140.933 536.607 141.248 536.291 c
141.564 535.975 142.008 535.791 142.455 535.791 c
142.902 535.791 143.346 535.975 143.661 536.291 c
143.977 536.607 144.161 537.051 144.161 537.498 c f
BT 149.574 534.530 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 522.625 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 509.938 m 
144.161 510.385 143.977 510.829 143.661 511.145 c
143.346 511.460 142.902 511.644 142.455 511.644 c
142.008 511.644 141.564 511.460 141.248 511.145 c
140.933 510.829 140.749 510.385 140.749 509.938 c
140.749 509.491 140.933 509.047 141.248 508.731 c
141.564 508.416 142.008 508.232 142.455 508.232 c
142.902 508.232 143.346 508.416 143.661 508.731 c
143.977 509.047 144.161 509.491 144.161 509.938 c f
BT 149.574 506.970 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 495.066 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 483.161 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 471.256 Td /F1 9.8 Tf  [(ABI PRISM 3730 \(Applied )] TJ ET
BT 149.574 459.351 Td /F1 9.8 Tf  [(Biosystems, Foster City, CA\) )] TJ ET
BT 149.574 447.447 Td /F1 9.8 Tf  [(was used to identify )] TJ ET
BT 237.909 447.447 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 435.542 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 435.542 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 435.542 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 423.637 Td /F1 9.8 Tf  [(variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 595.423 157.203 0.750 re f
283.469 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
302.806 588.867 m 
302.806 589.313 302.623 589.757 302.307 590.073 c
301.991 590.389 301.547 590.573 301.100 590.573 c
300.653 590.573 300.210 590.389 299.894 590.073 c
299.578 589.757 299.394 589.313 299.394 588.867 c
299.394 588.420 299.578 587.976 299.894 587.660 c
300.210 587.344 300.653 587.160 301.100 587.160 c
301.547 587.160 301.991 587.344 302.307 587.660 c
302.623 587.976 302.806 588.420 302.806 588.867 c f
BT 308.219 585.899 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 585.899 Td /F1 9.8 Tf  [( and )] TJ ET
BT 356.452 585.899 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 382.455 585.899 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 573.994 Td /F1 9.8 Tf  [(variants were identified in 35 )] TJ ET
BT 308.219 562.089 Td /F1 9.8 Tf  [(of 132 \(26.5%\) and 11 of )] TJ ET
BT 308.219 550.185 Td /F1 9.8 Tf  [(132 \(8.3%\) of pts )] TJ ET
BT 308.219 538.280 Td /F1 9.8 Tf  [(respectively. No pts had )] TJ ET
BT 308.219 526.375 Td /F1 9.8 Tf  [(both )] TJ ET
BT 329.903 526.375 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 356.452 526.375 Td /F1 9.8 Tf  [( and )] TJ ET
BT 378.136 526.375 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 514.470 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 501.783 m 
302.806 502.230 302.623 502.674 302.307 502.990 c
301.991 503.306 301.547 503.489 301.100 503.489 c
300.653 503.489 300.210 503.306 299.894 502.990 c
299.578 502.674 299.394 502.230 299.394 501.783 c
299.394 501.337 299.578 500.893 299.894 500.577 c
300.210 500.261 300.653 500.077 301.100 500.077 c
301.547 500.077 301.991 500.261 302.307 500.577 c
302.623 500.893 302.806 501.337 302.806 501.783 c f
BT 308.219 498.816 Td /F1 9.8 Tf  [(The relationship between )] TJ ET
BT 308.219 486.911 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 486.911 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 475.006 Td /F1 9.8 Tf  [(and response to treatment in )] TJ ET
BT 308.219 463.101 Td /F1 9.8 Tf  [(pts without )] TJ ET
BT 357.534 463.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 384.084 463.101 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 451.197 Td /F1 9.8 Tf  [(variants was not significant )] TJ ET
BT 308.219 439.292 Td /F1 9.8 Tf  [(\(OR, 0.24; 95% CI, 0.00-)] TJ ET
BT 308.219 427.387 Td /F1 9.8 Tf  [(3.09; P=0.265\).)] TJ ET
302.806 414.700 m 
302.806 415.147 302.623 415.591 302.307 415.907 c
301.991 416.222 301.547 416.406 301.100 416.406 c
300.653 416.406 300.210 416.222 299.894 415.907 c
299.578 415.591 299.394 415.147 299.394 414.700 c
299.394 414.253 299.578 413.809 299.894 413.493 c
300.210 413.178 300.653 412.994 301.100 412.994 c
301.547 412.994 301.991 413.178 302.307 413.493 c
302.623 413.809 302.806 414.253 302.806 414.700 c f
BT 308.219 411.732 Td /F1 9.8 Tf  [(PFS was not significantly )] TJ ET
BT 308.219 399.828 Td /F1 9.8 Tf  [(different between those with )] TJ ET
BT 308.219 387.923 Td /F1 9.8 Tf  [(and without )] TJ ET
BT 360.791 387.923 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 386.794 387.923 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 376.018 Td /F1 9.8 Tf  [(variants \(P=0.22\), however, )] TJ ET
BT 308.219 364.113 Td /F1 9.8 Tf  [(OS was longer in pts without )] TJ ET
BT 308.219 352.209 Td /F1 9.8 Tf  [(than with )] TJ ET
BT 349.949 352.209 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 375.952 352.209 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 340.304 Td /F1 9.8 Tf  [(variants \(HR 3.75; 95% CI, )] TJ ET
BT 308.219 328.399 Td /F1 9.8 Tf  [(1.29-10.90; P=0.015\).)] TJ ET
0.267 0.267 0.267 rg
439.922 595.423 147.993 0.750 re f
439.922 314.018 0.750 282.155 re f
587.165 314.018 0.750 282.155 re f
0.271 0.267 0.267 rg
459.259 588.867 m 
459.259 589.313 459.076 589.757 458.760 590.073 c
458.444 590.389 458.000 590.573 457.553 590.573 c
457.107 590.573 456.663 590.389 456.347 590.073 c
456.031 589.757 455.847 589.313 455.847 588.867 c
455.847 588.420 456.031 587.976 456.347 587.660 c
456.663 587.344 457.107 587.160 457.553 587.160 c
458.000 587.160 458.444 587.344 458.760 587.660 c
459.076 587.976 459.259 588.420 459.259 588.867 c f
BT 464.672 585.899 Td /F1 9.8 Tf  [(109 pts received )] TJ ET
BT 464.672 573.994 Td /F1 9.8 Tf  [(cetuximab, with 23 pts )] TJ ET
BT 464.672 562.089 Td /F1 9.8 Tf  [(receiving panitumumab.)] TJ ET
459.259 549.402 m 
459.259 549.849 459.076 550.293 458.760 550.609 c
458.444 550.925 458.000 551.109 457.553 551.109 c
457.107 551.109 456.663 550.925 456.347 550.609 c
456.031 550.293 455.847 549.849 455.847 549.402 c
455.847 548.956 456.031 548.512 456.347 548.196 c
456.663 547.880 457.107 547.696 457.553 547.696 c
458.000 547.696 458.444 547.880 458.760 548.196 c
459.076 548.512 459.259 548.956 459.259 549.402 c f
BT 464.672 546.435 Td /F1 9.8 Tf  [(This report came from the )] TJ ET
BT 464.672 534.530 Td /F1 9.8 Tf  [(same research group as )] TJ ET
BT 464.672 522.625 Td /F1 9.8 Tf  [(the report by Di )] TJ ET
BT 464.672 510.720 Td /F1 9.8 Tf  [(Nicolantonio and )] TJ ET
BT 464.672 498.816 Td /F1 9.8 Tf  [(colleagues )] TJ ET
0.267 0.267 0.267 rg
BT 513.987 498.816 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 530.250 498.816 Td /F1 9.8 Tf  [( and may )] TJ ET
BT 464.672 486.911 Td /F1 9.8 Tf  [(have included some of the )] TJ ET
BT 464.672 475.006 Td /F1 9.8 Tf  [(same pts.)] TJ ET
0.267 0.267 0.267 rg
26.625 314.018 98.949 0.750 re f
26.625 68.328 98.949 0.750 re f
26.625 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
BT 31.875 304.163 Td /F1 9.8 Tf  [(Souglakos and )] TJ ET
BT 31.875 296.532 Td /F1 9.8 Tf  [(colleagues \(2009\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 288.901 Td /F1 9.8 Tf  [([19])] TJ ET
124.824 314.018 159.395 0.750 re f
124.824 68.328 159.395 0.750 re f
124.824 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
144.161 307.462 m 
144.161 307.909 143.977 308.353 143.661 308.669 c
143.346 308.984 142.902 309.168 142.455 309.168 c
142.008 309.168 141.564 308.984 141.248 308.669 c
140.933 308.353 140.749 307.909 140.749 307.462 c
140.749 307.015 140.933 306.571 141.248 306.255 c
141.564 305.940 142.008 305.756 142.455 305.756 c
142.902 305.756 143.346 305.940 143.661 306.255 c
143.977 306.571 144.161 307.015 144.161 307.462 c f
BT 149.574 304.494 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 292.590 Td /F1 9.8 Tf  [(treated at 2 cancer centers in )] TJ ET
BT 149.574 280.685 Td /F1 9.8 Tf  [(the United States and )] TJ ET
BT 149.574 268.780 Td /F1 9.8 Tf  [(Greece; 100 pts received a )] TJ ET
BT 149.574 256.875 Td /F1 9.8 Tf  [(variety of chemotherapy )] TJ ET
BT 149.574 244.971 Td /F1 9.8 Tf  [(regimen that included )] TJ ET
BT 149.574 233.066 Td /F1 9.8 Tf  [(cetuximab.)] TJ ET
144.161 220.379 m 
144.161 220.825 143.977 221.269 143.661 221.585 c
143.346 221.901 142.902 222.085 142.455 222.085 c
142.008 222.085 141.564 221.901 141.248 221.585 c
140.933 221.269 140.749 220.825 140.749 220.379 c
140.749 219.932 140.933 219.488 141.248 219.172 c
141.564 218.856 142.008 218.672 142.455 218.672 c
142.902 218.672 143.346 218.856 143.661 219.172 c
143.977 219.488 144.161 219.932 144.161 220.379 c f
BT 149.574 217.411 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 205.506 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 192.819 m 
144.161 193.266 143.977 193.710 143.661 194.026 c
143.346 194.342 142.902 194.526 142.455 194.526 c
142.008 194.526 141.564 194.342 141.248 194.026 c
140.933 193.710 140.749 193.266 140.749 192.819 c
140.749 192.373 140.933 191.929 141.248 191.613 c
141.564 191.297 142.008 191.113 142.455 191.113 c
142.902 191.113 143.346 191.297 143.661 191.613 c
143.977 191.929 144.161 192.373 144.161 192.819 c f
BT 149.574 189.852 Td /F1 9.8 Tf  [(Sequence variants in )] TJ ET
BT 243.330 189.852 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 149.574 177.947 Td /F1 9.8 Tf  [(and )] TJ ET
BT 168.547 177.947 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 194.550 177.947 Td /F1 9.8 Tf  [( were identified )] TJ ET
BT 149.574 166.042 Td /F1 9.8 Tf  [(using PCR followed by mass-)] TJ ET
BT 149.574 154.137 Td /F1 9.8 Tf  [(spectrometric genotyping or )] TJ ET
BT 149.574 142.233 Td /F1 9.8 Tf  [(Sanger sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 314.018 157.203 0.750 re f
283.469 68.328 157.203 0.750 re f
283.469 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
302.806 307.462 m 
302.806 307.909 302.623 308.353 302.307 308.669 c
301.991 308.984 301.547 309.168 301.100 309.168 c
300.653 309.168 300.210 308.984 299.894 308.669 c
299.578 308.353 299.394 307.909 299.394 307.462 c
299.394 307.015 299.578 306.571 299.894 306.255 c
300.210 305.940 300.653 305.756 301.100 305.756 c
301.547 305.756 301.991 305.940 302.307 306.255 c
302.623 306.571 302.806 307.015 302.806 307.462 c f
BT 308.219 304.494 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 304.494 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 292.590 Td /F1 9.8 Tf  [(were found in 32 of 92 )] TJ ET
BT 308.219 280.685 Td /F1 9.8 Tf  [(\(34.8%\) of pts.)] TJ ET
302.806 267.998 m 
302.806 268.444 302.623 268.888 302.307 269.204 c
301.991 269.520 301.547 269.704 301.100 269.704 c
300.653 269.704 300.210 269.520 299.894 269.204 c
299.578 268.888 299.394 268.444 299.394 267.998 c
299.394 267.551 299.578 267.107 299.894 266.791 c
300.210 266.475 300.653 266.291 301.100 266.291 c
301.547 266.291 301.991 266.475 302.307 266.791 c
302.623 267.107 302.806 267.551 302.806 267.998 c f
BT 308.219 265.030 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 265.030 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 253.125 Td /F1 9.8 Tf  [(were identified in 9 of 92 )] TJ ET
BT 308.219 241.221 Td /F1 9.8 Tf  [(\(9.8%\) of pts. No pts that )] TJ ET
BT 308.219 229.316 Td /F1 9.8 Tf  [(had )] TJ ET
BT 327.192 229.316 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 353.196 229.316 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 217.411 Td /F1 9.8 Tf  [(variants responded to )] TJ ET
BT 308.219 205.506 Td /F1 9.8 Tf  [(treatment compared to 14 of )] TJ ET
BT 308.219 193.602 Td /F1 9.8 Tf  [(83 \(16.9%\) without )] TJ ET
BT 392.215 193.602 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 181.697 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
302.806 169.010 m 
302.806 169.456 302.623 169.900 302.307 170.216 c
301.991 170.532 301.547 170.716 301.100 170.716 c
300.653 170.716 300.210 170.532 299.894 170.216 c
299.578 169.900 299.394 169.456 299.394 169.010 c
299.394 168.563 299.578 168.119 299.894 167.803 c
300.210 167.487 300.653 167.304 301.100 167.304 c
301.547 167.304 301.991 167.487 302.307 167.803 c
302.623 168.119 302.806 168.563 302.806 169.010 c f
BT 308.219 166.042 Td /F1 9.8 Tf  [(PFS was significantly )] TJ ET
BT 308.219 154.137 Td /F1 9.8 Tf  [(shorter in those with than )] TJ ET
BT 308.219 142.233 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 142.233 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 142.233 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 130.328 Td /F1 9.8 Tf  [(variants that were treated )] TJ ET
BT 308.219 118.423 Td /F1 9.8 Tf  [(with first-line cetuximab )] TJ ET
BT 308.219 106.518 Td /F1 9.8 Tf  [(regimens \(2.0 mos versus )] TJ ET
BT 308.219 94.614 Td /F1 9.8 Tf  [(3.9 mos; HR 3.6; 95% CI )] TJ ET
BT 308.219 82.709 Td /F1 9.8 Tf  [(1.8-7.4\).)] TJ ET
0.267 0.267 0.267 rg
439.922 314.018 147.993 0.750 re f
439.922 68.328 147.993 0.750 re f
439.922 68.328 0.750 246.440 re f
587.165 68.328 0.750 246.440 re f
0.271 0.267 0.267 rg
459.259 307.462 m 
459.259 307.909 459.076 308.353 458.760 308.669 c
458.444 308.984 458.000 309.168 457.553 309.168 c
457.107 309.168 456.663 308.984 456.347 308.669 c
456.031 308.353 455.847 307.909 455.847 307.462 c
455.847 307.015 456.031 306.571 456.347 306.255 c
456.663 305.940 457.107 305.756 457.553 305.756 c
458.000 305.756 458.444 305.940 458.760 306.255 c
459.076 306.571 459.259 307.015 459.259 307.462 c f
BT 464.672 304.494 Td /F1 9.8 Tf  [(Of the 100 pts that )] TJ ET
BT 464.672 292.590 Td /F1 9.8 Tf  [(received cetuximab, it was )] TJ ET
BT 464.672 280.685 Td /F1 9.8 Tf  [(as first-line \(n=8\), second-)] TJ ET
BT 464.672 268.780 Td /F1 9.8 Tf  [(line \(n=37\) or third-line or )] TJ ET
BT 464.672 256.875 Td /F1 9.8 Tf  [(higher therapy \(n=55\).)] TJ ET
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BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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0.267 0.267 0.267 rg
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26.625 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Di Nicolantonio and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([41])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 718.700 m 
144.161 719.146 143.977 719.590 143.661 719.906 c
143.346 720.222 142.902 720.406 142.455 720.406 c
142.008 720.406 141.564 720.222 141.248 719.906 c
140.933 719.590 140.749 719.146 140.749 718.700 c
140.749 718.253 140.933 717.809 141.248 717.493 c
141.564 717.177 142.008 716.994 142.455 716.994 c
142.902 716.994 143.346 717.177 143.661 717.493 c
143.977 717.809 144.161 718.253 144.161 718.700 c f
BT 149.574 715.732 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 703.827 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 691.140 m 
144.161 691.587 143.977 692.031 143.661 692.347 c
143.346 692.663 142.902 692.846 142.455 692.846 c
142.008 692.846 141.564 692.663 141.248 692.347 c
140.933 692.031 140.749 691.587 140.749 691.140 c
140.749 690.694 140.933 690.250 141.248 689.934 c
141.564 689.618 142.008 689.434 142.455 689.434 c
142.902 689.434 143.346 689.618 143.661 689.934 c
143.977 690.250 144.161 690.694 144.161 691.140 c f
BT 149.574 688.173 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 676.268 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(ABI PRISM 3730 was used )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(to identify )] TJ ET
BT 194.014 640.554 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 220.563 640.554 Td /F1 9.8 Tf  [( and )] TJ ET
BT 242.247 640.554 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 628.649 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were found in 34 of 113 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(30.1%\) of pts. )] TJ ET
BT 374.334 743.292 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 731.387 Td /F1 9.8 Tf  [(sequence variants were )] TJ ET
BT 308.219 719.482 Td /F1 9.8 Tf  [(found in 11 of 79 \(13.9%\) )] TJ ET
BT 308.219 707.577 Td /F1 9.8 Tf  [(evaluable pts. The presence )] TJ ET
BT 308.219 695.673 Td /F1 9.8 Tf  [(of )] TJ ET
BT 319.061 695.673 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 345.064 695.673 Td /F1 9.8 Tf  [( and )] TJ ET
BT 366.748 695.673 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 683.768 Td /F1 9.8 Tf  [(sequence variants was )] TJ ET
BT 308.219 671.863 Td /F1 9.8 Tf  [(mutually exclusive.)] TJ ET
302.806 659.176 m 
302.806 659.623 302.623 660.067 302.307 660.383 c
301.991 660.698 301.547 660.882 301.100 660.882 c
300.653 660.882 300.210 660.698 299.894 660.383 c
299.578 660.067 299.394 659.623 299.394 659.176 c
299.394 658.729 299.578 658.285 299.894 657.969 c
300.210 657.654 300.653 657.470 301.100 657.470 c
301.547 657.470 301.991 657.654 302.307 657.969 c
302.623 658.285 302.806 658.729 302.806 659.176 c f
BT 308.219 656.208 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 644.304 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 632.399 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 632.399 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 632.399 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 620.494 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 608.589 Td /F1 9.8 Tf  [(32.4%; P=0.029\).)] TJ ET
302.806 595.902 m 
302.806 596.349 302.623 596.793 302.307 597.109 c
301.991 597.425 301.547 597.609 301.100 597.609 c
300.653 597.609 300.210 597.425 299.894 597.109 c
299.578 596.793 299.394 596.349 299.394 595.902 c
299.394 595.456 299.578 595.012 299.894 594.696 c
300.210 594.380 300.653 594.196 301.100 594.196 c
301.547 594.196 301.991 594.380 302.307 594.696 c
302.623 595.012 302.806 595.456 302.806 595.902 c f
BT 308.219 592.935 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 592.935 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 581.030 Td /F1 9.8 Tf  [(sequence variants, an )] TJ ET
BT 308.219 569.125 Td /F1 9.8 Tf  [(absence of )] TJ ET
BT 358.626 569.125 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 384.630 569.125 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 557.220 Td /F1 9.8 Tf  [(variants was associated with )] TJ ET
BT 308.219 545.316 Td /F1 9.8 Tf  [(increased PFS \(P=0.010\) )] TJ ET
BT 308.219 533.411 Td /F1 9.8 Tf  [(and OS \(P<0.0001\) in )] TJ ET
BT 308.219 521.506 Td /F1 9.8 Tf  [(Kaplan-Meier analyzes.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 507.125 0.750 270.250 re f
587.165 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(87 pts received cetuximab )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(and 26 received )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(panitumumab.)] TJ ET
459.259 730.605 m 
459.259 731.051 459.076 731.495 458.760 731.811 c
458.444 732.127 458.000 732.311 457.553 732.311 c
457.107 732.311 456.663 732.127 456.347 731.811 c
456.031 731.495 455.847 731.051 455.847 730.605 c
455.847 730.158 456.031 729.714 456.347 729.398 c
456.663 729.082 457.107 728.898 457.553 728.898 c
458.000 728.898 458.444 729.082 458.760 729.398 c
459.076 729.714 459.259 730.158 459.259 730.605 c f
BT 464.672 727.637 Td /F1 9.8 Tf  [(Over all pts in the study, )] TJ ET
BT 464.672 715.732 Td /F1 9.8 Tf  [(response to treatment was )] TJ ET
BT 464.672 703.827 Td /F1 9.8 Tf  [(seen in 24 of 133 \(21.2%\) )] TJ ET
BT 464.672 691.923 Td /F1 9.8 Tf  [(of pts and the median )] TJ ET
BT 464.672 680.018 Td /F1 9.8 Tf  [(duration of response was )] TJ ET
BT 464.672 668.113 Td /F1 9.8 Tf  [(25 wks.)] TJ ET
0.267 0.267 0.267 rg
26.625 507.125 98.949 0.750 re f
26.625 332.864 98.949 0.750 re f
26.625 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
BT 31.875 497.270 Td /F1 9.8 Tf  [(Freeman and )] TJ ET
BT 31.875 489.639 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 482.008 Td /F1 9.8 Tf  [([44])] TJ ET
124.824 507.125 159.395 0.750 re f
124.824 332.864 159.395 0.750 re f
124.824 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
144.161 500.569 m 
144.161 501.016 143.977 501.460 143.661 501.776 c
143.346 502.091 142.902 502.275 142.455 502.275 c
142.008 502.275 141.564 502.091 141.248 501.776 c
140.933 501.460 140.749 501.016 140.749 500.569 c
140.749 500.122 140.933 499.678 141.248 499.362 c
141.564 499.047 142.008 498.863 142.455 498.863 c
142.902 498.863 143.346 499.047 143.661 499.362 c
143.977 499.678 144.161 500.122 144.161 500.569 c f
BT 149.574 497.601 Td /F1 9.8 Tf  [(Retrospective analysis of 62 )] TJ ET
BT 149.574 485.697 Td /F1 9.8 Tf  [(of the 533 pts involved in )] TJ ET
BT 149.574 473.792 Td /F1 9.8 Tf  [(phase II clinical trials that )] TJ ET
BT 149.574 461.887 Td /F1 9.8 Tf  [(received panitumumab in the )] TJ ET
BT 149.574 449.982 Td /F1 9.8 Tf  [(United States.)] TJ ET
144.161 437.295 m 
144.161 437.742 143.977 438.186 143.661 438.502 c
143.346 438.818 142.902 439.002 142.455 439.002 c
142.008 439.002 141.564 438.818 141.248 438.502 c
140.933 438.186 140.749 437.742 140.749 437.295 c
140.749 436.849 140.933 436.405 141.248 436.089 c
141.564 435.773 142.008 435.589 142.455 435.589 c
142.902 435.589 143.346 435.773 143.661 436.089 c
143.977 436.405 144.161 436.849 144.161 437.295 c f
BT 149.574 434.328 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 422.423 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 409.736 m 
144.161 410.182 143.977 410.626 143.661 410.942 c
143.346 411.258 142.902 411.442 142.455 411.442 c
142.008 411.442 141.564 411.258 141.248 410.942 c
140.933 410.626 140.749 410.182 140.749 409.736 c
140.749 409.289 140.933 408.845 141.248 408.529 c
141.564 408.213 142.008 408.030 142.455 408.030 c
142.902 408.030 143.346 408.213 143.661 408.529 c
143.977 408.845 144.161 409.289 144.161 409.736 c f
BT 149.574 406.768 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 406.768 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 406.768 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 406.768 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 394.863 Td /F1 9.8 Tf  [(variants were analyzed using )] TJ ET
BT 149.574 382.959 Td /F1 9.8 Tf  [(PCR and sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 507.125 157.203 0.750 re f
283.469 332.864 157.203 0.750 re f
283.469 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
302.806 500.569 m 
302.806 501.016 302.623 501.460 302.307 501.776 c
301.991 502.091 301.547 502.275 301.100 502.275 c
300.653 502.275 300.210 502.091 299.894 501.776 c
299.578 501.460 299.394 501.016 299.394 500.569 c
299.394 500.122 299.578 499.678 299.894 499.362 c
300.210 499.047 300.653 498.863 301.100 498.863 c
301.547 498.863 301.991 499.047 302.307 499.362 c
302.623 499.678 302.806 500.122 302.806 500.569 c f
BT 308.219 497.601 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 497.601 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 485.697 Td /F1 9.8 Tf  [(were identified in 24 of 62 )] TJ ET
BT 308.219 473.792 Td /F1 9.8 Tf  [(\(38.7%\) pts.)] TJ ET
302.806 461.105 m 
302.806 461.551 302.623 461.995 302.307 462.311 c
301.991 462.627 301.547 462.811 301.100 462.811 c
300.653 462.811 300.210 462.627 299.894 462.311 c
299.578 461.995 299.394 461.551 299.394 461.105 c
299.394 460.658 299.578 460.214 299.894 459.898 c
300.210 459.582 300.653 459.399 301.100 459.399 c
301.547 459.399 301.991 459.582 302.307 459.898 c
302.623 460.214 302.806 460.658 302.806 461.105 c f
BT 308.219 458.137 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 458.137 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 446.232 Td /F1 9.8 Tf  [(were found in 4 of the 62 )] TJ ET
BT 308.219 434.328 Td /F1 9.8 Tf  [(\(6.4%\) pts. The )] TJ ET
BT 377.580 434.328 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 422.423 Td /F1 9.8 Tf  [(status of these pts was not )] TJ ET
BT 308.219 410.518 Td /F1 9.8 Tf  [(clearly reported.)] TJ ET
302.806 397.831 m 
302.806 398.278 302.623 398.722 302.307 399.038 c
301.991 399.353 301.547 399.537 301.100 399.537 c
300.653 399.537 300.210 399.353 299.894 399.038 c
299.578 398.722 299.394 398.278 299.394 397.831 c
299.394 397.384 299.578 396.940 299.894 396.624 c
300.210 396.309 300.653 396.125 301.100 396.125 c
301.547 396.125 301.991 396.309 302.307 396.624 c
302.623 396.940 302.806 397.384 302.806 397.831 c f
BT 308.219 394.863 Td /F1 9.8 Tf  [(Of the 4 pts with )] TJ ET
BT 381.383 394.863 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 382.959 Td /F1 9.8 Tf  [(sequence variants, 1 had a )] TJ ET
BT 308.219 371.054 Td /F1 9.8 Tf  [(partial response, 1 had )] TJ ET
BT 308.219 359.149 Td /F1 9.8 Tf  [(stable disease and 2 had )] TJ ET
BT 308.219 347.244 Td /F1 9.8 Tf  [(progressive disease.)] TJ ET
0.267 0.267 0.267 rg
439.922 507.125 147.993 0.750 re f
439.922 332.864 147.993 0.750 re f
439.922 332.864 0.750 175.012 re f
587.165 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
459.259 500.569 m 
459.259 501.016 459.076 501.460 458.760 501.776 c
458.444 502.091 458.000 502.275 457.553 502.275 c
457.107 502.275 456.663 502.091 456.347 501.776 c
456.031 501.460 455.847 501.016 455.847 500.569 c
455.847 500.122 456.031 499.678 456.347 499.362 c
456.663 499.047 457.107 498.863 457.553 498.863 c
458.000 498.863 458.444 499.047 458.760 499.362 c
459.076 499.678 459.259 500.122 459.259 500.569 c f
BT 464.672 497.601 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 485.697 Td /F1 9.8 Tf  [(treatment with )] TJ ET
BT 464.672 473.792 Td /F1 9.8 Tf  [(panitumumab was )] TJ ET
BT 464.672 461.887 Td /F1 9.8 Tf  [(observed by 4 of 62 )] TJ ET
BT 464.672 449.982 Td /F1 9.8 Tf  [(\(6.5%\) pts.)] TJ ET
40.337 288.432 m 
40.337 288.879 40.154 289.323 39.838 289.639 c
39.522 289.955 39.078 290.139 38.631 290.139 c
38.185 290.139 37.741 289.955 37.425 289.639 c
37.109 289.323 36.925 288.879 36.925 288.432 c
36.925 287.986 37.109 287.542 37.425 287.226 c
37.741 286.910 38.185 286.726 38.631 286.726 c
39.078 286.726 39.522 286.910 39.838 287.226 c
40.154 287.542 40.337 287.986 40.337 288.432 c f
BT 45.750 285.465 Td /F1 9.8 Tf  [(A meta-analysis of 4 of the above studies \(Di Nicolantonio )] TJ ET
0.267 0.267 0.267 rg
BT 298.275 285.465 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 314.538 285.465 Td /F1 9.8 Tf  [(, Laurent-Puig )] TJ ET
0.267 0.267 0.267 rg
BT 378.488 285.465 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 394.751 285.465 Td /F1 9.8 Tf  [(, Loupakis )] TJ ET
0.267 0.267 0.267 rg
BT 441.902 285.465 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 458.165 285.465 Td /F1 9.8 Tf  [(, and Sartore-Bianchi )] TJ ET
0.267 0.267 0.267 rg
BT 552.457 285.465 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 568.721 285.465 Td /F1 9.8 Tf  [( \) )] TJ ET
BT 45.750 273.560 Td /F1 9.8 Tf  [(was conducted in 2010 by Mao and colleagues to examine the relationship between BRAF sequence variants and )] TJ ET
BT 45.750 261.655 Td /F1 9.8 Tf  [(response to treatment with the EGFR monoclonal antibody inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 343.252 261.655 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 359.515 261.655 Td /F1 9.8 Tf  [(. The results of the meta-analysis indicate that in )] TJ ET
BT 45.750 249.750 Td /F1 9.8 Tf  [(patients without KRAS sequence variants, the objective response rate in patients with the BRAF p.Val600Glu sequence )] TJ ET
BT 45.750 237.846 Td /F1 9.8 Tf  [(variant was 0.0% \(0 of 40\); it was 36.3% \(122 of 336\) in patients without BRAF sequence variants. This resulted in a pooled )] TJ ET
BT 45.750 225.941 Td /F1 9.8 Tf  [(risk ratio of 0.14 \(95% CI, 0.04 to 0.53; P=0.004\). For progression-free survival, the difference between those with and )] TJ ET
BT 45.750 214.036 Td /F1 9.8 Tf  [(without BRAF sequence variants was not significant across the 2 studies that reported this endpoint. However, overall )] TJ ET
BT 45.750 202.131 Td /F1 9.8 Tf  [(survival was shorter for those patients with BRAF sequence variants compared to those without \(HR, 3.25; 95% CI, 1.63 to )] TJ ET
BT 45.750 190.227 Td /F1 9.8 Tf  [(6.47; P=0.001\) )] TJ ET
0.267 0.267 0.267 rg
BT 112.694 190.227 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 128.957 190.227 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 167.072 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 167.072 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 167.072 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 150.635 m 
40.337 151.081 40.154 151.525 39.838 151.841 c
39.522 152.157 39.078 152.341 38.631 152.341 c
38.185 152.341 37.741 152.157 37.425 151.841 c
37.109 151.525 36.925 151.081 36.925 150.635 c
36.925 150.188 37.109 149.744 37.425 149.428 c
37.741 149.112 38.185 148.929 38.631 148.929 c
39.078 148.929 39.522 149.112 39.838 149.428 c
40.154 149.744 40.337 150.188 40.337 150.635 c f
BT 45.750 147.667 Td /F1 9.8 Tf  [(No reports that prospectively investigated the clinical utility of genetic testing for the BRAF p.Val600Glu sequence variant )] TJ ET
BT 45.750 135.762 Td /F1 9.8 Tf  [(were identified. If detection of the BRAF p.Val600Glu sequence variant can be used to predict a lack of response to )] TJ ET
BT 45.750 123.858 Td /F1 9.8 Tf  [(treatment using cetuximab and panitumumab, such testing would have clinical utility in avoiding exposure to the EGFR )] TJ ET
BT 45.750 111.953 Td /F1 9.8 Tf  [(monoclonal antibody inhibitors, which are associated with serious adverse effects, in patients who are unlikely to benefit. A )] TJ ET
BT 45.750 100.048 Td /F1 9.8 Tf  [(potential harm of testing for the BRAF p.Val600Glu sequence variant is if the presence of this variant does not accurately )] TJ ET
BT 45.750 88.143 Td /F1 9.8 Tf  [(predict a lack of response to the anti-EGFR monoclonal antibody, a potentially efficacious treatment would be denied to )] TJ ET
BT 45.750 76.239 Td /F1 9.8 Tf  [(BRAF p.Val600Glu-positive patients.)] TJ ET
Q
q
15.000 25.456 577.500 751.544 re W n
1.000 1.000 1.000 rg
26.250 332.489 555.000 444.511 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Di Nicolantonio and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([41])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 718.700 m 
144.161 719.146 143.977 719.590 143.661 719.906 c
143.346 720.222 142.902 720.406 142.455 720.406 c
142.008 720.406 141.564 720.222 141.248 719.906 c
140.933 719.590 140.749 719.146 140.749 718.700 c
140.749 718.253 140.933 717.809 141.248 717.493 c
141.564 717.177 142.008 716.994 142.455 716.994 c
142.902 716.994 143.346 717.177 143.661 717.493 c
143.977 717.809 144.161 718.253 144.161 718.700 c f
BT 149.574 715.732 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 703.827 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 691.140 m 
144.161 691.587 143.977 692.031 143.661 692.347 c
143.346 692.663 142.902 692.846 142.455 692.846 c
142.008 692.846 141.564 692.663 141.248 692.347 c
140.933 692.031 140.749 691.587 140.749 691.140 c
140.749 690.694 140.933 690.250 141.248 689.934 c
141.564 689.618 142.008 689.434 142.455 689.434 c
142.902 689.434 143.346 689.618 143.661 689.934 c
143.977 690.250 144.161 690.694 144.161 691.140 c f
BT 149.574 688.173 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 676.268 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(ABI PRISM 3730 was used )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(to identify )] TJ ET
BT 194.014 640.554 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 220.563 640.554 Td /F1 9.8 Tf  [( and )] TJ ET
BT 242.247 640.554 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 628.649 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were found in 34 of 113 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(30.1%\) of pts. )] TJ ET
BT 374.334 743.292 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 731.387 Td /F1 9.8 Tf  [(sequence variants were )] TJ ET
BT 308.219 719.482 Td /F1 9.8 Tf  [(found in 11 of 79 \(13.9%\) )] TJ ET
BT 308.219 707.577 Td /F1 9.8 Tf  [(evaluable pts. The presence )] TJ ET
BT 308.219 695.673 Td /F1 9.8 Tf  [(of )] TJ ET
BT 319.061 695.673 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 345.064 695.673 Td /F1 9.8 Tf  [( and )] TJ ET
BT 366.748 695.673 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 683.768 Td /F1 9.8 Tf  [(sequence variants was )] TJ ET
BT 308.219 671.863 Td /F1 9.8 Tf  [(mutually exclusive.)] TJ ET
302.806 659.176 m 
302.806 659.623 302.623 660.067 302.307 660.383 c
301.991 660.698 301.547 660.882 301.100 660.882 c
300.653 660.882 300.210 660.698 299.894 660.383 c
299.578 660.067 299.394 659.623 299.394 659.176 c
299.394 658.729 299.578 658.285 299.894 657.969 c
300.210 657.654 300.653 657.470 301.100 657.470 c
301.547 657.470 301.991 657.654 302.307 657.969 c
302.623 658.285 302.806 658.729 302.806 659.176 c f
BT 308.219 656.208 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 644.304 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 632.399 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 632.399 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 632.399 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 620.494 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 608.589 Td /F1 9.8 Tf  [(32.4%; P=0.029\).)] TJ ET
302.806 595.902 m 
302.806 596.349 302.623 596.793 302.307 597.109 c
301.991 597.425 301.547 597.609 301.100 597.609 c
300.653 597.609 300.210 597.425 299.894 597.109 c
299.578 596.793 299.394 596.349 299.394 595.902 c
299.394 595.456 299.578 595.012 299.894 594.696 c
300.210 594.380 300.653 594.196 301.100 594.196 c
301.547 594.196 301.991 594.380 302.307 594.696 c
302.623 595.012 302.806 595.456 302.806 595.902 c f
BT 308.219 592.935 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 592.935 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 581.030 Td /F1 9.8 Tf  [(sequence variants, an )] TJ ET
BT 308.219 569.125 Td /F1 9.8 Tf  [(absence of )] TJ ET
BT 358.626 569.125 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 384.630 569.125 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 557.220 Td /F1 9.8 Tf  [(variants was associated with )] TJ ET
BT 308.219 545.316 Td /F1 9.8 Tf  [(increased PFS \(P=0.010\) )] TJ ET
BT 308.219 533.411 Td /F1 9.8 Tf  [(and OS \(P<0.0001\) in )] TJ ET
BT 308.219 521.506 Td /F1 9.8 Tf  [(Kaplan-Meier analyzes.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 507.125 0.750 270.250 re f
587.165 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(87 pts received cetuximab )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(and 26 received )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(panitumumab.)] TJ ET
459.259 730.605 m 
459.259 731.051 459.076 731.495 458.760 731.811 c
458.444 732.127 458.000 732.311 457.553 732.311 c
457.107 732.311 456.663 732.127 456.347 731.811 c
456.031 731.495 455.847 731.051 455.847 730.605 c
455.847 730.158 456.031 729.714 456.347 729.398 c
456.663 729.082 457.107 728.898 457.553 728.898 c
458.000 728.898 458.444 729.082 458.760 729.398 c
459.076 729.714 459.259 730.158 459.259 730.605 c f
BT 464.672 727.637 Td /F1 9.8 Tf  [(Over all pts in the study, )] TJ ET
BT 464.672 715.732 Td /F1 9.8 Tf  [(response to treatment was )] TJ ET
BT 464.672 703.827 Td /F1 9.8 Tf  [(seen in 24 of 133 \(21.2%\) )] TJ ET
BT 464.672 691.923 Td /F1 9.8 Tf  [(of pts and the median )] TJ ET
BT 464.672 680.018 Td /F1 9.8 Tf  [(duration of response was )] TJ ET
BT 464.672 668.113 Td /F1 9.8 Tf  [(25 wks.)] TJ ET
0.267 0.267 0.267 rg
26.625 507.125 98.949 0.750 re f
26.625 332.864 98.949 0.750 re f
26.625 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
BT 31.875 497.270 Td /F1 9.8 Tf  [(Freeman and )] TJ ET
BT 31.875 489.639 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 482.008 Td /F1 9.8 Tf  [([44])] TJ ET
124.824 507.125 159.395 0.750 re f
124.824 332.864 159.395 0.750 re f
124.824 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
144.161 500.569 m 
144.161 501.016 143.977 501.460 143.661 501.776 c
143.346 502.091 142.902 502.275 142.455 502.275 c
142.008 502.275 141.564 502.091 141.248 501.776 c
140.933 501.460 140.749 501.016 140.749 500.569 c
140.749 500.122 140.933 499.678 141.248 499.362 c
141.564 499.047 142.008 498.863 142.455 498.863 c
142.902 498.863 143.346 499.047 143.661 499.362 c
143.977 499.678 144.161 500.122 144.161 500.569 c f
BT 149.574 497.601 Td /F1 9.8 Tf  [(Retrospective analysis of 62 )] TJ ET
BT 149.574 485.697 Td /F1 9.8 Tf  [(of the 533 pts involved in )] TJ ET
BT 149.574 473.792 Td /F1 9.8 Tf  [(phase II clinical trials that )] TJ ET
BT 149.574 461.887 Td /F1 9.8 Tf  [(received panitumumab in the )] TJ ET
BT 149.574 449.982 Td /F1 9.8 Tf  [(United States.)] TJ ET
144.161 437.295 m 
144.161 437.742 143.977 438.186 143.661 438.502 c
143.346 438.818 142.902 439.002 142.455 439.002 c
142.008 439.002 141.564 438.818 141.248 438.502 c
140.933 438.186 140.749 437.742 140.749 437.295 c
140.749 436.849 140.933 436.405 141.248 436.089 c
141.564 435.773 142.008 435.589 142.455 435.589 c
142.902 435.589 143.346 435.773 143.661 436.089 c
143.977 436.405 144.161 436.849 144.161 437.295 c f
BT 149.574 434.328 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 422.423 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 409.736 m 
144.161 410.182 143.977 410.626 143.661 410.942 c
143.346 411.258 142.902 411.442 142.455 411.442 c
142.008 411.442 141.564 411.258 141.248 410.942 c
140.933 410.626 140.749 410.182 140.749 409.736 c
140.749 409.289 140.933 408.845 141.248 408.529 c
141.564 408.213 142.008 408.030 142.455 408.030 c
142.902 408.030 143.346 408.213 143.661 408.529 c
143.977 408.845 144.161 409.289 144.161 409.736 c f
BT 149.574 406.768 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 406.768 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 406.768 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 406.768 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 394.863 Td /F1 9.8 Tf  [(variants were analyzed using )] TJ ET
BT 149.574 382.959 Td /F1 9.8 Tf  [(PCR and sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 507.125 157.203 0.750 re f
283.469 332.864 157.203 0.750 re f
283.469 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
302.806 500.569 m 
302.806 501.016 302.623 501.460 302.307 501.776 c
301.991 502.091 301.547 502.275 301.100 502.275 c
300.653 502.275 300.210 502.091 299.894 501.776 c
299.578 501.460 299.394 501.016 299.394 500.569 c
299.394 500.122 299.578 499.678 299.894 499.362 c
300.210 499.047 300.653 498.863 301.100 498.863 c
301.547 498.863 301.991 499.047 302.307 499.362 c
302.623 499.678 302.806 500.122 302.806 500.569 c f
BT 308.219 497.601 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 497.601 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 485.697 Td /F1 9.8 Tf  [(were identified in 24 of 62 )] TJ ET
BT 308.219 473.792 Td /F1 9.8 Tf  [(\(38.7%\) pts.)] TJ ET
302.806 461.105 m 
302.806 461.551 302.623 461.995 302.307 462.311 c
301.991 462.627 301.547 462.811 301.100 462.811 c
300.653 462.811 300.210 462.627 299.894 462.311 c
299.578 461.995 299.394 461.551 299.394 461.105 c
299.394 460.658 299.578 460.214 299.894 459.898 c
300.210 459.582 300.653 459.399 301.100 459.399 c
301.547 459.399 301.991 459.582 302.307 459.898 c
302.623 460.214 302.806 460.658 302.806 461.105 c f
BT 308.219 458.137 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 458.137 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 446.232 Td /F1 9.8 Tf  [(were found in 4 of the 62 )] TJ ET
BT 308.219 434.328 Td /F1 9.8 Tf  [(\(6.4%\) pts. The )] TJ ET
BT 377.580 434.328 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 422.423 Td /F1 9.8 Tf  [(status of these pts was not )] TJ ET
BT 308.219 410.518 Td /F1 9.8 Tf  [(clearly reported.)] TJ ET
302.806 397.831 m 
302.806 398.278 302.623 398.722 302.307 399.038 c
301.991 399.353 301.547 399.537 301.100 399.537 c
300.653 399.537 300.210 399.353 299.894 399.038 c
299.578 398.722 299.394 398.278 299.394 397.831 c
299.394 397.384 299.578 396.940 299.894 396.624 c
300.210 396.309 300.653 396.125 301.100 396.125 c
301.547 396.125 301.991 396.309 302.307 396.624 c
302.623 396.940 302.806 397.384 302.806 397.831 c f
BT 308.219 394.863 Td /F1 9.8 Tf  [(Of the 4 pts with )] TJ ET
BT 381.383 394.863 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 382.959 Td /F1 9.8 Tf  [(sequence variants, 1 had a )] TJ ET
BT 308.219 371.054 Td /F1 9.8 Tf  [(partial response, 1 had )] TJ ET
BT 308.219 359.149 Td /F1 9.8 Tf  [(stable disease and 2 had )] TJ ET
BT 308.219 347.244 Td /F1 9.8 Tf  [(progressive disease.)] TJ ET
0.267 0.267 0.267 rg
439.922 507.125 147.993 0.750 re f
439.922 332.864 147.993 0.750 re f
439.922 332.864 0.750 175.012 re f
587.165 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
459.259 500.569 m 
459.259 501.016 459.076 501.460 458.760 501.776 c
458.444 502.091 458.000 502.275 457.553 502.275 c
457.107 502.275 456.663 502.091 456.347 501.776 c
456.031 501.460 455.847 501.016 455.847 500.569 c
455.847 500.122 456.031 499.678 456.347 499.362 c
456.663 499.047 457.107 498.863 457.553 498.863 c
458.000 498.863 458.444 499.047 458.760 499.362 c
459.076 499.678 459.259 500.122 459.259 500.569 c f
BT 464.672 497.601 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 485.697 Td /F1 9.8 Tf  [(treatment with )] TJ ET
BT 464.672 473.792 Td /F1 9.8 Tf  [(panitumumab was )] TJ ET
BT 464.672 461.887 Td /F1 9.8 Tf  [(observed by 4 of 62 )] TJ ET
BT 464.672 449.982 Td /F1 9.8 Tf  [(\(6.5%\) pts.)] TJ ET
40.337 288.432 m 
40.337 288.879 40.154 289.323 39.838 289.639 c
39.522 289.955 39.078 290.139 38.631 290.139 c
38.185 290.139 37.741 289.955 37.425 289.639 c
37.109 289.323 36.925 288.879 36.925 288.432 c
36.925 287.986 37.109 287.542 37.425 287.226 c
37.741 286.910 38.185 286.726 38.631 286.726 c
39.078 286.726 39.522 286.910 39.838 287.226 c
40.154 287.542 40.337 287.986 40.337 288.432 c f
BT 45.750 285.465 Td /F1 9.8 Tf  [(A meta-analysis of 4 of the above studies \(Di Nicolantonio )] TJ ET
0.267 0.267 0.267 rg
BT 298.275 285.465 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 314.538 285.465 Td /F1 9.8 Tf  [(, Laurent-Puig )] TJ ET
0.267 0.267 0.267 rg
BT 378.488 285.465 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 394.751 285.465 Td /F1 9.8 Tf  [(, Loupakis )] TJ ET
0.267 0.267 0.267 rg
BT 441.902 285.465 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 458.165 285.465 Td /F1 9.8 Tf  [(, and Sartore-Bianchi )] TJ ET
0.267 0.267 0.267 rg
BT 552.457 285.465 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 568.721 285.465 Td /F1 9.8 Tf  [( \) )] TJ ET
BT 45.750 273.560 Td /F1 9.8 Tf  [(was conducted in 2010 by Mao and colleagues to examine the relationship between BRAF sequence variants and )] TJ ET
BT 45.750 261.655 Td /F1 9.8 Tf  [(response to treatment with the EGFR monoclonal antibody inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 343.252 261.655 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 359.515 261.655 Td /F1 9.8 Tf  [(. The results of the meta-analysis indicate that in )] TJ ET
BT 45.750 249.750 Td /F1 9.8 Tf  [(patients without KRAS sequence variants, the objective response rate in patients with the BRAF p.Val600Glu sequence )] TJ ET
BT 45.750 237.846 Td /F1 9.8 Tf  [(variant was 0.0% \(0 of 40\); it was 36.3% \(122 of 336\) in patients without BRAF sequence variants. This resulted in a pooled )] TJ ET
BT 45.750 225.941 Td /F1 9.8 Tf  [(risk ratio of 0.14 \(95% CI, 0.04 to 0.53; P=0.004\). For progression-free survival, the difference between those with and )] TJ ET
BT 45.750 214.036 Td /F1 9.8 Tf  [(without BRAF sequence variants was not significant across the 2 studies that reported this endpoint. However, overall )] TJ ET
BT 45.750 202.131 Td /F1 9.8 Tf  [(survival was shorter for those patients with BRAF sequence variants compared to those without \(HR, 3.25; 95% CI, 1.63 to )] TJ ET
BT 45.750 190.227 Td /F1 9.8 Tf  [(6.47; P=0.001\) )] TJ ET
0.267 0.267 0.267 rg
BT 112.694 190.227 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 128.957 190.227 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 167.072 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 167.072 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 167.072 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 150.635 m 
40.337 151.081 40.154 151.525 39.838 151.841 c
39.522 152.157 39.078 152.341 38.631 152.341 c
38.185 152.341 37.741 152.157 37.425 151.841 c
37.109 151.525 36.925 151.081 36.925 150.635 c
36.925 150.188 37.109 149.744 37.425 149.428 c
37.741 149.112 38.185 148.929 38.631 148.929 c
39.078 148.929 39.522 149.112 39.838 149.428 c
40.154 149.744 40.337 150.188 40.337 150.635 c f
BT 45.750 147.667 Td /F1 9.8 Tf  [(No reports that prospectively investigated the clinical utility of genetic testing for the BRAF p.Val600Glu sequence variant )] TJ ET
BT 45.750 135.762 Td /F1 9.8 Tf  [(were identified. If detection of the BRAF p.Val600Glu sequence variant can be used to predict a lack of response to )] TJ ET
BT 45.750 123.858 Td /F1 9.8 Tf  [(treatment using cetuximab and panitumumab, such testing would have clinical utility in avoiding exposure to the EGFR )] TJ ET
BT 45.750 111.953 Td /F1 9.8 Tf  [(monoclonal antibody inhibitors, which are associated with serious adverse effects, in patients who are unlikely to benefit. A )] TJ ET
BT 45.750 100.048 Td /F1 9.8 Tf  [(potential harm of testing for the BRAF p.Val600Glu sequence variant is if the presence of this variant does not accurately )] TJ ET
BT 45.750 88.143 Td /F1 9.8 Tf  [(predict a lack of response to the anti-EGFR monoclonal antibody, a potentially efficacious treatment would be denied to )] TJ ET
BT 45.750 76.239 Td /F1 9.8 Tf  [(BRAF p.Val600Glu-positive patients.)] TJ ET
Q
q
15.000 25.456 577.500 751.544 re W n
1.000 1.000 1.000 rg
26.250 332.489 555.000 444.511 re f
0.267 0.267 0.267 rg
26.625 776.625 98.949 0.750 re f
26.625 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
BT 31.875 766.770 Td /F1 9.8 Tf  [(Di Nicolantonio and )] TJ ET
BT 31.875 759.139 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 751.508 Td /F1 9.8 Tf  [([41])] TJ ET
124.824 776.625 159.395 0.750 re f
124.824 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
144.161 770.069 m 
144.161 770.515 143.977 770.959 143.661 771.275 c
143.346 771.591 142.902 771.775 142.455 771.775 c
142.008 771.775 141.564 771.591 141.248 771.275 c
140.933 770.959 140.749 770.515 140.749 770.069 c
140.749 769.622 140.933 769.178 141.248 768.862 c
141.564 768.546 142.008 768.363 142.455 768.363 c
142.902 768.363 143.346 768.546 143.661 768.862 c
143.977 769.178 144.161 769.622 144.161 770.069 c f
BT 149.574 767.101 Td /F1 9.8 Tf  [(Retrospective analysis of pts )] TJ ET
BT 149.574 755.196 Td /F1 9.8 Tf  [(treated with cetuximab or )] TJ ET
BT 149.574 743.292 Td /F1 9.8 Tf  [(panitumumab at an Italian )] TJ ET
BT 149.574 731.387 Td /F1 9.8 Tf  [(and a Swiss cancer center.)] TJ ET
144.161 718.700 m 
144.161 719.146 143.977 719.590 143.661 719.906 c
143.346 720.222 142.902 720.406 142.455 720.406 c
142.008 720.406 141.564 720.222 141.248 719.906 c
140.933 719.590 140.749 719.146 140.749 718.700 c
140.749 718.253 140.933 717.809 141.248 717.493 c
141.564 717.177 142.008 716.994 142.455 716.994 c
142.902 716.994 143.346 717.177 143.661 717.493 c
143.977 717.809 144.161 718.253 144.161 718.700 c f
BT 149.574 715.732 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 703.827 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 691.140 m 
144.161 691.587 143.977 692.031 143.661 692.347 c
143.346 692.663 142.902 692.846 142.455 692.846 c
142.008 692.846 141.564 692.663 141.248 692.347 c
140.933 692.031 140.749 691.587 140.749 691.140 c
140.749 690.694 140.933 690.250 141.248 689.934 c
141.564 689.618 142.008 689.434 142.455 689.434 c
142.902 689.434 143.346 689.618 143.661 689.934 c
143.977 690.250 144.161 690.694 144.161 691.140 c f
BT 149.574 688.173 Td /F1 9.8 Tf  [(PCR amplification with )] TJ ET
BT 149.574 676.268 Td /F1 9.8 Tf  [(specific primers followed by )] TJ ET
BT 149.574 664.363 Td /F1 9.8 Tf  [(automated sequencing by )] TJ ET
BT 149.574 652.458 Td /F1 9.8 Tf  [(ABI PRISM 3730 was used )] TJ ET
BT 149.574 640.554 Td /F1 9.8 Tf  [(to identify )] TJ ET
BT 194.014 640.554 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 220.563 640.554 Td /F1 9.8 Tf  [( and )] TJ ET
BT 242.247 640.554 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 149.574 628.649 Td /F1 9.8 Tf  [(sequence variants.)] TJ ET
0.267 0.267 0.267 rg
283.469 776.625 157.203 0.750 re f
283.469 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
302.806 770.069 m 
302.806 770.515 302.623 770.959 302.307 771.275 c
301.991 771.591 301.547 771.775 301.100 771.775 c
300.653 771.775 300.210 771.591 299.894 771.275 c
299.578 770.959 299.394 770.515 299.394 770.069 c
299.394 769.622 299.578 769.178 299.894 768.862 c
300.210 768.546 300.653 768.363 301.100 768.363 c
301.547 768.363 301.991 768.546 302.307 768.862 c
302.623 769.178 302.806 769.622 302.806 770.069 c f
BT 308.219 767.101 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 767.101 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 755.196 Td /F1 9.8 Tf  [(were found in 34 of 113 )] TJ ET
BT 308.219 743.292 Td /F1 9.8 Tf  [(\(30.1%\) of pts. )] TJ ET
BT 374.334 743.292 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 731.387 Td /F1 9.8 Tf  [(sequence variants were )] TJ ET
BT 308.219 719.482 Td /F1 9.8 Tf  [(found in 11 of 79 \(13.9%\) )] TJ ET
BT 308.219 707.577 Td /F1 9.8 Tf  [(evaluable pts. The presence )] TJ ET
BT 308.219 695.673 Td /F1 9.8 Tf  [(of )] TJ ET
BT 319.061 695.673 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 345.064 695.673 Td /F1 9.8 Tf  [( and )] TJ ET
BT 366.748 695.673 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 683.768 Td /F1 9.8 Tf  [(sequence variants was )] TJ ET
BT 308.219 671.863 Td /F1 9.8 Tf  [(mutually exclusive.)] TJ ET
302.806 659.176 m 
302.806 659.623 302.623 660.067 302.307 660.383 c
301.991 660.698 301.547 660.882 301.100 660.882 c
300.653 660.882 300.210 660.698 299.894 660.383 c
299.578 660.067 299.394 659.623 299.394 659.176 c
299.394 658.729 299.578 658.285 299.894 657.969 c
300.210 657.654 300.653 657.470 301.100 657.470 c
301.547 657.470 301.991 657.654 302.307 657.969 c
302.623 658.285 302.806 658.729 302.806 659.176 c f
BT 308.219 656.208 Td /F1 9.8 Tf  [(Response to treatment was )] TJ ET
BT 308.219 644.304 Td /F1 9.8 Tf  [(lower in pts with than )] TJ ET
BT 308.219 632.399 Td /F1 9.8 Tf  [(without )] TJ ET
BT 341.817 632.399 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 367.821 632.399 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 620.494 Td /F1 9.8 Tf  [(variants \(0.0% versus )] TJ ET
BT 308.219 608.589 Td /F1 9.8 Tf  [(32.4%; P=0.029\).)] TJ ET
302.806 595.902 m 
302.806 596.349 302.623 596.793 302.307 597.109 c
301.991 597.425 301.547 597.609 301.100 597.609 c
300.653 597.609 300.210 597.425 299.894 597.109 c
299.578 596.793 299.394 596.349 299.394 595.902 c
299.394 595.456 299.578 595.012 299.894 594.696 c
300.210 594.380 300.653 594.196 301.100 594.196 c
301.547 594.196 301.991 594.380 302.307 594.696 c
302.623 595.012 302.806 595.456 302.806 595.902 c f
BT 308.219 592.935 Td /F1 9.8 Tf  [(In pts without )] TJ ET
BT 368.376 592.935 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 581.030 Td /F1 9.8 Tf  [(sequence variants, an )] TJ ET
BT 308.219 569.125 Td /F1 9.8 Tf  [(absence of )] TJ ET
BT 358.626 569.125 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 384.630 569.125 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 308.219 557.220 Td /F1 9.8 Tf  [(variants was associated with )] TJ ET
BT 308.219 545.316 Td /F1 9.8 Tf  [(increased PFS \(P=0.010\) )] TJ ET
BT 308.219 533.411 Td /F1 9.8 Tf  [(and OS \(P<0.0001\) in )] TJ ET
BT 308.219 521.506 Td /F1 9.8 Tf  [(Kaplan-Meier analyzes.)] TJ ET
0.267 0.267 0.267 rg
439.922 776.625 147.993 0.750 re f
439.922 507.125 0.750 270.250 re f
587.165 507.125 0.750 270.250 re f
0.271 0.267 0.267 rg
459.259 770.069 m 
459.259 770.515 459.076 770.959 458.760 771.275 c
458.444 771.591 458.000 771.775 457.553 771.775 c
457.107 771.775 456.663 771.591 456.347 771.275 c
456.031 770.959 455.847 770.515 455.847 770.069 c
455.847 769.622 456.031 769.178 456.347 768.862 c
456.663 768.546 457.107 768.363 457.553 768.363 c
458.000 768.363 458.444 768.546 458.760 768.862 c
459.076 769.178 459.259 769.622 459.259 770.069 c f
BT 464.672 767.101 Td /F1 9.8 Tf  [(87 pts received cetuximab )] TJ ET
BT 464.672 755.196 Td /F1 9.8 Tf  [(and 26 received )] TJ ET
BT 464.672 743.292 Td /F1 9.8 Tf  [(panitumumab.)] TJ ET
459.259 730.605 m 
459.259 731.051 459.076 731.495 458.760 731.811 c
458.444 732.127 458.000 732.311 457.553 732.311 c
457.107 732.311 456.663 732.127 456.347 731.811 c
456.031 731.495 455.847 731.051 455.847 730.605 c
455.847 730.158 456.031 729.714 456.347 729.398 c
456.663 729.082 457.107 728.898 457.553 728.898 c
458.000 728.898 458.444 729.082 458.760 729.398 c
459.076 729.714 459.259 730.158 459.259 730.605 c f
BT 464.672 727.637 Td /F1 9.8 Tf  [(Over all pts in the study, )] TJ ET
BT 464.672 715.732 Td /F1 9.8 Tf  [(response to treatment was )] TJ ET
BT 464.672 703.827 Td /F1 9.8 Tf  [(seen in 24 of 133 \(21.2%\) )] TJ ET
BT 464.672 691.923 Td /F1 9.8 Tf  [(of pts and the median )] TJ ET
BT 464.672 680.018 Td /F1 9.8 Tf  [(duration of response was )] TJ ET
BT 464.672 668.113 Td /F1 9.8 Tf  [(25 wks.)] TJ ET
0.267 0.267 0.267 rg
26.625 507.125 98.949 0.750 re f
26.625 332.864 98.949 0.750 re f
26.625 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
BT 31.875 497.270 Td /F1 9.8 Tf  [(Freeman and )] TJ ET
BT 31.875 489.639 Td /F1 9.8 Tf  [(colleagues \(2008\) )] TJ ET
0.267 0.267 0.267 rg
BT 31.875 482.008 Td /F1 9.8 Tf  [([44])] TJ ET
124.824 507.125 159.395 0.750 re f
124.824 332.864 159.395 0.750 re f
124.824 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
144.161 500.569 m 
144.161 501.016 143.977 501.460 143.661 501.776 c
143.346 502.091 142.902 502.275 142.455 502.275 c
142.008 502.275 141.564 502.091 141.248 501.776 c
140.933 501.460 140.749 501.016 140.749 500.569 c
140.749 500.122 140.933 499.678 141.248 499.362 c
141.564 499.047 142.008 498.863 142.455 498.863 c
142.902 498.863 143.346 499.047 143.661 499.362 c
143.977 499.678 144.161 500.122 144.161 500.569 c f
BT 149.574 497.601 Td /F1 9.8 Tf  [(Retrospective analysis of 62 )] TJ ET
BT 149.574 485.697 Td /F1 9.8 Tf  [(of the 533 pts involved in )] TJ ET
BT 149.574 473.792 Td /F1 9.8 Tf  [(phase II clinical trials that )] TJ ET
BT 149.574 461.887 Td /F1 9.8 Tf  [(received panitumumab in the )] TJ ET
BT 149.574 449.982 Td /F1 9.8 Tf  [(United States.)] TJ ET
144.161 437.295 m 
144.161 437.742 143.977 438.186 143.661 438.502 c
143.346 438.818 142.902 439.002 142.455 439.002 c
142.008 439.002 141.564 438.818 141.248 438.502 c
140.933 438.186 140.749 437.742 140.749 437.295 c
140.749 436.849 140.933 436.405 141.248 436.089 c
141.564 435.773 142.008 435.589 142.455 435.589 c
142.902 435.589 143.346 435.773 143.661 436.089 c
143.977 436.405 144.161 436.849 144.161 437.295 c f
BT 149.574 434.328 Td /F1 9.8 Tf  [(Primary or secondary )] TJ ET
BT 149.574 422.423 Td /F1 9.8 Tf  [(endpoints were not defined.)] TJ ET
144.161 409.736 m 
144.161 410.182 143.977 410.626 143.661 410.942 c
143.346 411.258 142.902 411.442 142.455 411.442 c
142.008 411.442 141.564 411.258 141.248 410.942 c
140.933 410.626 140.749 410.182 140.749 409.736 c
140.749 409.289 140.933 408.845 141.248 408.529 c
141.564 408.213 142.008 408.030 142.455 408.030 c
142.902 408.030 143.346 408.213 143.661 408.529 c
143.977 408.845 144.161 409.289 144.161 409.736 c f
BT 149.574 406.768 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 175.577 406.768 Td /F1 9.8 Tf  [( and )] TJ ET
BT 197.261 406.768 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 223.810 406.768 Td /F1 9.8 Tf  [( sequence )] TJ ET
BT 149.574 394.863 Td /F1 9.8 Tf  [(variants were analyzed using )] TJ ET
BT 149.574 382.959 Td /F1 9.8 Tf  [(PCR and sequencing.)] TJ ET
0.267 0.267 0.267 rg
283.469 507.125 157.203 0.750 re f
283.469 332.864 157.203 0.750 re f
283.469 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
302.806 500.569 m 
302.806 501.016 302.623 501.460 302.307 501.776 c
301.991 502.091 301.547 502.275 301.100 502.275 c
300.653 502.275 300.210 502.091 299.894 501.776 c
299.578 501.460 299.394 501.016 299.394 500.569 c
299.394 500.122 299.578 499.678 299.894 499.362 c
300.210 499.047 300.653 498.863 301.100 498.863 c
301.547 498.863 301.991 499.047 302.307 499.362 c
302.623 499.678 302.806 500.122 302.806 500.569 c f
BT 308.219 497.601 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 334.768 497.601 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 485.697 Td /F1 9.8 Tf  [(were identified in 24 of 62 )] TJ ET
BT 308.219 473.792 Td /F1 9.8 Tf  [(\(38.7%\) pts.)] TJ ET
302.806 461.105 m 
302.806 461.551 302.623 461.995 302.307 462.311 c
301.991 462.627 301.547 462.811 301.100 462.811 c
300.653 462.811 300.210 462.627 299.894 462.311 c
299.578 461.995 299.394 461.551 299.394 461.105 c
299.394 460.658 299.578 460.214 299.894 459.898 c
300.210 459.582 300.653 459.399 301.100 459.399 c
301.547 459.399 301.991 459.582 302.307 459.898 c
302.623 460.214 302.806 460.658 302.806 461.105 c f
BT 308.219 458.137 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 334.222 458.137 Td /F1 9.8 Tf  [( sequence variants )] TJ ET
BT 308.219 446.232 Td /F1 9.8 Tf  [(were found in 4 of the 62 )] TJ ET
BT 308.219 434.328 Td /F1 9.8 Tf  [(\(6.4%\) pts. The )] TJ ET
BT 377.580 434.328 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 308.219 422.423 Td /F1 9.8 Tf  [(status of these pts was not )] TJ ET
BT 308.219 410.518 Td /F1 9.8 Tf  [(clearly reported.)] TJ ET
302.806 397.831 m 
302.806 398.278 302.623 398.722 302.307 399.038 c
301.991 399.353 301.547 399.537 301.100 399.537 c
300.653 399.537 300.210 399.353 299.894 399.038 c
299.578 398.722 299.394 398.278 299.394 397.831 c
299.394 397.384 299.578 396.940 299.894 396.624 c
300.210 396.309 300.653 396.125 301.100 396.125 c
301.547 396.125 301.991 396.309 302.307 396.624 c
302.623 396.940 302.806 397.384 302.806 397.831 c f
BT 308.219 394.863 Td /F1 9.8 Tf  [(Of the 4 pts with )] TJ ET
BT 381.383 394.863 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 308.219 382.959 Td /F1 9.8 Tf  [(sequence variants, 1 had a )] TJ ET
BT 308.219 371.054 Td /F1 9.8 Tf  [(partial response, 1 had )] TJ ET
BT 308.219 359.149 Td /F1 9.8 Tf  [(stable disease and 2 had )] TJ ET
BT 308.219 347.244 Td /F1 9.8 Tf  [(progressive disease.)] TJ ET
0.267 0.267 0.267 rg
439.922 507.125 147.993 0.750 re f
439.922 332.864 147.993 0.750 re f
439.922 332.864 0.750 175.012 re f
587.165 332.864 0.750 175.012 re f
0.271 0.267 0.267 rg
459.259 500.569 m 
459.259 501.016 459.076 501.460 458.760 501.776 c
458.444 502.091 458.000 502.275 457.553 502.275 c
457.107 502.275 456.663 502.091 456.347 501.776 c
456.031 501.460 455.847 501.016 455.847 500.569 c
455.847 500.122 456.031 499.678 456.347 499.362 c
456.663 499.047 457.107 498.863 457.553 498.863 c
458.000 498.863 458.444 499.047 458.760 499.362 c
459.076 499.678 459.259 500.122 459.259 500.569 c f
BT 464.672 497.601 Td /F1 9.8 Tf  [(Across all pts, response to )] TJ ET
BT 464.672 485.697 Td /F1 9.8 Tf  [(treatment with )] TJ ET
BT 464.672 473.792 Td /F1 9.8 Tf  [(panitumumab was )] TJ ET
BT 464.672 461.887 Td /F1 9.8 Tf  [(observed by 4 of 62 )] TJ ET
BT 464.672 449.982 Td /F1 9.8 Tf  [(\(6.5%\) pts.)] TJ ET
40.337 288.432 m 
40.337 288.879 40.154 289.323 39.838 289.639 c
39.522 289.955 39.078 290.139 38.631 290.139 c
38.185 290.139 37.741 289.955 37.425 289.639 c
37.109 289.323 36.925 288.879 36.925 288.432 c
36.925 287.986 37.109 287.542 37.425 287.226 c
37.741 286.910 38.185 286.726 38.631 286.726 c
39.078 286.726 39.522 286.910 39.838 287.226 c
40.154 287.542 40.337 287.986 40.337 288.432 c f
BT 45.750 285.465 Td /F1 9.8 Tf  [(A meta-analysis of 4 of the above studies \(Di Nicolantonio )] TJ ET
0.267 0.267 0.267 rg
BT 298.275 285.465 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 314.538 285.465 Td /F1 9.8 Tf  [(, Laurent-Puig )] TJ ET
0.267 0.267 0.267 rg
BT 378.488 285.465 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 394.751 285.465 Td /F1 9.8 Tf  [(, Loupakis )] TJ ET
0.267 0.267 0.267 rg
BT 441.902 285.465 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 458.165 285.465 Td /F1 9.8 Tf  [(, and Sartore-Bianchi )] TJ ET
0.267 0.267 0.267 rg
BT 552.457 285.465 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 568.721 285.465 Td /F1 9.8 Tf  [( \) )] TJ ET
BT 45.750 273.560 Td /F1 9.8 Tf  [(was conducted in 2010 by Mao and colleagues to examine the relationship between BRAF sequence variants and )] TJ ET
BT 45.750 261.655 Td /F1 9.8 Tf  [(response to treatment with the EGFR monoclonal antibody inhibitors )] TJ ET
0.267 0.267 0.267 rg
BT 343.252 261.655 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 359.515 261.655 Td /F1 9.8 Tf  [(. The results of the meta-analysis indicate that in )] TJ ET
BT 45.750 249.750 Td /F1 9.8 Tf  [(patients without KRAS sequence variants, the objective response rate in patients with the BRAF p.Val600Glu sequence )] TJ ET
BT 45.750 237.846 Td /F1 9.8 Tf  [(variant was 0.0% \(0 of 40\); it was 36.3% \(122 of 336\) in patients without BRAF sequence variants. This resulted in a pooled )] TJ ET
BT 45.750 225.941 Td /F1 9.8 Tf  [(risk ratio of 0.14 \(95% CI, 0.04 to 0.53; P=0.004\). For progression-free survival, the difference between those with and )] TJ ET
BT 45.750 214.036 Td /F1 9.8 Tf  [(without BRAF sequence variants was not significant across the 2 studies that reported this endpoint. However, overall )] TJ ET
BT 45.750 202.131 Td /F1 9.8 Tf  [(survival was shorter for those patients with BRAF sequence variants compared to those without \(HR, 3.25; 95% CI, 1.63 to )] TJ ET
BT 45.750 190.227 Td /F1 9.8 Tf  [(6.47; P=0.001\) )] TJ ET
0.267 0.267 0.267 rg
BT 112.694 190.227 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 128.957 190.227 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 167.072 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 167.072 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 167.072 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 150.635 m 
40.337 151.081 40.154 151.525 39.838 151.841 c
39.522 152.157 39.078 152.341 38.631 152.341 c
38.185 152.341 37.741 152.157 37.425 151.841 c
37.109 151.525 36.925 151.081 36.925 150.635 c
36.925 150.188 37.109 149.744 37.425 149.428 c
37.741 149.112 38.185 148.929 38.631 148.929 c
39.078 148.929 39.522 149.112 39.838 149.428 c
40.154 149.744 40.337 150.188 40.337 150.635 c f
BT 45.750 147.667 Td /F1 9.8 Tf  [(No reports that prospectively investigated the clinical utility of genetic testing for the BRAF p.Val600Glu sequence variant )] TJ ET
BT 45.750 135.762 Td /F1 9.8 Tf  [(were identified. If detection of the BRAF p.Val600Glu sequence variant can be used to predict a lack of response to )] TJ ET
BT 45.750 123.858 Td /F1 9.8 Tf  [(treatment using cetuximab and panitumumab, such testing would have clinical utility in avoiding exposure to the EGFR )] TJ ET
BT 45.750 111.953 Td /F1 9.8 Tf  [(monoclonal antibody inhibitors, which are associated with serious adverse effects, in patients who are unlikely to benefit. A )] TJ ET
BT 45.750 100.048 Td /F1 9.8 Tf  [(potential harm of testing for the BRAF p.Val600Glu sequence variant is if the presence of this variant does not accurately )] TJ ET
BT 45.750 88.143 Td /F1 9.8 Tf  [(predict a lack of response to the anti-EGFR monoclonal antibody, a potentially efficacious treatment would be denied to )] TJ ET
BT 45.750 76.239 Td /F1 9.8 Tf  [(BRAF p.Val600Glu-positive patients.)] TJ ET
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BT 291.710 19.825 Td /F1 11.0 Tf  [(6)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 26.250 750.278 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
0.271 0.267 0.267 RG
40.337 733.292 m 
40.337 733.738 40.154 734.182 39.838 734.498 c
39.522 734.814 39.078 734.998 38.631 734.998 c
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BT 45.750 730.324 Td /F1 9.8 Tf  [(Data that define the analytical validity of the commercially available assays for the)] TJ ET
BT 397.978 730.324 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 429.403 730.324 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant are )] TJ ET
BT 45.750 718.419 Td /F1 9.8 Tf  [(limited.)] TJ ET
40.337 705.732 m 
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38.185 707.438 37.741 707.255 37.425 706.939 c
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36.925 705.286 37.109 704.842 37.425 704.526 c
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39.078 704.026 39.522 704.210 39.838 704.526 c
40.154 704.842 40.337 705.286 40.337 705.732 c f
BT 45.750 702.765 Td /F1 9.8 Tf  [(The clinical validity of testing for the)] TJ ET
BT 199.644 702.765 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 231.068 702.765 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant to predict response to treatment with cetuximab )] TJ ET
BT 45.750 690.860 Td /F1 9.8 Tf  [(or panitumumab has been investigated in mainly retrospective cohort studies )] TJ ET
0.267 0.267 0.267 rg
BT 379.561 690.860 Td /F1 9.8 Tf  [([19] [39] [40] [41] [42] [43] [44] [46])] TJ ET
0.271 0.267 0.267 rg
BT 528.638 690.860 Td /F1 9.8 Tf  [(. Across )] TJ ET
BT 45.750 678.955 Td /F1 9.8 Tf  [(these studies, the incidence of)] TJ ET
BT 176.907 678.955 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 208.331 678.955 Td /F1 9.8 Tf  [(sequence variants ranged from 4.3% to 14.9% of patients with CRC. Two of these )] TJ ET
BT 45.750 667.050 Td /F1 9.8 Tf  [(studies only reported data from patients who had previously tested negative for)] TJ ET
BT 386.084 667.050 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 418.054 667.050 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 499.886 667.050 Td /F1 9.8 Tf  [([39][43])] TJ ET
0.271 0.267 0.267 rg
BT 532.412 667.050 Td /F1 9.8 Tf  [(; however, )] TJ ET
BT 45.750 655.146 Td /F1 9.8 Tf  [(since patients tend not to have both )] TJ ET
BT 202.393 655.146 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 231.653 655.146 Td /F1 9.8 Tf  [(and)] TJ ET
BT 247.916 655.146 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 279.341 655.146 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 361.172 655.146 Td /F1 9.8 Tf  [([19] [40] [42] [46])] TJ ET
0.271 0.267 0.267 rg
BT 434.356 655.146 Td /F1 9.8 Tf  [(, only including patients who are)] TJ ET
BT 45.750 643.241 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 75.010 643.241 Td /F1 9.8 Tf  [(negative should not greatly affect the proportion of patients with )] TJ ET
BT 351.413 643.241 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 380.126 643.241 Td /F1 9.8 Tf  [(sequence variants. Seven studies reported )] TJ ET
BT 45.750 631.336 Td /F1 9.8 Tf  [(the response to treatment with cetuximab or panitumumab in patients with the)] TJ ET
BT 380.653 631.336 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 409.367 631.336 Td /F1 9.8 Tf  [( p.Val600Glu sequence variants and )] TJ ET
BT 45.750 619.431 Td /F1 9.8 Tf  [(observed the following responses: 1 of 34 patients \(excluding the patient with the p.Asp549Gly sequence variant\) )] TJ ET
0.267 0.267 0.267 rg
BT 535.668 619.431 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 551.931 619.431 Td /F1 9.8 Tf  [(; 0 of )] TJ ET
BT 45.750 607.527 Td /F1 9.8 Tf  [(13 patients )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 607.527 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 607.527 Td /F1 9.8 Tf  [(; 0 of 11 patients )] TJ ET
0.267 0.267 0.267 rg
BT 187.223 607.527 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 203.486 607.527 Td /F1 9.8 Tf  [(; 0 of 9 patients )] TJ ET
0.267 0.267 0.267 rg
BT 272.867 607.527 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 289.130 607.527 Td /F1 9.8 Tf  [(; 0 of 5 patients )] TJ ET
0.267 0.267 0.267 rg
BT 358.511 607.527 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 374.774 607.527 Td /F1 9.8 Tf  [(; 1 of 4 patients )] TJ ET
0.267 0.267 0.267 rg
BT 444.154 607.527 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 460.417 607.527 Td /F1 9.8 Tf  [(; and 1 of 2 patients )] TJ ET
0.267 0.267 0.267 rg
BT 548.772 607.527 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 565.035 607.527 Td /F1 9.8 Tf  [(. )] TJ ET
BT 45.750 595.622 Td /F1 9.8 Tf  [(Across these 7 studies, only 3 of 78 patients with a )] TJ ET
BT 267.406 595.622 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 293.410 595.622 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant responded to treatment with )] TJ ET
BT 45.750 583.717 Td /F1 9.8 Tf  [(cetuximab or panitumumab. Caution should be used in interpreting these data as there is an overlap in patients included in )] TJ ET
BT 45.750 571.812 Td /F1 9.8 Tf  [(the study of De Roock and colleagues and other European studies, )] TJ ET
0.267 0.267 0.267 rg
BT 337.870 571.812 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 354.133 571.812 Td /F1 9.8 Tf  [( and all studies were retrospective in design.)] TJ ET
40.337 559.125 m 
40.337 559.572 40.154 560.016 39.838 560.332 c
39.522 560.648 39.078 560.831 38.631 560.831 c
38.185 560.831 37.741 560.648 37.425 560.332 c
37.109 560.016 36.925 559.572 36.925 559.125 c
36.925 558.679 37.109 558.235 37.425 557.919 c
37.741 557.603 38.185 557.419 38.631 557.419 c
39.078 557.419 39.522 557.603 39.838 557.919 c
40.154 558.235 40.337 558.679 40.337 559.125 c f
BT 45.750 556.158 Td /F1 9.8 Tf  [(The response to treatment with anti-EGFR monoclonal antibodies in patients without )] TJ ET
BT 412.077 556.158 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 438.626 556.158 Td /F1 9.8 Tf  [( variants or the)] TJ ET
BT 503.113 556.158 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 45.750 544.253 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant ranged from 27.6% to 46.4% in the 6 studies that reported this figure )] TJ ET
0.267 0.267 0.267 rg
BT 477.149 544.253 Td /F1 9.8 Tf  [([19] [40] [41] [42] [43] )] TJ ET
BT 45.750 532.348 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 532.348 Td /F1 9.8 Tf  [(, with 4 studies finding significant difference in response rates between patients with and without the )] TJ ET
BT 495.020 532.348 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 523.734 532.348 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 520.443 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 520.443 Td /F1 9.8 Tf  [([19][39][41][46])] TJ ET
0.271 0.267 0.267 rg
BT 187.759 520.443 Td /F1 9.8 Tf  [(. The presence of the)] TJ ET
BT 279.896 520.443 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 311.321 520.443 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated )] TJ ET
BT 45.750 508.539 Td /F1 9.8 Tf  [(with progression-free survival in 4 studies )] TJ ET
0.267 0.267 0.267 rg
BT 227.266 508.539 Td /F1 9.8 Tf  [([19][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 292.318 508.539 Td /F1 9.8 Tf  [(, but no association was found in 2 studies that reported this )] TJ ET
BT 45.750 496.634 Td /F1 9.8 Tf  [(endpoint )] TJ ET
0.267 0.267 0.267 rg
BT 85.862 496.634 Td /F1 9.8 Tf  [([39][40])] TJ ET
0.271 0.267 0.267 rg
BT 118.388 496.634 Td /F1 9.8 Tf  [(. Similarly, the presence of the )] TJ ET
BT 252.236 496.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 280.949 496.634 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated with )] TJ ET
BT 45.750 484.729 Td /F1 9.8 Tf  [(overall survival in all of the 5 studies )] TJ ET
0.267 0.267 0.267 rg
BT 204.519 484.729 Td /F1 9.8 Tf  [([39][40][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 285.834 484.729 Td /F1 9.8 Tf  [( that reported this endpoint.)] TJ ET
40.337 472.042 m 
40.337 472.489 40.154 472.933 39.838 473.249 c
39.522 473.564 39.078 473.748 38.631 473.748 c
38.185 473.748 37.741 473.564 37.425 473.249 c
37.109 472.933 36.925 472.489 36.925 472.042 c
36.925 471.595 37.109 471.151 37.425 470.835 c
37.741 470.520 38.185 470.336 38.631 470.336 c
39.078 470.336 39.522 470.520 39.838 470.835 c
40.154 471.151 40.337 471.595 40.337 472.042 c f
BT 45.750 469.074 Td /F1 9.8 Tf  [(Available data suggest that CRC patients with the)] TJ ET
BT 259.811 469.074 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 291.236 469.074 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant rarely respond to treatment with )] TJ ET
BT 45.750 457.170 Td /F1 9.8 Tf  [(cetuximab or panitumumab. However, data are only available from retrospective studies that consisted mostly of cohorts of )] TJ ET
BT 45.750 445.265 Td /F1 9.8 Tf  [(patients, rather than from randomized trials. Only 4.3% to 14.9% of patients with CRC were found to have the )] TJ ET
BT 519.385 445.265 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 433.360 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant. As a consequence, the number of patients with)] TJ ET
BT 384.475 433.360 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 415.899 433.360 Td /F1 9.8 Tf  [(sequence variants in the CRC )] TJ ET
BT 45.750 421.455 Td /F1 9.8 Tf  [(population who are negative for)] TJ ET
BT 181.782 421.455 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 213.752 421.455 Td /F1 9.8 Tf  [(sequence variants is small. This is much lower than the percentage of )] TJ ET
BT 517.211 421.455 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 409.551 Td /F1 9.8 Tf  [(sequence variants found in the CRC population at 40% to 45% )] TJ ET
0.267 0.267 0.267 rg
BT 318.896 409.551 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 335.159 409.551 Td /F1 9.8 Tf  [(. In the studies included in this review, a total of only 78 )] TJ ET
BT 45.750 397.646 Td /F1 9.8 Tf  [(patients with the )] TJ ET
BT 118.914 397.646 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 147.628 397.646 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant were available to assess the response to treatment \(and there was )] TJ ET
BT 45.750 385.741 Td /F1 9.8 Tf  [(some overlap in patients between studies\). Available data suggest that testing for the)] TJ ET
BT 412.106 385.741 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 440.820 385.741 Td /F1 9.8 Tf  [( sequence variant has promise )] TJ ET
BT 45.750 373.836 Td /F1 9.8 Tf  [(in predicting which patients will not respond to treatment with EGFR monoclonal antibody inhibitors. However, the )] TJ ET
BT 45.750 361.932 Td /F1 9.8 Tf  [(retrospective nature of the studies combined with the low number of patients included in)] TJ ET
BT 424.011 361.932 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 455.435 361.932 Td /F1 9.8 Tf  [(p.Val600Glu sequence )] TJ ET
BT 45.750 350.027 Td /F1 9.8 Tf  [(variant testing means that confirmation in larger prospective studies is needed before routine testing for the )] TJ ET
BT 509.635 350.027 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 338.122 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant can be recommended.)] TJ ET
BT 26.250 297.770 Td /F4 12.0 Tf  [(Links)] TJ ET
40.337 280.783 m 
40.337 281.230 40.154 281.674 39.838 281.990 c
39.522 282.305 39.078 282.489 38.631 282.489 c
38.185 282.489 37.741 282.305 37.425 281.990 c
37.109 281.674 36.925 281.230 36.925 280.783 c
36.925 280.336 37.109 279.892 37.425 279.576 c
37.741 279.261 38.185 279.077 38.631 279.077 c
39.078 279.077 39.522 279.261 39.838 279.576 c
40.154 279.892 40.337 280.336 40.337 280.783 c f
0.267 0.267 0.267 rg
BT 45.750 277.815 Td /F1 9.8 Tf  [(Clinical Trials.gov)] TJ ET
0.271 0.267 0.267 rg
BT 122.132 277.815 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 127.553 277.815 Td /F1 9.8 Tf  [(BRAF and colorectal cancer)] TJ ET
0.271 0.267 0.267 rg
40.337 265.128 m 
40.337 265.575 40.154 266.019 39.838 266.335 c
39.522 266.651 39.078 266.834 38.631 266.834 c
38.185 266.834 37.741 266.651 37.425 266.335 c
37.109 266.019 36.925 265.575 36.925 265.128 c
36.925 264.682 37.109 264.238 37.425 263.922 c
37.741 263.606 38.185 263.422 38.631 263.422 c
39.078 263.422 39.522 263.606 39.838 263.922 c
40.154 264.238 40.337 264.682 40.337 265.128 c f
0.267 0.267 0.267 rg
BT 45.750 262.161 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man)] TJ ET
0.271 0.267 0.267 rg
BT 204.529 262.161 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 209.950 262.161 Td /F1 9.8 Tf  [(BRAF)] TJ ET
0.271 0.267 0.267 rg
40.337 249.473 m 
40.337 249.920 40.154 250.364 39.838 250.680 c
39.522 250.996 39.078 251.180 38.631 251.180 c
38.185 251.180 37.741 250.996 37.425 250.680 c
37.109 250.364 36.925 249.920 36.925 249.473 c
36.925 249.027 37.109 248.583 37.425 248.267 c
37.741 247.951 38.185 247.767 38.631 247.767 c
39.078 247.767 39.522 247.951 39.838 248.267 c
40.154 248.583 40.337 249.027 40.337 249.473 c f
0.267 0.267 0.267 rg
BT 45.750 246.506 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration)] TJ ET
0.271 0.267 0.267 rg
BT 196.934 246.506 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 202.355 246.506 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 223.351 Td /F1 9.8 Tf  [(Last updated: October 17, 2010)] TJ ET
BT 26.250 186.749 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 166.794 Td /F1 9.8 Tf  [(The authors would like to acknowledge the contributions of the members of the Hayes Genetic Test Evaluation team, )] TJ ET
BT 26.250 154.890 Td /F1 9.8 Tf  [(particularly Lisa Spock, Linnie Wieselquist and Charlotte Kuo-Benitez.)] TJ ET
BT 26.250 118.287 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 98.333 Td /F1 9.8 Tf  [(Funding for the Health Technology Assessment that informed this work was provided by Hayes, Incorporated. Funding to create )] TJ ET
BT 26.250 86.428 Td /F1 9.8 Tf  [(this Knol was provided by the Centers for Disease Control and Prevention under Contract No. 200-2009-F-32675.This funding )] TJ ET
BT 26.250 74.523 Td /F1 9.8 Tf  [(was provided through the Genetic Alliance.)] TJ ET
Q
q
15.000 27.490 577.500 749.510 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
0.271 0.267 0.267 RG
40.337 733.292 m 
40.337 733.738 40.154 734.182 39.838 734.498 c
39.522 734.814 39.078 734.998 38.631 734.998 c
38.185 734.998 37.741 734.814 37.425 734.498 c
37.109 734.182 36.925 733.738 36.925 733.292 c
36.925 732.845 37.109 732.401 37.425 732.085 c
37.741 731.769 38.185 731.586 38.631 731.586 c
39.078 731.586 39.522 731.769 39.838 732.085 c
40.154 732.401 40.337 732.845 40.337 733.292 c f
BT 45.750 730.324 Td /F1 9.8 Tf  [(Data that define the analytical validity of the commercially available assays for the)] TJ ET
BT 397.978 730.324 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 429.403 730.324 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant are )] TJ ET
BT 45.750 718.419 Td /F1 9.8 Tf  [(limited.)] TJ ET
40.337 705.732 m 
40.337 706.179 40.154 706.623 39.838 706.939 c
39.522 707.255 39.078 707.438 38.631 707.438 c
38.185 707.438 37.741 707.255 37.425 706.939 c
37.109 706.623 36.925 706.179 36.925 705.732 c
36.925 705.286 37.109 704.842 37.425 704.526 c
37.741 704.210 38.185 704.026 38.631 704.026 c
39.078 704.026 39.522 704.210 39.838 704.526 c
40.154 704.842 40.337 705.286 40.337 705.732 c f
BT 45.750 702.765 Td /F1 9.8 Tf  [(The clinical validity of testing for the)] TJ ET
BT 199.644 702.765 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 231.068 702.765 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant to predict response to treatment with cetuximab )] TJ ET
BT 45.750 690.860 Td /F1 9.8 Tf  [(or panitumumab has been investigated in mainly retrospective cohort studies )] TJ ET
0.267 0.267 0.267 rg
BT 379.561 690.860 Td /F1 9.8 Tf  [([19] [39] [40] [41] [42] [43] [44] [46])] TJ ET
0.271 0.267 0.267 rg
BT 528.638 690.860 Td /F1 9.8 Tf  [(. Across )] TJ ET
BT 45.750 678.955 Td /F1 9.8 Tf  [(these studies, the incidence of)] TJ ET
BT 176.907 678.955 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 208.331 678.955 Td /F1 9.8 Tf  [(sequence variants ranged from 4.3% to 14.9% of patients with CRC. Two of these )] TJ ET
BT 45.750 667.050 Td /F1 9.8 Tf  [(studies only reported data from patients who had previously tested negative for)] TJ ET
BT 386.084 667.050 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 418.054 667.050 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 499.886 667.050 Td /F1 9.8 Tf  [([39][43])] TJ ET
0.271 0.267 0.267 rg
BT 532.412 667.050 Td /F1 9.8 Tf  [(; however, )] TJ ET
BT 45.750 655.146 Td /F1 9.8 Tf  [(since patients tend not to have both )] TJ ET
BT 202.393 655.146 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 231.653 655.146 Td /F1 9.8 Tf  [(and)] TJ ET
BT 247.916 655.146 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 279.341 655.146 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 361.172 655.146 Td /F1 9.8 Tf  [([19] [40] [42] [46])] TJ ET
0.271 0.267 0.267 rg
BT 434.356 655.146 Td /F1 9.8 Tf  [(, only including patients who are)] TJ ET
BT 45.750 643.241 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 75.010 643.241 Td /F1 9.8 Tf  [(negative should not greatly affect the proportion of patients with )] TJ ET
BT 351.413 643.241 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 380.126 643.241 Td /F1 9.8 Tf  [(sequence variants. Seven studies reported )] TJ ET
BT 45.750 631.336 Td /F1 9.8 Tf  [(the response to treatment with cetuximab or panitumumab in patients with the)] TJ ET
BT 380.653 631.336 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 409.367 631.336 Td /F1 9.8 Tf  [( p.Val600Glu sequence variants and )] TJ ET
BT 45.750 619.431 Td /F1 9.8 Tf  [(observed the following responses: 1 of 34 patients \(excluding the patient with the p.Asp549Gly sequence variant\) )] TJ ET
0.267 0.267 0.267 rg
BT 535.668 619.431 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 551.931 619.431 Td /F1 9.8 Tf  [(; 0 of )] TJ ET
BT 45.750 607.527 Td /F1 9.8 Tf  [(13 patients )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 607.527 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 607.527 Td /F1 9.8 Tf  [(; 0 of 11 patients )] TJ ET
0.267 0.267 0.267 rg
BT 187.223 607.527 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 203.486 607.527 Td /F1 9.8 Tf  [(; 0 of 9 patients )] TJ ET
0.267 0.267 0.267 rg
BT 272.867 607.527 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 289.130 607.527 Td /F1 9.8 Tf  [(; 0 of 5 patients )] TJ ET
0.267 0.267 0.267 rg
BT 358.511 607.527 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 374.774 607.527 Td /F1 9.8 Tf  [(; 1 of 4 patients )] TJ ET
0.267 0.267 0.267 rg
BT 444.154 607.527 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 460.417 607.527 Td /F1 9.8 Tf  [(; and 1 of 2 patients )] TJ ET
0.267 0.267 0.267 rg
BT 548.772 607.527 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 565.035 607.527 Td /F1 9.8 Tf  [(. )] TJ ET
BT 45.750 595.622 Td /F1 9.8 Tf  [(Across these 7 studies, only 3 of 78 patients with a )] TJ ET
BT 267.406 595.622 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 293.410 595.622 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant responded to treatment with )] TJ ET
BT 45.750 583.717 Td /F1 9.8 Tf  [(cetuximab or panitumumab. Caution should be used in interpreting these data as there is an overlap in patients included in )] TJ ET
BT 45.750 571.812 Td /F1 9.8 Tf  [(the study of De Roock and colleagues and other European studies, )] TJ ET
0.267 0.267 0.267 rg
BT 337.870 571.812 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 354.133 571.812 Td /F1 9.8 Tf  [( and all studies were retrospective in design.)] TJ ET
40.337 559.125 m 
40.337 559.572 40.154 560.016 39.838 560.332 c
39.522 560.648 39.078 560.831 38.631 560.831 c
38.185 560.831 37.741 560.648 37.425 560.332 c
37.109 560.016 36.925 559.572 36.925 559.125 c
36.925 558.679 37.109 558.235 37.425 557.919 c
37.741 557.603 38.185 557.419 38.631 557.419 c
39.078 557.419 39.522 557.603 39.838 557.919 c
40.154 558.235 40.337 558.679 40.337 559.125 c f
BT 45.750 556.158 Td /F1 9.8 Tf  [(The response to treatment with anti-EGFR monoclonal antibodies in patients without )] TJ ET
BT 412.077 556.158 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 438.626 556.158 Td /F1 9.8 Tf  [( variants or the)] TJ ET
BT 503.113 556.158 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 45.750 544.253 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant ranged from 27.6% to 46.4% in the 6 studies that reported this figure )] TJ ET
0.267 0.267 0.267 rg
BT 477.149 544.253 Td /F1 9.8 Tf  [([19] [40] [41] [42] [43] )] TJ ET
BT 45.750 532.348 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 532.348 Td /F1 9.8 Tf  [(, with 4 studies finding significant difference in response rates between patients with and without the )] TJ ET
BT 495.020 532.348 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 523.734 532.348 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 520.443 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 520.443 Td /F1 9.8 Tf  [([19][39][41][46])] TJ ET
0.271 0.267 0.267 rg
BT 187.759 520.443 Td /F1 9.8 Tf  [(. The presence of the)] TJ ET
BT 279.896 520.443 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 311.321 520.443 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated )] TJ ET
BT 45.750 508.539 Td /F1 9.8 Tf  [(with progression-free survival in 4 studies )] TJ ET
0.267 0.267 0.267 rg
BT 227.266 508.539 Td /F1 9.8 Tf  [([19][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 292.318 508.539 Td /F1 9.8 Tf  [(, but no association was found in 2 studies that reported this )] TJ ET
BT 45.750 496.634 Td /F1 9.8 Tf  [(endpoint )] TJ ET
0.267 0.267 0.267 rg
BT 85.862 496.634 Td /F1 9.8 Tf  [([39][40])] TJ ET
0.271 0.267 0.267 rg
BT 118.388 496.634 Td /F1 9.8 Tf  [(. Similarly, the presence of the )] TJ ET
BT 252.236 496.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 280.949 496.634 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated with )] TJ ET
BT 45.750 484.729 Td /F1 9.8 Tf  [(overall survival in all of the 5 studies )] TJ ET
0.267 0.267 0.267 rg
BT 204.519 484.729 Td /F1 9.8 Tf  [([39][40][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 285.834 484.729 Td /F1 9.8 Tf  [( that reported this endpoint.)] TJ ET
40.337 472.042 m 
40.337 472.489 40.154 472.933 39.838 473.249 c
39.522 473.564 39.078 473.748 38.631 473.748 c
38.185 473.748 37.741 473.564 37.425 473.249 c
37.109 472.933 36.925 472.489 36.925 472.042 c
36.925 471.595 37.109 471.151 37.425 470.835 c
37.741 470.520 38.185 470.336 38.631 470.336 c
39.078 470.336 39.522 470.520 39.838 470.835 c
40.154 471.151 40.337 471.595 40.337 472.042 c f
BT 45.750 469.074 Td /F1 9.8 Tf  [(Available data suggest that CRC patients with the)] TJ ET
BT 259.811 469.074 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 291.236 469.074 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant rarely respond to treatment with )] TJ ET
BT 45.750 457.170 Td /F1 9.8 Tf  [(cetuximab or panitumumab. However, data are only available from retrospective studies that consisted mostly of cohorts of )] TJ ET
BT 45.750 445.265 Td /F1 9.8 Tf  [(patients, rather than from randomized trials. Only 4.3% to 14.9% of patients with CRC were found to have the )] TJ ET
BT 519.385 445.265 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 433.360 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant. As a consequence, the number of patients with)] TJ ET
BT 384.475 433.360 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 415.899 433.360 Td /F1 9.8 Tf  [(sequence variants in the CRC )] TJ ET
BT 45.750 421.455 Td /F1 9.8 Tf  [(population who are negative for)] TJ ET
BT 181.782 421.455 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 213.752 421.455 Td /F1 9.8 Tf  [(sequence variants is small. This is much lower than the percentage of )] TJ ET
BT 517.211 421.455 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 409.551 Td /F1 9.8 Tf  [(sequence variants found in the CRC population at 40% to 45% )] TJ ET
0.267 0.267 0.267 rg
BT 318.896 409.551 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 335.159 409.551 Td /F1 9.8 Tf  [(. In the studies included in this review, a total of only 78 )] TJ ET
BT 45.750 397.646 Td /F1 9.8 Tf  [(patients with the )] TJ ET
BT 118.914 397.646 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 147.628 397.646 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant were available to assess the response to treatment \(and there was )] TJ ET
BT 45.750 385.741 Td /F1 9.8 Tf  [(some overlap in patients between studies\). Available data suggest that testing for the)] TJ ET
BT 412.106 385.741 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 440.820 385.741 Td /F1 9.8 Tf  [( sequence variant has promise )] TJ ET
BT 45.750 373.836 Td /F1 9.8 Tf  [(in predicting which patients will not respond to treatment with EGFR monoclonal antibody inhibitors. However, the )] TJ ET
BT 45.750 361.932 Td /F1 9.8 Tf  [(retrospective nature of the studies combined with the low number of patients included in)] TJ ET
BT 424.011 361.932 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 455.435 361.932 Td /F1 9.8 Tf  [(p.Val600Glu sequence )] TJ ET
BT 45.750 350.027 Td /F1 9.8 Tf  [(variant testing means that confirmation in larger prospective studies is needed before routine testing for the )] TJ ET
BT 509.635 350.027 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 338.122 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant can be recommended.)] TJ ET
BT 26.250 297.770 Td /F4 12.0 Tf  [(Links)] TJ ET
40.337 280.783 m 
40.337 281.230 40.154 281.674 39.838 281.990 c
39.522 282.305 39.078 282.489 38.631 282.489 c
38.185 282.489 37.741 282.305 37.425 281.990 c
37.109 281.674 36.925 281.230 36.925 280.783 c
36.925 280.336 37.109 279.892 37.425 279.576 c
37.741 279.261 38.185 279.077 38.631 279.077 c
39.078 279.077 39.522 279.261 39.838 279.576 c
40.154 279.892 40.337 280.336 40.337 280.783 c f
0.267 0.267 0.267 rg
BT 45.750 277.815 Td /F1 9.8 Tf  [(Clinical Trials.gov)] TJ ET
0.271 0.267 0.267 rg
BT 122.132 277.815 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 127.553 277.815 Td /F1 9.8 Tf  [(BRAF and colorectal cancer)] TJ ET
0.271 0.267 0.267 rg
40.337 265.128 m 
40.337 265.575 40.154 266.019 39.838 266.335 c
39.522 266.651 39.078 266.834 38.631 266.834 c
38.185 266.834 37.741 266.651 37.425 266.335 c
37.109 266.019 36.925 265.575 36.925 265.128 c
36.925 264.682 37.109 264.238 37.425 263.922 c
37.741 263.606 38.185 263.422 38.631 263.422 c
39.078 263.422 39.522 263.606 39.838 263.922 c
40.154 264.238 40.337 264.682 40.337 265.128 c f
0.267 0.267 0.267 rg
BT 45.750 262.161 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man)] TJ ET
0.271 0.267 0.267 rg
BT 204.529 262.161 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 209.950 262.161 Td /F1 9.8 Tf  [(BRAF)] TJ ET
0.271 0.267 0.267 rg
40.337 249.473 m 
40.337 249.920 40.154 250.364 39.838 250.680 c
39.522 250.996 39.078 251.180 38.631 251.180 c
38.185 251.180 37.741 250.996 37.425 250.680 c
37.109 250.364 36.925 249.920 36.925 249.473 c
36.925 249.027 37.109 248.583 37.425 248.267 c
37.741 247.951 38.185 247.767 38.631 247.767 c
39.078 247.767 39.522 247.951 39.838 248.267 c
40.154 248.583 40.337 249.027 40.337 249.473 c f
0.267 0.267 0.267 rg
BT 45.750 246.506 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration)] TJ ET
0.271 0.267 0.267 rg
BT 196.934 246.506 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 202.355 246.506 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 223.351 Td /F1 9.8 Tf  [(Last updated: October 17, 2010)] TJ ET
BT 26.250 186.749 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 166.794 Td /F1 9.8 Tf  [(The authors would like to acknowledge the contributions of the members of the Hayes Genetic Test Evaluation team, )] TJ ET
BT 26.250 154.890 Td /F1 9.8 Tf  [(particularly Lisa Spock, Linnie Wieselquist and Charlotte Kuo-Benitez.)] TJ ET
BT 26.250 118.287 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 98.333 Td /F1 9.8 Tf  [(Funding for the Health Technology Assessment that informed this work was provided by Hayes, Incorporated. Funding to create )] TJ ET
BT 26.250 86.428 Td /F1 9.8 Tf  [(this Knol was provided by the Centers for Disease Control and Prevention under Contract No. 200-2009-F-32675.This funding )] TJ ET
BT 26.250 74.523 Td /F1 9.8 Tf  [(was provided through the Genetic Alliance.)] TJ ET
Q
q
15.000 27.490 577.500 749.510 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
0.271 0.267 0.267 RG
40.337 733.292 m 
40.337 733.738 40.154 734.182 39.838 734.498 c
39.522 734.814 39.078 734.998 38.631 734.998 c
38.185 734.998 37.741 734.814 37.425 734.498 c
37.109 734.182 36.925 733.738 36.925 733.292 c
36.925 732.845 37.109 732.401 37.425 732.085 c
37.741 731.769 38.185 731.586 38.631 731.586 c
39.078 731.586 39.522 731.769 39.838 732.085 c
40.154 732.401 40.337 732.845 40.337 733.292 c f
BT 45.750 730.324 Td /F1 9.8 Tf  [(Data that define the analytical validity of the commercially available assays for the)] TJ ET
BT 397.978 730.324 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 429.403 730.324 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant are )] TJ ET
BT 45.750 718.419 Td /F1 9.8 Tf  [(limited.)] TJ ET
40.337 705.732 m 
40.337 706.179 40.154 706.623 39.838 706.939 c
39.522 707.255 39.078 707.438 38.631 707.438 c
38.185 707.438 37.741 707.255 37.425 706.939 c
37.109 706.623 36.925 706.179 36.925 705.732 c
36.925 705.286 37.109 704.842 37.425 704.526 c
37.741 704.210 38.185 704.026 38.631 704.026 c
39.078 704.026 39.522 704.210 39.838 704.526 c
40.154 704.842 40.337 705.286 40.337 705.732 c f
BT 45.750 702.765 Td /F1 9.8 Tf  [(The clinical validity of testing for the)] TJ ET
BT 199.644 702.765 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 231.068 702.765 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant to predict response to treatment with cetuximab )] TJ ET
BT 45.750 690.860 Td /F1 9.8 Tf  [(or panitumumab has been investigated in mainly retrospective cohort studies )] TJ ET
0.267 0.267 0.267 rg
BT 379.561 690.860 Td /F1 9.8 Tf  [([19] [39] [40] [41] [42] [43] [44] [46])] TJ ET
0.271 0.267 0.267 rg
BT 528.638 690.860 Td /F1 9.8 Tf  [(. Across )] TJ ET
BT 45.750 678.955 Td /F1 9.8 Tf  [(these studies, the incidence of)] TJ ET
BT 176.907 678.955 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 208.331 678.955 Td /F1 9.8 Tf  [(sequence variants ranged from 4.3% to 14.9% of patients with CRC. Two of these )] TJ ET
BT 45.750 667.050 Td /F1 9.8 Tf  [(studies only reported data from patients who had previously tested negative for)] TJ ET
BT 386.084 667.050 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 418.054 667.050 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 499.886 667.050 Td /F1 9.8 Tf  [([39][43])] TJ ET
0.271 0.267 0.267 rg
BT 532.412 667.050 Td /F1 9.8 Tf  [(; however, )] TJ ET
BT 45.750 655.146 Td /F1 9.8 Tf  [(since patients tend not to have both )] TJ ET
BT 202.393 655.146 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 231.653 655.146 Td /F1 9.8 Tf  [(and)] TJ ET
BT 247.916 655.146 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 279.341 655.146 Td /F1 9.8 Tf  [(sequence variants )] TJ ET
0.267 0.267 0.267 rg
BT 361.172 655.146 Td /F1 9.8 Tf  [([19] [40] [42] [46])] TJ ET
0.271 0.267 0.267 rg
BT 434.356 655.146 Td /F1 9.8 Tf  [(, only including patients who are)] TJ ET
BT 45.750 643.241 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 75.010 643.241 Td /F1 9.8 Tf  [(negative should not greatly affect the proportion of patients with )] TJ ET
BT 351.413 643.241 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 380.126 643.241 Td /F1 9.8 Tf  [(sequence variants. Seven studies reported )] TJ ET
BT 45.750 631.336 Td /F1 9.8 Tf  [(the response to treatment with cetuximab or panitumumab in patients with the)] TJ ET
BT 380.653 631.336 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 409.367 631.336 Td /F1 9.8 Tf  [( p.Val600Glu sequence variants and )] TJ ET
BT 45.750 619.431 Td /F1 9.8 Tf  [(observed the following responses: 1 of 34 patients \(excluding the patient with the p.Asp549Gly sequence variant\) )] TJ ET
0.267 0.267 0.267 rg
BT 535.668 619.431 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 551.931 619.431 Td /F1 9.8 Tf  [(; 0 of )] TJ ET
BT 45.750 607.527 Td /F1 9.8 Tf  [(13 patients )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 607.527 Td /F1 9.8 Tf  [([39])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 607.527 Td /F1 9.8 Tf  [(; 0 of 11 patients )] TJ ET
0.267 0.267 0.267 rg
BT 187.223 607.527 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 203.486 607.527 Td /F1 9.8 Tf  [(; 0 of 9 patients )] TJ ET
0.267 0.267 0.267 rg
BT 272.867 607.527 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 289.130 607.527 Td /F1 9.8 Tf  [(; 0 of 5 patients )] TJ ET
0.267 0.267 0.267 rg
BT 358.511 607.527 Td /F1 9.8 Tf  [([43])] TJ ET
0.271 0.267 0.267 rg
BT 374.774 607.527 Td /F1 9.8 Tf  [(; 1 of 4 patients )] TJ ET
0.267 0.267 0.267 rg
BT 444.154 607.527 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 460.417 607.527 Td /F1 9.8 Tf  [(; and 1 of 2 patients )] TJ ET
0.267 0.267 0.267 rg
BT 548.772 607.527 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 565.035 607.527 Td /F1 9.8 Tf  [(. )] TJ ET
BT 45.750 595.622 Td /F1 9.8 Tf  [(Across these 7 studies, only 3 of 78 patients with a )] TJ ET
BT 267.406 595.622 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 293.410 595.622 Td /F1 9.8 Tf  [( p.Val600Glu sequence variant responded to treatment with )] TJ ET
BT 45.750 583.717 Td /F1 9.8 Tf  [(cetuximab or panitumumab. Caution should be used in interpreting these data as there is an overlap in patients included in )] TJ ET
BT 45.750 571.812 Td /F1 9.8 Tf  [(the study of De Roock and colleagues and other European studies, )] TJ ET
0.267 0.267 0.267 rg
BT 337.870 571.812 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 354.133 571.812 Td /F1 9.8 Tf  [( and all studies were retrospective in design.)] TJ ET
40.337 559.125 m 
40.337 559.572 40.154 560.016 39.838 560.332 c
39.522 560.648 39.078 560.831 38.631 560.831 c
38.185 560.831 37.741 560.648 37.425 560.332 c
37.109 560.016 36.925 559.572 36.925 559.125 c
36.925 558.679 37.109 558.235 37.425 557.919 c
37.741 557.603 38.185 557.419 38.631 557.419 c
39.078 557.419 39.522 557.603 39.838 557.919 c
40.154 558.235 40.337 558.679 40.337 559.125 c f
BT 45.750 556.158 Td /F1 9.8 Tf  [(The response to treatment with anti-EGFR monoclonal antibodies in patients without )] TJ ET
BT 412.077 556.158 Td /F5 9.8 Tf  [(KRAS)] TJ ET
BT 438.626 556.158 Td /F1 9.8 Tf  [( variants or the)] TJ ET
BT 503.113 556.158 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 45.750 544.253 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant ranged from 27.6% to 46.4% in the 6 studies that reported this figure )] TJ ET
0.267 0.267 0.267 rg
BT 477.149 544.253 Td /F1 9.8 Tf  [([19] [40] [41] [42] [43] )] TJ ET
BT 45.750 532.348 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 532.348 Td /F1 9.8 Tf  [(, with 4 studies finding significant difference in response rates between patients with and without the )] TJ ET
BT 495.020 532.348 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 523.734 532.348 Td /F1 9.8 Tf  [(p.Val600Glu )] TJ ET
BT 45.750 520.443 Td /F1 9.8 Tf  [(sequence variant )] TJ ET
0.267 0.267 0.267 rg
BT 122.707 520.443 Td /F1 9.8 Tf  [([19][39][41][46])] TJ ET
0.271 0.267 0.267 rg
BT 187.759 520.443 Td /F1 9.8 Tf  [(. The presence of the)] TJ ET
BT 279.896 520.443 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 311.321 520.443 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated )] TJ ET
BT 45.750 508.539 Td /F1 9.8 Tf  [(with progression-free survival in 4 studies )] TJ ET
0.267 0.267 0.267 rg
BT 227.266 508.539 Td /F1 9.8 Tf  [([19][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 292.318 508.539 Td /F1 9.8 Tf  [(, but no association was found in 2 studies that reported this )] TJ ET
BT 45.750 496.634 Td /F1 9.8 Tf  [(endpoint )] TJ ET
0.267 0.267 0.267 rg
BT 85.862 496.634 Td /F1 9.8 Tf  [([39][40])] TJ ET
0.271 0.267 0.267 rg
BT 118.388 496.634 Td /F1 9.8 Tf  [(. Similarly, the presence of the )] TJ ET
BT 252.236 496.634 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 280.949 496.634 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant was found to be associated with )] TJ ET
BT 45.750 484.729 Td /F1 9.8 Tf  [(overall survival in all of the 5 studies )] TJ ET
0.267 0.267 0.267 rg
BT 204.519 484.729 Td /F1 9.8 Tf  [([39][40][41][43][46])] TJ ET
0.271 0.267 0.267 rg
BT 285.834 484.729 Td /F1 9.8 Tf  [( that reported this endpoint.)] TJ ET
40.337 472.042 m 
40.337 472.489 40.154 472.933 39.838 473.249 c
39.522 473.564 39.078 473.748 38.631 473.748 c
38.185 473.748 37.741 473.564 37.425 473.249 c
37.109 472.933 36.925 472.489 36.925 472.042 c
36.925 471.595 37.109 471.151 37.425 470.835 c
37.741 470.520 38.185 470.336 38.631 470.336 c
39.078 470.336 39.522 470.520 39.838 470.835 c
40.154 471.151 40.337 471.595 40.337 472.042 c f
BT 45.750 469.074 Td /F1 9.8 Tf  [(Available data suggest that CRC patients with the)] TJ ET
BT 259.811 469.074 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 291.236 469.074 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant rarely respond to treatment with )] TJ ET
BT 45.750 457.170 Td /F1 9.8 Tf  [(cetuximab or panitumumab. However, data are only available from retrospective studies that consisted mostly of cohorts of )] TJ ET
BT 45.750 445.265 Td /F1 9.8 Tf  [(patients, rather than from randomized trials. Only 4.3% to 14.9% of patients with CRC were found to have the )] TJ ET
BT 519.385 445.265 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 433.360 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant. As a consequence, the number of patients with)] TJ ET
BT 384.475 433.360 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 415.899 433.360 Td /F1 9.8 Tf  [(sequence variants in the CRC )] TJ ET
BT 45.750 421.455 Td /F1 9.8 Tf  [(population who are negative for)] TJ ET
BT 181.782 421.455 Td /F5 9.8 Tf  [( KRAS )] TJ ET
BT 213.752 421.455 Td /F1 9.8 Tf  [(sequence variants is small. This is much lower than the percentage of )] TJ ET
BT 517.211 421.455 Td /F5 9.8 Tf  [(KRAS )] TJ ET
BT 45.750 409.551 Td /F1 9.8 Tf  [(sequence variants found in the CRC population at 40% to 45% )] TJ ET
0.267 0.267 0.267 rg
BT 318.896 409.551 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 335.159 409.551 Td /F1 9.8 Tf  [(. In the studies included in this review, a total of only 78 )] TJ ET
BT 45.750 397.646 Td /F1 9.8 Tf  [(patients with the )] TJ ET
BT 118.914 397.646 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 147.628 397.646 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant were available to assess the response to treatment \(and there was )] TJ ET
BT 45.750 385.741 Td /F1 9.8 Tf  [(some overlap in patients between studies\). Available data suggest that testing for the)] TJ ET
BT 412.106 385.741 Td /F5 9.8 Tf  [( BRAF)] TJ ET
BT 440.820 385.741 Td /F1 9.8 Tf  [( sequence variant has promise )] TJ ET
BT 45.750 373.836 Td /F1 9.8 Tf  [(in predicting which patients will not respond to treatment with EGFR monoclonal antibody inhibitors. However, the )] TJ ET
BT 45.750 361.932 Td /F1 9.8 Tf  [(retrospective nature of the studies combined with the low number of patients included in)] TJ ET
BT 424.011 361.932 Td /F5 9.8 Tf  [( BRAF )] TJ ET
BT 455.435 361.932 Td /F1 9.8 Tf  [(p.Val600Glu sequence )] TJ ET
BT 45.750 350.027 Td /F1 9.8 Tf  [(variant testing means that confirmation in larger prospective studies is needed before routine testing for the )] TJ ET
BT 509.635 350.027 Td /F5 9.8 Tf  [(BRAF )] TJ ET
BT 45.750 338.122 Td /F1 9.8 Tf  [(p.Val600Glu sequence variant can be recommended.)] TJ ET
BT 26.250 297.770 Td /F4 12.0 Tf  [(Links)] TJ ET
40.337 280.783 m 
40.337 281.230 40.154 281.674 39.838 281.990 c
39.522 282.305 39.078 282.489 38.631 282.489 c
38.185 282.489 37.741 282.305 37.425 281.990 c
37.109 281.674 36.925 281.230 36.925 280.783 c
36.925 280.336 37.109 279.892 37.425 279.576 c
37.741 279.261 38.185 279.077 38.631 279.077 c
39.078 279.077 39.522 279.261 39.838 279.576 c
40.154 279.892 40.337 280.336 40.337 280.783 c f
0.267 0.267 0.267 rg
BT 45.750 277.815 Td /F1 9.8 Tf  [(Clinical Trials.gov)] TJ ET
0.271 0.267 0.267 rg
BT 122.132 277.815 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 127.553 277.815 Td /F1 9.8 Tf  [(BRAF and colorectal cancer)] TJ ET
0.271 0.267 0.267 rg
40.337 265.128 m 
40.337 265.575 40.154 266.019 39.838 266.335 c
39.522 266.651 39.078 266.834 38.631 266.834 c
38.185 266.834 37.741 266.651 37.425 266.335 c
37.109 266.019 36.925 265.575 36.925 265.128 c
36.925 264.682 37.109 264.238 37.425 263.922 c
37.741 263.606 38.185 263.422 38.631 263.422 c
39.078 263.422 39.522 263.606 39.838 263.922 c
40.154 264.238 40.337 264.682 40.337 265.128 c f
0.267 0.267 0.267 rg
BT 45.750 262.161 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man)] TJ ET
0.271 0.267 0.267 rg
BT 204.529 262.161 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 209.950 262.161 Td /F1 9.8 Tf  [(BRAF)] TJ ET
0.271 0.267 0.267 rg
40.337 249.473 m 
40.337 249.920 40.154 250.364 39.838 250.680 c
39.522 250.996 39.078 251.180 38.631 251.180 c
38.185 251.180 37.741 250.996 37.425 250.680 c
37.109 250.364 36.925 249.920 36.925 249.473 c
36.925 249.027 37.109 248.583 37.425 248.267 c
37.741 247.951 38.185 247.767 38.631 247.767 c
39.078 247.767 39.522 247.951 39.838 248.267 c
40.154 248.583 40.337 249.027 40.337 249.473 c f
0.267 0.267 0.267 rg
BT 45.750 246.506 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration)] TJ ET
0.271 0.267 0.267 rg
BT 196.934 246.506 Td /F1 9.8 Tf  [(: )] TJ ET
0.267 0.267 0.267 rg
BT 202.355 246.506 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 223.351 Td /F1 9.8 Tf  [(Last updated: October 17, 2010)] TJ ET
BT 26.250 186.749 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 166.794 Td /F1 9.8 Tf  [(The authors would like to acknowledge the contributions of the members of the Hayes Genetic Test Evaluation team, )] TJ ET
BT 26.250 154.890 Td /F1 9.8 Tf  [(particularly Lisa Spock, Linnie Wieselquist and Charlotte Kuo-Benitez.)] TJ ET
BT 26.250 118.287 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 98.333 Td /F1 9.8 Tf  [(Funding for the Health Technology Assessment that informed this work was provided by Hayes, Incorporated. Funding to create )] TJ ET
BT 26.250 86.428 Td /F1 9.8 Tf  [(this Knol was provided by the Centers for Disease Control and Prevention under Contract No. 200-2009-F-32675.This funding )] TJ ET
BT 26.250 74.523 Td /F1 9.8 Tf  [(was provided through the Genetic Alliance.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(7)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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BT 26.250 718.419 Td /F1 9.8 Tf  [(employees at this company has any financial or personal interest in any of the technologies reviewed by Hayes, Inc. No input on )] TJ ET
BT 26.250 706.515 Td /F1 9.8 Tf  [(report content or conclusions is permitted by manufacturers. Although the CDC funded the work to produce this article, the )] TJ ET
BT 26.250 694.610 Td /F1 9.8 Tf  [(content is based entirely on Hayes, Inc.�s own analysis and there was no input from the CDC.)] TJ ET
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BT 43.553 269.839 Td /F1 9.8 Tf  [(Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A. Biomarkers predicting clinical outcome of epidermal )] TJ ET
BT 26.250 257.934 Td /F1 9.8 Tf  [(growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009 Oct 7;101\(19\):1308-24. Epub )] TJ ET
BT 26.250 246.030 Td /F1 9.8 Tf  [(2009 Sep 8. Review. PubMed PMID: 19738166; PubMed Central PMCID: PMC2758310.)] TJ ET
BT 26.250 226.625 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 226.625 Td /F1 9.8 Tf  [(Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008 Mar 13;358\(11\):1160-74. Review. )] TJ ET
BT 26.250 214.720 Td /F1 9.8 Tf  [(Erratum in: N Engl J Med. 2009 Apr 9;360\(15\):1579. PubMed PMID: 18337605.)] TJ ET
BT 26.250 195.315 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 195.315 Td /F1 9.8 Tf  [(Food and Drug Administration \(FDA\) [website]. Center for Drug Evaluation and Research \(CDER\). Cetuximab \(Erbitux\) and )] TJ ET
BT 26.250 183.411 Td /F1 9.8 Tf  [(Panitumumab \(Vectibix\). Updated January 11, 2010. Available at: )] TJ ET
BT 26.250 171.506 Td /F1 9.8 Tf  [(https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm172905.htm. Accessed September 23, 2010.)] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 152.101 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) [website]. V-raf murine sarcome viral oncogene homolog B1, BRAF )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(\(*164757\). Updated May 19, 2010. Available at: https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757.Accessed )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 108.887 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 108.887 Td /F1 9.8 Tf  [(Ensembl [website].Transcript: BRAF-001 \(ENST00000288602\). August 2010. Available at: )] TJ ET
BT 26.250 96.982 Td /F1 9.8 Tf  [(https://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000157764;r=7:140424943-)] TJ ET
BT 26.250 85.077 Td /F1 9.8 Tf  [(140624564;t=ENST00000288602. Accessed September 23, 2010.)] TJ ET
BT 26.250 65.673 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 65.673 Td /F1 9.8 Tf  [(Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, Wolff RK, Slattery ML. Poor survival associated )] TJ ET
BT 26.250 53.768 Td /F1 9.8 Tf  [(with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005 Jul 15;65\(14\):6063-9. PubMed PMID: )] TJ ET
Q
q
15.000 39.482 577.500 737.518 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The authors are employees at Hayes, Inc., an independent health technology research and consulting company. None of the )] TJ ET
BT 26.250 718.419 Td /F1 9.8 Tf  [(employees at this company has any financial or personal interest in any of the technologies reviewed by Hayes, Inc. No input on )] TJ ET
BT 26.250 706.515 Td /F1 9.8 Tf  [(report content or conclusions is permitted by manufacturers. Although the CDC funded the work to produce this article, the )] TJ ET
BT 26.250 694.610 Td /F1 9.8 Tf  [(content is based entirely on Hayes, Inc.�s own analysis and there was no input from the CDC.)] TJ ET
BT 26.250 658.007 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 630.553 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 630.553 Td /F1 9.8 Tf  [(American Cancer Society \(ACS\) [website]. Cancer Facts & Figures 2009. 2009. Available at: https://www.cancer.org/ )] TJ ET
BT 26.250 618.648 Td /F1 9.8 Tf  [(docroot/STT/content/STT_1x_Cancer_Facts__Figures_2009.asp. Accessed September 23, 2010.)] TJ ET
BT 26.250 599.244 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 599.244 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Surveillance Epidemiology and End Results \(SEER\). SEER Stat Fact Sheets. )] TJ ET
BT 26.250 587.339 Td /F1 9.8 Tf  [(Cancer: Colon and Rectum. 2010. Available at: https://seer.cancer.gov/statfacts/html/colorect.html. Accessed September 23, )] TJ ET
BT 26.250 575.434 Td /F1 9.8 Tf  [(2010.)] TJ ET
BT 26.250 556.029 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 556.029 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Colon Cancer Treatment \(PDQ�\). Modified August 19, 2009. Available at: )] TJ ET
BT 26.250 544.125 Td /F1 9.8 Tf  [(https://www.cancer.gov/cancertopics/pdq/treatment/colon/healthprofessional/allpages. Accessed September 23, 2010.)] TJ ET
BT 26.250 524.720 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 524.720 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Rectal Cancer Treatment \(PDQ�\). Modified August 23, 2010. Available at: )] TJ ET
BT 26.250 512.815 Td /F1 9.8 Tf  [(https://www.cancer.gov/cancertopics/pdq/treatment/rectal/healthprofessional/allpages. Accessed September 23, 2010.)] TJ ET
BT 26.250 493.410 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 493.410 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network \(NCCN\) [website]. NCCN Clinical Practice Guidelines in Oncology. Rectal Cancer. )] TJ ET
BT 26.250 481.506 Td /F1 9.8 Tf  [(V.1.2011. September 10, 2010. Available at https://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf. Accessed )] TJ ET
BT 26.250 469.601 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 450.196 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 450.196 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network \(NCCN\) [website]. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. )] TJ ET
BT 26.250 438.291 Td /F1 9.8 Tf  [(V.1.2011. September 10, 2010. Available at: https://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed )] TJ ET
BT 26.250 426.387 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 406.982 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 406.982 Td /F1 9.8 Tf  [(Amgen Inc. [website]. Vectibix� \(panitumumab\) Prescribing Information. May 2010. Available at )] TJ ET
BT 26.250 395.077 Td /F1 9.8 Tf  [(https://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 375.672 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 375.672 Td /F1 9.8 Tf  [(Bristol-Myers Squibb and ImClone Systems [website]. ERBITUX� \(Cetuximab\). March 2010. Available at )] TJ ET
BT 26.250 363.768 Td /F1 9.8 Tf  [(https://packageinserts.bms.com/pi/pi_erbitux.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 344.363 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 344.363 Td /F1 9.8 Tf  [(Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, )] TJ ET
BT 26.250 332.458 Td /F1 9.8 Tf  [(van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov )] TJ ET
BT 26.250 320.553 Td /F1 9.8 Tf  [(15;357\(20\):2040-8. PubMed PMID: 18003960.)] TJ ET
BT 26.250 301.149 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 301.149 Td /F1 9.8 Tf  [(Kyoto Encyclopedia of Genes and Genomes \(KEGG\) [website]. MAPK signaling pathway � Homo sapiens \(human\). )] TJ ET
BT 26.250 289.244 Td /F1 9.8 Tf  [(February 4, 2010. Available at: https://www.genome.jp/kegg/pathway/hsa/hsa04010.html. Accessed September 23, 2010.)] TJ ET
BT 26.250 269.839 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 269.839 Td /F1 9.8 Tf  [(Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A. Biomarkers predicting clinical outcome of epidermal )] TJ ET
BT 26.250 257.934 Td /F1 9.8 Tf  [(growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009 Oct 7;101\(19\):1308-24. Epub )] TJ ET
BT 26.250 246.030 Td /F1 9.8 Tf  [(2009 Sep 8. Review. PubMed PMID: 19738166; PubMed Central PMCID: PMC2758310.)] TJ ET
BT 26.250 226.625 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 226.625 Td /F1 9.8 Tf  [(Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008 Mar 13;358\(11\):1160-74. Review. )] TJ ET
BT 26.250 214.720 Td /F1 9.8 Tf  [(Erratum in: N Engl J Med. 2009 Apr 9;360\(15\):1579. PubMed PMID: 18337605.)] TJ ET
BT 26.250 195.315 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 195.315 Td /F1 9.8 Tf  [(Food and Drug Administration \(FDA\) [website]. Center for Drug Evaluation and Research \(CDER\). Cetuximab \(Erbitux\) and )] TJ ET
BT 26.250 183.411 Td /F1 9.8 Tf  [(Panitumumab \(Vectibix\). Updated January 11, 2010. Available at: )] TJ ET
BT 26.250 171.506 Td /F1 9.8 Tf  [(https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm172905.htm. Accessed September 23, 2010.)] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 152.101 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) [website]. V-raf murine sarcome viral oncogene homolog B1, BRAF )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(\(*164757\). Updated May 19, 2010. Available at: https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757.Accessed )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 108.887 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 108.887 Td /F1 9.8 Tf  [(Ensembl [website].Transcript: BRAF-001 \(ENST00000288602\). August 2010. Available at: )] TJ ET
BT 26.250 96.982 Td /F1 9.8 Tf  [(https://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000157764;r=7:140424943-)] TJ ET
BT 26.250 85.077 Td /F1 9.8 Tf  [(140624564;t=ENST00000288602. Accessed September 23, 2010.)] TJ ET
BT 26.250 65.673 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 65.673 Td /F1 9.8 Tf  [(Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, Wolff RK, Slattery ML. Poor survival associated )] TJ ET
BT 26.250 53.768 Td /F1 9.8 Tf  [(with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005 Jul 15;65\(14\):6063-9. PubMed PMID: )] TJ ET
Q
q
15.000 39.482 577.500 737.518 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The authors are employees at Hayes, Inc., an independent health technology research and consulting company. None of the )] TJ ET
BT 26.250 718.419 Td /F1 9.8 Tf  [(employees at this company has any financial or personal interest in any of the technologies reviewed by Hayes, Inc. No input on )] TJ ET
BT 26.250 706.515 Td /F1 9.8 Tf  [(report content or conclusions is permitted by manufacturers. Although the CDC funded the work to produce this article, the )] TJ ET
BT 26.250 694.610 Td /F1 9.8 Tf  [(content is based entirely on Hayes, Inc.�s own analysis and there was no input from the CDC.)] TJ ET
BT 26.250 658.007 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 630.553 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 630.553 Td /F1 9.8 Tf  [(American Cancer Society \(ACS\) [website]. Cancer Facts & Figures 2009. 2009. Available at: https://www.cancer.org/ )] TJ ET
BT 26.250 618.648 Td /F1 9.8 Tf  [(docroot/STT/content/STT_1x_Cancer_Facts__Figures_2009.asp. Accessed September 23, 2010.)] TJ ET
BT 26.250 599.244 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 599.244 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Surveillance Epidemiology and End Results \(SEER\). SEER Stat Fact Sheets. )] TJ ET
BT 26.250 587.339 Td /F1 9.8 Tf  [(Cancer: Colon and Rectum. 2010. Available at: https://seer.cancer.gov/statfacts/html/colorect.html. Accessed September 23, )] TJ ET
BT 26.250 575.434 Td /F1 9.8 Tf  [(2010.)] TJ ET
BT 26.250 556.029 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 556.029 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Colon Cancer Treatment \(PDQ�\). Modified August 19, 2009. Available at: )] TJ ET
BT 26.250 544.125 Td /F1 9.8 Tf  [(https://www.cancer.gov/cancertopics/pdq/treatment/colon/healthprofessional/allpages. Accessed September 23, 2010.)] TJ ET
BT 26.250 524.720 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 524.720 Td /F1 9.8 Tf  [(National Cancer Institute \(NCI\) [website]. Rectal Cancer Treatment \(PDQ�\). Modified August 23, 2010. Available at: )] TJ ET
BT 26.250 512.815 Td /F1 9.8 Tf  [(https://www.cancer.gov/cancertopics/pdq/treatment/rectal/healthprofessional/allpages. Accessed September 23, 2010.)] TJ ET
BT 26.250 493.410 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 493.410 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network \(NCCN\) [website]. NCCN Clinical Practice Guidelines in Oncology. Rectal Cancer. )] TJ ET
BT 26.250 481.506 Td /F1 9.8 Tf  [(V.1.2011. September 10, 2010. Available at https://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf. Accessed )] TJ ET
BT 26.250 469.601 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 450.196 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 450.196 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network \(NCCN\) [website]. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. )] TJ ET
BT 26.250 438.291 Td /F1 9.8 Tf  [(V.1.2011. September 10, 2010. Available at: https://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed )] TJ ET
BT 26.250 426.387 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 406.982 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 406.982 Td /F1 9.8 Tf  [(Amgen Inc. [website]. Vectibix� \(panitumumab\) Prescribing Information. May 2010. Available at )] TJ ET
BT 26.250 395.077 Td /F1 9.8 Tf  [(https://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 375.672 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 375.672 Td /F1 9.8 Tf  [(Bristol-Myers Squibb and ImClone Systems [website]. ERBITUX� \(Cetuximab\). March 2010. Available at )] TJ ET
BT 26.250 363.768 Td /F1 9.8 Tf  [(https://packageinserts.bms.com/pi/pi_erbitux.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 344.363 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 344.363 Td /F1 9.8 Tf  [(Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, )] TJ ET
BT 26.250 332.458 Td /F1 9.8 Tf  [(van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov )] TJ ET
BT 26.250 320.553 Td /F1 9.8 Tf  [(15;357\(20\):2040-8. PubMed PMID: 18003960.)] TJ ET
BT 26.250 301.149 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 301.149 Td /F1 9.8 Tf  [(Kyoto Encyclopedia of Genes and Genomes \(KEGG\) [website]. MAPK signaling pathway � Homo sapiens \(human\). )] TJ ET
BT 26.250 289.244 Td /F1 9.8 Tf  [(February 4, 2010. Available at: https://www.genome.jp/kegg/pathway/hsa/hsa04010.html. Accessed September 23, 2010.)] TJ ET
BT 26.250 269.839 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 269.839 Td /F1 9.8 Tf  [(Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A. Biomarkers predicting clinical outcome of epidermal )] TJ ET
BT 26.250 257.934 Td /F1 9.8 Tf  [(growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009 Oct 7;101\(19\):1308-24. Epub )] TJ ET
BT 26.250 246.030 Td /F1 9.8 Tf  [(2009 Sep 8. Review. PubMed PMID: 19738166; PubMed Central PMCID: PMC2758310.)] TJ ET
BT 26.250 226.625 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 226.625 Td /F1 9.8 Tf  [(Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008 Mar 13;358\(11\):1160-74. Review. )] TJ ET
BT 26.250 214.720 Td /F1 9.8 Tf  [(Erratum in: N Engl J Med. 2009 Apr 9;360\(15\):1579. PubMed PMID: 18337605.)] TJ ET
BT 26.250 195.315 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 195.315 Td /F1 9.8 Tf  [(Food and Drug Administration \(FDA\) [website]. Center for Drug Evaluation and Research \(CDER\). Cetuximab \(Erbitux\) and )] TJ ET
BT 26.250 183.411 Td /F1 9.8 Tf  [(Panitumumab \(Vectibix\). Updated January 11, 2010. Available at: )] TJ ET
BT 26.250 171.506 Td /F1 9.8 Tf  [(https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm172905.htm. Accessed September 23, 2010.)] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 152.101 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) [website]. V-raf murine sarcome viral oncogene homolog B1, BRAF )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(\(*164757\). Updated May 19, 2010. Available at: https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757.Accessed )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(September 23, 2010.)] TJ ET
BT 26.250 108.887 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 108.887 Td /F1 9.8 Tf  [(Ensembl [website].Transcript: BRAF-001 \(ENST00000288602\). August 2010. Available at: )] TJ ET
BT 26.250 96.982 Td /F1 9.8 Tf  [(https://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000157764;r=7:140424943-)] TJ ET
BT 26.250 85.077 Td /F1 9.8 Tf  [(140624564;t=ENST00000288602. Accessed September 23, 2010.)] TJ ET
BT 26.250 65.673 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 65.673 Td /F1 9.8 Tf  [(Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, Wolff RK, Slattery ML. Poor survival associated )] TJ ET
BT 26.250 53.768 Td /F1 9.8 Tf  [(with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005 Jul 15;65\(14\):6063-9. PubMed PMID: )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(8)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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0.271 0.267 0.267 rg
0.39 w 1 J 1 j
q
15.000 51.167 577.500 725.833 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(16024606.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009 Dec 10;27\(35\):5931-7. Epub 2009 Nov 2. PubMed PMID: )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(19884549.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA. Prognostic and predictive value )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(4;101\(3\):465-72. Epub 2009 Jul 14. PubMed PMID: 19603024; PubMed Central PMCID: PMC2720232.)] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 606.524 Td /F1 9.8 Tf  [(Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, Stathopoulos E, Georgoulias V, )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Souglakos J. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(outcome. Br J Cancer. 2010 Jun 8;102\(12\):1762-8. Epub 2010 May 18. PubMed PMID: 20485284; PubMed Central PMCID: )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(PMC2883698.)] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 551.405 Td /F1 9.8 Tf  [(Shaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Dig Dis Sci. 2010 Aug;55\(8\):2352-6. Epub 2010 Mar 19. PubMed PMID: 20300843.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010 Feb )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(1;16\(3\):790-9. Epub 2010 Jan 26. PubMed PMID: 20103678.)] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 445.572 Td /F1 9.8 Tf  [(Italiano A, Hostein I, Soubeyran I, Fabas T, Benchimol D, Evrard S, Gugenheim J, Becouarn Y, Brunet R, Fonck M, )] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(Fran�ois E, Saint-Paul MC, Pedeutour F. KRAS and BRAF mutational status in primary colorectal tumors and related metastatic )] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(sites: biological and clinical implications. Ann Surg Oncol. 2010 May;17\(5\):1429-34. Epub 2010 Jan 5. PubMed PMID: )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(20049644.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. BRAF codon 600 Mutation Detection by Pyrosequencing: 2002498. 2010. Available at: )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2002498.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. KRAS Mutation Detection with BRAF reflex: 2001932. 2010. Available at: )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2001932.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) [website]. Test Menu [search: BRAF]. 2010. Available at: )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(https://www.labcorp.com/wps/portal/provider/testmenu. Accessed September 23, 2010.)] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 296.524 Td /F1 9.8 Tf  [(Mayo Medical Laboratories [website]. Unit Code 87980: BRAF Mutation Analysis \(V600E\), Tumor. 2010. Available at: )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(https://www.mayomedicallaboratories.com/test-catalog/Overview/87980. Accessed September 23, 2010.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. BRAF Mutation Analysis \(16767\). 2010. Available at: )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16767.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. EGFR Pathway \(KRAS with Reflex to NRAS, BRAF\) \(16819\). 2010. Available at: )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16819.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories [website]. Molecular Genetics Laboratory. Modified November 9, 2009. )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(Available at: https://labs.unchealthcare.org/forms/braf.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services [website]. Test Directory. BRAF\(V600E\)\(V6A\). 2010. Available at: )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(https://www.mc.vanderbilt.edu/root/vumc.php?test_id=896&doc=24499&site=vpls. Accessed September 23, 2010.)] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 116.167 Td /F1 9.8 Tf  [(Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by )] TJ ET
BT 26.250 104.262 Td /F1 9.8 Tf  [(pyrosequencing. Pathology. 2008 Apr;40\(3\):295-8. PubMed PMID: 18428050.)] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 84.858 Td /F1 9.8 Tf  [(Lurkin I, Stoehr R, Hurst CD, van Tilborg AA, Knowles MA, Hartmann A, Zwarthoff EC. Two multiplex assays that )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(simultaneously identify 22 possible mutation sites in the KRAS, BRAF, NRAS and PIK3CA genes. PLoS One. 2010 Jan )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(21;5\(1\):e8802. PubMed PMID: 20098682; PubMed Central PMCID: PMC2809099.)] TJ ET
Q
q
15.000 51.167 577.500 725.833 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(16024606.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009 Dec 10;27\(35\):5931-7. Epub 2009 Nov 2. PubMed PMID: )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(19884549.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA. Prognostic and predictive value )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(4;101\(3\):465-72. Epub 2009 Jul 14. PubMed PMID: 19603024; PubMed Central PMCID: PMC2720232.)] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 606.524 Td /F1 9.8 Tf  [(Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, Stathopoulos E, Georgoulias V, )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Souglakos J. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(outcome. Br J Cancer. 2010 Jun 8;102\(12\):1762-8. Epub 2010 May 18. PubMed PMID: 20485284; PubMed Central PMCID: )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(PMC2883698.)] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 551.405 Td /F1 9.8 Tf  [(Shaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Dig Dis Sci. 2010 Aug;55\(8\):2352-6. Epub 2010 Mar 19. PubMed PMID: 20300843.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010 Feb )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(1;16\(3\):790-9. Epub 2010 Jan 26. PubMed PMID: 20103678.)] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 445.572 Td /F1 9.8 Tf  [(Italiano A, Hostein I, Soubeyran I, Fabas T, Benchimol D, Evrard S, Gugenheim J, Becouarn Y, Brunet R, Fonck M, )] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(Fran�ois E, Saint-Paul MC, Pedeutour F. KRAS and BRAF mutational status in primary colorectal tumors and related metastatic )] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(sites: biological and clinical implications. Ann Surg Oncol. 2010 May;17\(5\):1429-34. Epub 2010 Jan 5. PubMed PMID: )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(20049644.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. BRAF codon 600 Mutation Detection by Pyrosequencing: 2002498. 2010. Available at: )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2002498.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. KRAS Mutation Detection with BRAF reflex: 2001932. 2010. Available at: )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2001932.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) [website]. Test Menu [search: BRAF]. 2010. Available at: )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(https://www.labcorp.com/wps/portal/provider/testmenu. Accessed September 23, 2010.)] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 296.524 Td /F1 9.8 Tf  [(Mayo Medical Laboratories [website]. Unit Code 87980: BRAF Mutation Analysis \(V600E\), Tumor. 2010. Available at: )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(https://www.mayomedicallaboratories.com/test-catalog/Overview/87980. Accessed September 23, 2010.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. BRAF Mutation Analysis \(16767\). 2010. Available at: )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16767.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. EGFR Pathway \(KRAS with Reflex to NRAS, BRAF\) \(16819\). 2010. Available at: )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16819.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories [website]. Molecular Genetics Laboratory. Modified November 9, 2009. )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(Available at: https://labs.unchealthcare.org/forms/braf.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services [website]. Test Directory. BRAF\(V600E\)\(V6A\). 2010. Available at: )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(https://www.mc.vanderbilt.edu/root/vumc.php?test_id=896&doc=24499&site=vpls. Accessed September 23, 2010.)] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 116.167 Td /F1 9.8 Tf  [(Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by )] TJ ET
BT 26.250 104.262 Td /F1 9.8 Tf  [(pyrosequencing. Pathology. 2008 Apr;40\(3\):295-8. PubMed PMID: 18428050.)] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 84.858 Td /F1 9.8 Tf  [(Lurkin I, Stoehr R, Hurst CD, van Tilborg AA, Knowles MA, Hartmann A, Zwarthoff EC. Two multiplex assays that )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(simultaneously identify 22 possible mutation sites in the KRAS, BRAF, NRAS and PIK3CA genes. PLoS One. 2010 Jan )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(21;5\(1\):e8802. PubMed PMID: 20098682; PubMed Central PMCID: PMC2809099.)] TJ ET
Q
q
15.000 51.167 577.500 725.833 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(16024606.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009 Dec 10;27\(35\):5931-7. Epub 2009 Nov 2. PubMed PMID: )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(19884549.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA. Prognostic and predictive value )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug )] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(4;101\(3\):465-72. Epub 2009 Jul 14. PubMed PMID: 19603024; PubMed Central PMCID: PMC2720232.)] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 606.524 Td /F1 9.8 Tf  [(Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, Stathopoulos E, Georgoulias V, )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Souglakos J. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(outcome. Br J Cancer. 2010 Jun 8;102\(12\):1762-8. Epub 2010 May 18. PubMed PMID: 20485284; PubMed Central PMCID: )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(PMC2883698.)] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 551.405 Td /F1 9.8 Tf  [(Shaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Dig Dis Sci. 2010 Aug;55\(8\):2352-6. Epub 2010 Mar 19. PubMed PMID: 20300843.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(mutated colorectal cancer and implications for prognosis. Int J Cancer. 2010 Jul 15;127\(2\):367-80. PubMed PMID: 19908233.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010 Feb )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(1;16\(3\):790-9. Epub 2010 Jan 26. PubMed PMID: 20103678.)] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 445.572 Td /F1 9.8 Tf  [(Italiano A, Hostein I, Soubeyran I, Fabas T, Benchimol D, Evrard S, Gugenheim J, Becouarn Y, Brunet R, Fonck M, )] TJ ET
BT 26.250 433.667 Td /F1 9.8 Tf  [(Fran�ois E, Saint-Paul MC, Pedeutour F. KRAS and BRAF mutational status in primary colorectal tumors and related metastatic )] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(sites: biological and clinical implications. Ann Surg Oncol. 2010 May;17\(5\):1429-34. Epub 2010 Jan 5. PubMed PMID: )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(20049644.)] TJ ET
BT 26.250 390.453 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 390.453 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. BRAF codon 600 Mutation Detection by Pyrosequencing: 2002498. 2010. Available at: )] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2002498.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 359.143 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 359.143 Td /F1 9.8 Tf  [(ARUP Laboratories [website]. KRAS Mutation Detection with BRAF reflex: 2001932. 2010. Available at: )] TJ ET
BT 26.250 347.238 Td /F1 9.8 Tf  [(https://www.aruplab.com/guides/ug/tests/2001932.jsp. Accessed September 23, 2010.)] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 327.834 Td /F1 9.8 Tf  [(Laboratory Corporation of America \(LabCorp\) [website]. Test Menu [search: BRAF]. 2010. Available at: )] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(https://www.labcorp.com/wps/portal/provider/testmenu. Accessed September 23, 2010.)] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 296.524 Td /F1 9.8 Tf  [(Mayo Medical Laboratories [website]. Unit Code 87980: BRAF Mutation Analysis \(V600E\), Tumor. 2010. Available at: )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(https://www.mayomedicallaboratories.com/test-catalog/Overview/87980. Accessed September 23, 2010.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. BRAF Mutation Analysis \(16767\). 2010. Available at: )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16767.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(Quest Diagnostics Inc. [website]. EGFR Pathway \(KRAS with Reflex to NRAS, BRAF\) \(16819\). 2010. Available at: )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(https://www.questdiagnostics.com/hcp/testmenu/jsp/showTestMenu.jsp?fn=16819.html&labCode=PHP. Accessed September )] TJ ET
BT 26.250 198.191 Td /F1 9.8 Tf  [(23, 2010.)] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 178.786 Td /F1 9.8 Tf  [(UNC Health Care McLendon Clinical Laboratories [website]. Molecular Genetics Laboratory. Modified November 9, 2009. )] TJ ET
BT 26.250 166.881 Td /F1 9.8 Tf  [(Available at: https://labs.unchealthcare.org/forms/braf.pdf. Accessed September 23, 2010.)] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 147.477 Td /F1 9.8 Tf  [(Vanderbilt Pathology Laboratory Services [website]. Test Directory. BRAF\(V600E\)\(V6A\). 2010. Available at: )] TJ ET
BT 26.250 135.572 Td /F1 9.8 Tf  [(https://www.mc.vanderbilt.edu/root/vumc.php?test_id=896&doc=24499&site=vpls. Accessed September 23, 2010.)] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 116.167 Td /F1 9.8 Tf  [(Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by )] TJ ET
BT 26.250 104.262 Td /F1 9.8 Tf  [(pyrosequencing. Pathology. 2008 Apr;40\(3\):295-8. PubMed PMID: 18428050.)] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 84.858 Td /F1 9.8 Tf  [(Lurkin I, Stoehr R, Hurst CD, van Tilborg AA, Knowles MA, Hartmann A, Zwarthoff EC. Two multiplex assays that )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(simultaneously identify 22 possible mutation sites in the KRAS, BRAF, NRAS and PIK3CA genes. PLoS One. 2010 Jan )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(21;5\(1\):e8802. PubMed PMID: 20098682; PubMed Central PMCID: PMC2809099.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(9)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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0.271 0.267 0.267 rg
0.39 w 1 J 1 j
q
15.000 104.977 577.500 672.023 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Bentivegna S, Zheng J, Namsaraev E, Carlton VE, Pavlicek A, Moorhead M, Siddiqui F, Wang Z, Lee L, Ireland JS, )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Suyenaga K, Willis TD, Faham M, Seymour AB. Rapid identification of somatic mutations in colorectal and breast cancer tissues )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(using mismatch repair detection \(MRD\). Hum Mutat. 2008 Mar;29\(3\):441-50. PubMed PMID: 18186519.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Packham D, Ward RL, Ap Lin V, Hawkins NJ, Hitchins MP. Implementation of novel pyrosequencing assays to screen for )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(common mutations of BRAF and KRAS in a cohort of sporadic colorectal cancers. Diagn Mol Pathol. 2009 Jun;18\(2\):62-71. )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(PubMed PMID: 19430299.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 673.548 Td /F1 9.8 Tf  [(Pichler M, Balic M, Stadelmeyer E, Ausch C, Wild M, Guelly C, Bauernhofer T, Samonigg H, Hoefler G, Dandachi N. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Evaluation of high-resolution melting analysis as a diagnostic tool to detect the BRAF V600E mutation in colorectal tumors. J )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Mol Diagn. 2009 Mar;11\(2\):140-7. Epub 2009 Feb 12. PubMed PMID: 19213871; PubMed Central PMCID: PMC2665863.)] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 630.333 Td /F1 9.8 Tf  [(Jakubauskas A, Griskevicius L. KRas and BRaf mutational status analysis from formalin-fixed, paraffin-embedded tissues )] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(using multiplex polymerase chain reaction-based assay. Arch Pathol Lab Med. 2010 Apr;134\(4\):620-4. PubMed PMID: )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20367313.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS codon 61, )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(colorectal cancer. Br J Cancer. 2009 Aug 18;101\(4\):715-21. Epub 2009 Jul 14. PubMed PMID: 19603018; PubMed Central )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(PMCID: PMC2736831.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S. Multi-determinants analysis of molecular alterations for )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009 Oct 2;4\(10\):e7287. )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(PubMed PMID: 19806185; PubMed Central PMCID: PMC2750753.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(Clin Oncol. 2008 Dec 10;26\(35\):5705-12. Epub 2008 Nov 10. PubMed PMID: 19001320.)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Bertario L, Leo E, Pierotti MA, Pilotti S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients. Ann Oncol. 2009 Jan;20\(1\):84-90. Epub 2008 Jul 31. PubMed PMID: 18669866.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(Ychou M, Bibeau F, Bouch� O, Reid J, Stone S, Penault-Llorca F. Analysis of PTEN, BRAF, and EGFR status in determining )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009 Dec 10;27\(35\):5924-30. Epub )] TJ ET
BT 26.250 342.834 Td /F1 9.8 Tf  [(2009 Nov 2. PubMed PMID: 19884556.)] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 323.429 Td /F1 9.8 Tf  [(Freeman DJ, Juan T, Reiner M, Hecht JR, Meropol NJ, Berlin J, Mitchell E, Sarosi I, Radinsky R, Amado RG. Association of )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin )] TJ ET
BT 26.250 299.619 Td /F1 9.8 Tf  [(Colorectal Cancer. 2008 May;7\(3\):184-90. PubMed PMID: 18621636.)] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 280.215 Td /F1 9.8 Tf  [(Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(Natl Cancer Inst. 2000 Feb 2;92\(3\):205-16. PubMed PMID: 10655437.)] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 225.096 Td /F1 9.8 Tf  [(De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, )] TJ ET
BT 26.250 189.381 Td /F1 9.8 Tf  [(Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S. Effects of KRAS, )] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010 Aug;11\(8\):753-62. Epub 2010 Jul 8. PubMed PMID: )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(20619739.)] TJ ET
BT 26.250 134.262 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 134.262 Td /F1 9.8 Tf  [(Mao C, Liao RY, Chen Q. BRAF mutation predicts resistance to anti-EGFR monoclonal antibodies in wild-type KRAS )] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Cancer Res Clin Oncol. 2010 Aug;136\(8\):1293-4. Epub 2010 Jun 1. PubMed PMID: 20514492.)] TJ ET
Q
q
15.000 104.977 577.500 672.023 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Bentivegna S, Zheng J, Namsaraev E, Carlton VE, Pavlicek A, Moorhead M, Siddiqui F, Wang Z, Lee L, Ireland JS, )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Suyenaga K, Willis TD, Faham M, Seymour AB. Rapid identification of somatic mutations in colorectal and breast cancer tissues )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(using mismatch repair detection \(MRD\). Hum Mutat. 2008 Mar;29\(3\):441-50. PubMed PMID: 18186519.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Packham D, Ward RL, Ap Lin V, Hawkins NJ, Hitchins MP. Implementation of novel pyrosequencing assays to screen for )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(common mutations of BRAF and KRAS in a cohort of sporadic colorectal cancers. Diagn Mol Pathol. 2009 Jun;18\(2\):62-71. )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(PubMed PMID: 19430299.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 673.548 Td /F1 9.8 Tf  [(Pichler M, Balic M, Stadelmeyer E, Ausch C, Wild M, Guelly C, Bauernhofer T, Samonigg H, Hoefler G, Dandachi N. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Evaluation of high-resolution melting analysis as a diagnostic tool to detect the BRAF V600E mutation in colorectal tumors. J )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Mol Diagn. 2009 Mar;11\(2\):140-7. Epub 2009 Feb 12. PubMed PMID: 19213871; PubMed Central PMCID: PMC2665863.)] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 630.333 Td /F1 9.8 Tf  [(Jakubauskas A, Griskevicius L. KRas and BRaf mutational status analysis from formalin-fixed, paraffin-embedded tissues )] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(using multiplex polymerase chain reaction-based assay. Arch Pathol Lab Med. 2010 Apr;134\(4\):620-4. PubMed PMID: )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20367313.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS codon 61, )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(colorectal cancer. Br J Cancer. 2009 Aug 18;101\(4\):715-21. Epub 2009 Jul 14. PubMed PMID: 19603018; PubMed Central )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(PMCID: PMC2736831.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S. Multi-determinants analysis of molecular alterations for )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009 Oct 2;4\(10\):e7287. )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(PubMed PMID: 19806185; PubMed Central PMCID: PMC2750753.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(Clin Oncol. 2008 Dec 10;26\(35\):5705-12. Epub 2008 Nov 10. PubMed PMID: 19001320.)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Bertario L, Leo E, Pierotti MA, Pilotti S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients. Ann Oncol. 2009 Jan;20\(1\):84-90. Epub 2008 Jul 31. PubMed PMID: 18669866.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(Ychou M, Bibeau F, Bouch� O, Reid J, Stone S, Penault-Llorca F. Analysis of PTEN, BRAF, and EGFR status in determining )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009 Dec 10;27\(35\):5924-30. Epub )] TJ ET
BT 26.250 342.834 Td /F1 9.8 Tf  [(2009 Nov 2. PubMed PMID: 19884556.)] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 323.429 Td /F1 9.8 Tf  [(Freeman DJ, Juan T, Reiner M, Hecht JR, Meropol NJ, Berlin J, Mitchell E, Sarosi I, Radinsky R, Amado RG. Association of )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin )] TJ ET
BT 26.250 299.619 Td /F1 9.8 Tf  [(Colorectal Cancer. 2008 May;7\(3\):184-90. PubMed PMID: 18621636.)] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 280.215 Td /F1 9.8 Tf  [(Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(Natl Cancer Inst. 2000 Feb 2;92\(3\):205-16. PubMed PMID: 10655437.)] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 225.096 Td /F1 9.8 Tf  [(De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, )] TJ ET
BT 26.250 189.381 Td /F1 9.8 Tf  [(Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S. Effects of KRAS, )] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010 Aug;11\(8\):753-62. Epub 2010 Jul 8. PubMed PMID: )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(20619739.)] TJ ET
BT 26.250 134.262 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 134.262 Td /F1 9.8 Tf  [(Mao C, Liao RY, Chen Q. BRAF mutation predicts resistance to anti-EGFR monoclonal antibodies in wild-type KRAS )] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Cancer Res Clin Oncol. 2010 Aug;136\(8\):1293-4. Epub 2010 Jun 1. PubMed PMID: 20514492.)] TJ ET
Q
q
15.000 104.977 577.500 672.023 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Bentivegna S, Zheng J, Namsaraev E, Carlton VE, Pavlicek A, Moorhead M, Siddiqui F, Wang Z, Lee L, Ireland JS, )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Suyenaga K, Willis TD, Faham M, Seymour AB. Rapid identification of somatic mutations in colorectal and breast cancer tissues )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(using mismatch repair detection \(MRD\). Hum Mutat. 2008 Mar;29\(3\):441-50. PubMed PMID: 18186519.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Packham D, Ward RL, Ap Lin V, Hawkins NJ, Hitchins MP. Implementation of novel pyrosequencing assays to screen for )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(common mutations of BRAF and KRAS in a cohort of sporadic colorectal cancers. Diagn Mol Pathol. 2009 Jun;18\(2\):62-71. )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(PubMed PMID: 19430299.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 673.548 Td /F1 9.8 Tf  [(Pichler M, Balic M, Stadelmeyer E, Ausch C, Wild M, Guelly C, Bauernhofer T, Samonigg H, Hoefler G, Dandachi N. )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(Evaluation of high-resolution melting analysis as a diagnostic tool to detect the BRAF V600E mutation in colorectal tumors. J )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Mol Diagn. 2009 Mar;11\(2\):140-7. Epub 2009 Feb 12. PubMed PMID: 19213871; PubMed Central PMCID: PMC2665863.)] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 630.333 Td /F1 9.8 Tf  [(Jakubauskas A, Griskevicius L. KRas and BRaf mutational status analysis from formalin-fixed, paraffin-embedded tissues )] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(using multiplex polymerase chain reaction-based assay. Arch Pathol Lab Med. 2010 Apr;134\(4\):620-4. PubMed PMID: )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(20367313.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS codon 61, )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(colorectal cancer. Br J Cancer. 2009 Aug 18;101\(4\):715-21. Epub 2009 Jul 14. PubMed PMID: 19603018; PubMed Central )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(PMCID: PMC2736831.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S. Multi-determinants analysis of molecular alterations for )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009 Oct 2;4\(10\):e7287. )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(PubMed PMID: 19806185; PubMed Central PMCID: PMC2750753.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(Clin Oncol. 2008 Dec 10;26\(35\):5705-12. Epub 2008 Nov 10. PubMed PMID: 19001320.)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Bertario L, Leo E, Pierotti MA, Pilotti S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients. Ann Oncol. 2009 Jan;20\(1\):84-90. Epub 2008 Jul 31. PubMed PMID: 18669866.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(Ychou M, Bibeau F, Bouch� O, Reid J, Stone S, Penault-Llorca F. Analysis of PTEN, BRAF, and EGFR status in determining )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009 Dec 10;27\(35\):5924-30. Epub )] TJ ET
BT 26.250 342.834 Td /F1 9.8 Tf  [(2009 Nov 2. PubMed PMID: 19884556.)] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 323.429 Td /F1 9.8 Tf  [(Freeman DJ, Juan T, Reiner M, Hecht JR, Meropol NJ, Berlin J, Mitchell E, Sarosi I, Radinsky R, Amado RG. Association of )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin )] TJ ET
BT 26.250 299.619 Td /F1 9.8 Tf  [(Colorectal Cancer. 2008 May;7\(3\):184-90. PubMed PMID: 18621636.)] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 280.215 Td /F1 9.8 Tf  [(Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J )] TJ ET
BT 26.250 244.500 Td /F1 9.8 Tf  [(Natl Cancer Inst. 2000 Feb 2;92\(3\):205-16. PubMed PMID: 10655437.)] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 225.096 Td /F1 9.8 Tf  [(De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, )] TJ ET
BT 26.250 189.381 Td /F1 9.8 Tf  [(Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S. Effects of KRAS, )] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010 Aug;11\(8\):753-62. Epub 2010 Jul 8. PubMed PMID: )] TJ ET
BT 26.250 153.667 Td /F1 9.8 Tf  [(20619739.)] TJ ET
BT 26.250 134.262 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 134.262 Td /F1 9.8 Tf  [(Mao C, Liao RY, Chen Q. BRAF mutation predicts resistance to anti-EGFR monoclonal antibodies in wild-type KRAS )] TJ ET
BT 26.250 122.358 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Cancer Res Clin Oncol. 2010 Aug;136\(8\):1293-4. Epub 2010 Jun 1. PubMed PMID: 20514492.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(10)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
Q
endstream
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