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BT 15.000 696.472 Td /F2 13.5 Tf  [(Application: Pharmacogenomic)] TJ ET
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BT 26.250 613.245 Td /F4 12.0 Tf  [(Abstract)] TJ ET
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BT 26.250 404.894 Td /F4 12.0 Tf  [(Test Description)] TJ ET
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BT 26.250 292.668 Td /F1 9.8 Tf  [(women\) will be diagnosed with and 51,370 men and women will die of colorectal cancer in 2010. The age-adjusted incidence )] TJ ET
BT 26.250 280.764 Td /F1 9.8 Tf  [(rate for colorectal cancer is 47.9 per 100,000 men and women per year. Median age at diagnosis is 70 years. The overall 5-year )] TJ ET
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BT 26.250 180.993 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 161.588 Td /F1 9.8 Tf  [(BlueCross BlueShield Technology Evaluation Center \(BCBS TEC\) published a systematic review in January 2009 based on )] TJ ET
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BT 26.250 581.386 Td /F1 9.8 Tf  [(mutant\) in tumors from patients with metastatic colorectal cancer \(CRC\). Persons whose tumors are wild type may respond to )] TJ ET
BT 26.250 569.481 Td /F1 9.8 Tf  [(therapies cetuximab \(Erbitux\) or panitumumab \(Vectibix\).)] TJ ET
BT 26.250 532.879 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 512.925 Td /F1 9.8 Tf  [(In patients with metastatic colorectal cancer \(CRC\), KRAS mutational analysis is used to determine the status of the KRAS )] TJ ET
BT 26.250 501.020 Td /F1 9.8 Tf  [(gene \(wild type or mutant\) in tumor specimens. Persons whose tumors are wild type may respond to therapies cetuximab )] TJ ET
BT 26.250 489.115 Td /F1 9.8 Tf  [(\(Erbitux\) or panitumumab \(Vectibix\). )] TJ ET
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BT 185.000 489.115 Td /F1 9.8 Tf  [([1])] TJ ET
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BT 26.250 465.306 Td /F1 9.8 Tf  [(prognostic \(i.e. whether it influences patient outcomes independent of treatment\). KRAS mutational analysis is also used to )] TJ ET
BT 26.250 453.401 Td /F1 9.8 Tf  [(refine prognosis and treatment decisions in patients with non-small cell lung cancer \(NSCLC\) and is under investigation as a )] TJ ET
BT 26.250 441.496 Td /F1 9.8 Tf  [(prognostic and/or predictive factor in other malignancies.)] TJ ET
BT 26.250 404.894 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 384.939 Td /F1 9.8 Tf  [(KRAS mutational analysis is commercially available as a laboratory-developed test on tumor tissue. PCR methods are used to )] TJ ET
BT 26.250 373.035 Td /F1 9.8 Tf  [(detect the most common mutations in codons 12, 13, and 61 of the KRAS gene in formalin fixed paraffin-embedded or frozen )] TJ ET
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BT 26.250 304.573 Td /F1 9.8 Tf  [(This test applies to persons with colorectal cancer. It is estimated that 142,570 men and women \(72,090 men and 70,480 )] TJ ET
BT 26.250 292.668 Td /F1 9.8 Tf  [(women\) will be diagnosed with and 51,370 men and women will die of colorectal cancer in 2010. The age-adjusted incidence )] TJ ET
BT 26.250 280.764 Td /F1 9.8 Tf  [(rate for colorectal cancer is 47.9 per 100,000 men and women per year. Median age at diagnosis is 70 years. The overall 5-year )] TJ ET
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BT 26.250 161.588 Td /F1 9.8 Tf  [(BlueCross BlueShield Technology Evaluation Center \(BCBS TEC\) published a systematic review in January 2009 based on )] TJ ET
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BT 26.250 642.348 Td /F1 9.8 Tf  [(on Genomic Tests. 2010 Sep 2 . Edition 1. doi: 10.1371/currents.RRN1175.)] TJ ET
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BT 26.250 593.291 Td /F1 9.8 Tf  [(KRAS mutational analysis is a genetic test used in clinical practice for determining the status of the KRAS gene \(wild type or )] TJ ET
BT 26.250 581.386 Td /F1 9.8 Tf  [(mutant\) in tumors from patients with metastatic colorectal cancer \(CRC\). Persons whose tumors are wild type may respond to )] TJ ET
BT 26.250 569.481 Td /F1 9.8 Tf  [(therapies cetuximab \(Erbitux\) or panitumumab \(Vectibix\).)] TJ ET
BT 26.250 532.879 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 512.925 Td /F1 9.8 Tf  [(In patients with metastatic colorectal cancer \(CRC\), KRAS mutational analysis is used to determine the status of the KRAS )] TJ ET
BT 26.250 501.020 Td /F1 9.8 Tf  [(gene \(wild type or mutant\) in tumor specimens. Persons whose tumors are wild type may respond to therapies cetuximab )] TJ ET
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BT 195.842 489.115 Td /F1 9.8 Tf  [( Patients whose tumors harbor a mutation in codons 12, 13, or 61 of the KRAS gene do )] TJ ET
BT 26.250 477.210 Td /F1 9.8 Tf  [(not benefit from cetuximab or panitumumab. Data are mixed whether the presence of a KRAS mutation in colorectal tumors is )] TJ ET
BT 26.250 465.306 Td /F1 9.8 Tf  [(prognostic \(i.e. whether it influences patient outcomes independent of treatment\). KRAS mutational analysis is also used to )] TJ ET
BT 26.250 453.401 Td /F1 9.8 Tf  [(refine prognosis and treatment decisions in patients with non-small cell lung cancer \(NSCLC\) and is under investigation as a )] TJ ET
BT 26.250 441.496 Td /F1 9.8 Tf  [(prognostic and/or predictive factor in other malignancies.)] TJ ET
BT 26.250 404.894 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 384.939 Td /F1 9.8 Tf  [(KRAS mutational analysis is commercially available as a laboratory-developed test on tumor tissue. PCR methods are used to )] TJ ET
BT 26.250 373.035 Td /F1 9.8 Tf  [(detect the most common mutations in codons 12, 13, and 61 of the KRAS gene in formalin fixed paraffin-embedded or frozen )] TJ ET
BT 26.250 361.130 Td /F1 9.8 Tf  [(tumor tissue. Results are reported as positive \(presence of a mutation\) or negative \(no mutation detected\). )] TJ ET
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BT 26.250 304.573 Td /F1 9.8 Tf  [(This test applies to persons with colorectal cancer. It is estimated that 142,570 men and women \(72,090 men and 70,480 )] TJ ET
BT 26.250 292.668 Td /F1 9.8 Tf  [(women\) will be diagnosed with and 51,370 men and women will die of colorectal cancer in 2010. The age-adjusted incidence )] TJ ET
BT 26.250 280.764 Td /F1 9.8 Tf  [(rate for colorectal cancer is 47.9 per 100,000 men and women per year. Median age at diagnosis is 70 years. The overall 5-year )] TJ ET
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0.271 0.267 0.267 rg
BT 26.250 249.454 Td /F1 9.8 Tf  [(Approximately 20% of colorectal cancer diagnoses are in the distant or metastatic stage \(for whom cetuximab or panitumumab )] TJ ET
BT 26.250 237.549 Td /F1 9.8 Tf  [(may be indicated\). The median survival in patients with metastatic CRC is less than 2 years. )] TJ ET
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BT 425.600 237.549 Td /F1 9.8 Tf  [([3])] TJ ET
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BT 26.250 180.993 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 161.588 Td /F1 9.8 Tf  [(BlueCross BlueShield Technology Evaluation Center \(BCBS TEC\) published a systematic review in January 2009 based on )] TJ ET
BT 26.250 149.683 Td /F1 9.8 Tf  [(retrospective analyses of 5 RCT and 5 single-arm studies. )] TJ ET
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BT 26.250 110.874 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 91.469 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network \(NCCN\) and the American Society of Clinical Oncology \(ASCO\) have issued clinical )] TJ ET
BT 26.250 79.564 Td /F1 9.8 Tf  [(guidelines recommending )] TJ ET
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BT 166.591 79.564 Td /F1 9.8 Tf  [( mutational analysis on the tumors of all patients with metastatic CRC prior to prescribing )] TJ ET
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BT 404.014 569.372 Td /F1 9.8 Tf  [([19])] TJ ET
BT 420.277 569.372 Td /F1 9.8 Tf  [([20])] TJ ET
BT 436.540 569.372 Td /F1 9.8 Tf  [([21])] TJ ET
BT 452.803 569.372 Td /F1 9.8 Tf  [([22])] TJ ET
BT 469.066 569.372 Td /F1 9.8 Tf  [([23])] TJ ET
BT 485.329 569.372 Td /F1 9.8 Tf  [([24])] TJ ET
BT 501.592 569.372 Td /F1 9.8 Tf  [([25])] TJ ET
BT 517.855 569.372 Td /F1 9.8 Tf  [([26])] TJ ET
BT 534.118 569.372 Td /F1 9.8 Tf  [([27])] TJ ET
BT 550.381 569.372 Td /F1 9.8 Tf  [([28])] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [([29])] TJ ET
BT 42.513 557.467 Td /F1 9.8 Tf  [([30])] TJ ET
BT 58.776 557.467 Td /F1 9.8 Tf  [([31])] TJ ET
BT 75.039 557.467 Td /F1 9.8 Tf  [([32])] TJ ET
BT 91.302 557.467 Td /F1 9.8 Tf  [([33])] TJ ET
BT 107.565 557.467 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 123.828 557.467 Td /F1 9.8 Tf  [( The strength of this association has been substantiated in retrospective analyses of patients treated in )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(six, large randomized studies. )] TJ ET
0.267 0.267 0.267 rg
BT 157.924 545.562 Td /F1 9.8 Tf  [([35])] TJ ET
BT 174.187 545.562 Td /F1 9.8 Tf  [([36])] TJ ET
BT 190.450 545.562 Td /F1 9.8 Tf  [([37])] TJ ET
BT 206.713 545.562 Td /F1 9.8 Tf  [([38])] TJ ET
BT 222.976 545.562 Td /F1 9.8 Tf  [([39])] TJ ET
BT 239.239 545.562 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 526.158 Td /F1 9.8 Tf  [(A review of 8 studies \(306 of 817 patients with tumors mutant for the KRAS gene\) conducted by Linardou et al found that KRAS )] TJ ET
BT 26.250 514.253 Td /F1 9.8 Tf  [(mutations were significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments )] TJ ET
BT 26.250 502.348 Td /F1 9.8 Tf  [(\(sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57\). )] TJ ET
0.267 0.267 0.267 rg
BT 370.123 502.348 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.943 Td /F1 9.8 Tf  [(A recent meta-analysis of 22 studies including persons with metastatic colorectal cancer treated with cetuximab found that )] TJ ET
BT 26.250 471.039 Td /F1 9.8 Tf  [(progression free and overall survival in persons with wildtype KRAS tumors was better compared to persons with mutated )] TJ ET
BT 26.250 459.134 Td /F1 9.8 Tf  [(KRAS tumors. )] TJ ET
0.267 0.267 0.267 rg
BT 90.727 459.134 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.729 Td /F1 9.8 Tf  [(The data are mixed whether KRAS mutation is indicative of worse prognosis independent of therapy. At present, KRAS )] TJ ET
BT 26.250 427.824 Td /F1 9.8 Tf  [(mutational analysis is not recommended for risk assessment.)] TJ ET
BT 26.250 408.420 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 408.420 Td /F4 9.8 Tf  [( :)] TJ ET
BT 26.250 389.015 Td /F1 9.8 Tf  [(NCCN and BCBS TEC conclude that tumor testing for KRAS mutation offers clinical utility, and testing is available outside of )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(research settings in clinical practice. However, we did not identify studies reporting physician and patient acceptance or )] TJ ET
BT 26.250 365.205 Td /F1 9.8 Tf  [(population-based health outcomes data from use in clinical practice.)] TJ ET
BT 26.250 328.603 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 308.649 Td /F1 9.8 Tf  [(The lab-based tests are regulated under the Clinical Laboratory Improvement Amendments \(CLIA\), and FDA premarket )] TJ ET
BT 26.250 296.744 Td /F1 9.8 Tf  [(approval is not required. )] TJ ET
0.267 0.267 0.267 rg
BT 133.549 296.744 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 260.141 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 222.989 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 203.035 Td /F1 9.8 Tf  [(This project was funded in part by the National Cancer Institute, grant # P01CA130818.)] TJ ET
BT 26.250 166.433 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 146.478 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 109.876 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 82.422 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 82.422 Td /F1 9.8 Tf  [(Normanno, N., et al., Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol, )] TJ ET
BT 26.250 70.517 Td /F1 9.8 Tf  [(2009. 6\(9\): p. 519-27.)] TJ ET
BT 26.250 51.112 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 51.112 Td /F1 9.8 Tf  [(KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. Technol Eval Cent )] TJ ET
Q
q
15.000 36.826 577.500 740.174 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 730.324 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 730.324 Td /F4 9.8 Tf  [( :)] TJ ET
BT 26.250 710.919 Td /F1 9.8 Tf  [(KRAS gene mutation analysis is commercially available through several labs. However, the labs themselves have not provided )] TJ ET
BT 26.250 699.015 Td /F1 9.8 Tf  [(information on analytic performance. )] TJ ET
0.267 0.267 0.267 rg
BT 186.647 699.015 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 679.610 Td /F1 9.8 Tf  [(A recent, industry sponsored study compared different KRAS testing assays from 5 labs \(Agencourt, Gentris, Genzyme, )] TJ ET
BT 26.250 667.705 Td /F1 9.8 Tf  [(HistoGeneX, and Invitek\) against the Amgen DNA Sequencing Laboratory direct sequencing assay. KRAS was classified as )] TJ ET
BT 26.250 655.800 Td /F1 9.8 Tf  [(either wild type or mutant. Techniques were in agreement if both assays identified wild type or a mutant. Agreement was )] TJ ET
BT 26.250 643.896 Td /F1 9.8 Tf  [(assessed by ? statistics. Agreement for each assay were reported as: HistoGeneX \(kappa=0.95\), Genzyme \(kappa=0.94\), )] TJ ET
BT 26.250 631.991 Td /F1 9.8 Tf  [(Agencourt \(kappa=0.94\), Gentris \(kappa=0.75\), and Invitek \(kappa=0.13\). )] TJ ET
0.267 0.267 0.267 rg
BT 346.820 631.991 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 612.586 Td /F6 9.8 Tf  [(Clinical Validity in Metastatic Colorectal Cancer)] TJ ET
BT 246.239 612.586 Td /F1 9.8 Tf  [( : )] TJ ET
BT 26.250 593.181 Td /F1 9.8 Tf  [(Retrospective, subset analyses of tumor tissue samples from small clinical trials have demonstrated that tumor KRAS gene )] TJ ET
BT 26.250 581.277 Td /F1 9.8 Tf  [(mutations are associated with lack of response to both of the EGFR-targeted monoclonal antibodies approved for use in )] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(colorectal cancer, cetuximab and panitumumab. )] TJ ET
0.267 0.267 0.267 rg
BT 235.963 569.372 Td /F1 9.8 Tf  [([8])] TJ ET
BT 246.805 569.372 Td /F1 9.8 Tf  [([9])] TJ ET
BT 257.647 569.372 Td /F1 9.8 Tf  [([10])] TJ ET
BT 273.910 569.372 Td /F1 9.8 Tf  [([11])] TJ ET
BT 290.173 569.372 Td /F1 9.8 Tf  [([12])] TJ ET
BT 306.436 569.372 Td /F1 9.8 Tf  [([13])] TJ ET
BT 322.699 569.372 Td /F1 9.8 Tf  [([14])] TJ ET
BT 338.962 569.372 Td /F1 9.8 Tf  [([15])] TJ ET
BT 355.225 569.372 Td /F1 9.8 Tf  [([16])] TJ ET
BT 371.488 569.372 Td /F1 9.8 Tf  [([17])] TJ ET
BT 387.751 569.372 Td /F1 9.8 Tf  [([18])] TJ ET
BT 404.014 569.372 Td /F1 9.8 Tf  [([19])] TJ ET
BT 420.277 569.372 Td /F1 9.8 Tf  [([20])] TJ ET
BT 436.540 569.372 Td /F1 9.8 Tf  [([21])] TJ ET
BT 452.803 569.372 Td /F1 9.8 Tf  [([22])] TJ ET
BT 469.066 569.372 Td /F1 9.8 Tf  [([23])] TJ ET
BT 485.329 569.372 Td /F1 9.8 Tf  [([24])] TJ ET
BT 501.592 569.372 Td /F1 9.8 Tf  [([25])] TJ ET
BT 517.855 569.372 Td /F1 9.8 Tf  [([26])] TJ ET
BT 534.118 569.372 Td /F1 9.8 Tf  [([27])] TJ ET
BT 550.381 569.372 Td /F1 9.8 Tf  [([28])] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [([29])] TJ ET
BT 42.513 557.467 Td /F1 9.8 Tf  [([30])] TJ ET
BT 58.776 557.467 Td /F1 9.8 Tf  [([31])] TJ ET
BT 75.039 557.467 Td /F1 9.8 Tf  [([32])] TJ ET
BT 91.302 557.467 Td /F1 9.8 Tf  [([33])] TJ ET
BT 107.565 557.467 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 123.828 557.467 Td /F1 9.8 Tf  [( The strength of this association has been substantiated in retrospective analyses of patients treated in )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(six, large randomized studies. )] TJ ET
0.267 0.267 0.267 rg
BT 157.924 545.562 Td /F1 9.8 Tf  [([35])] TJ ET
BT 174.187 545.562 Td /F1 9.8 Tf  [([36])] TJ ET
BT 190.450 545.562 Td /F1 9.8 Tf  [([37])] TJ ET
BT 206.713 545.562 Td /F1 9.8 Tf  [([38])] TJ ET
BT 222.976 545.562 Td /F1 9.8 Tf  [([39])] TJ ET
BT 239.239 545.562 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 526.158 Td /F1 9.8 Tf  [(A review of 8 studies \(306 of 817 patients with tumors mutant for the KRAS gene\) conducted by Linardou et al found that KRAS )] TJ ET
BT 26.250 514.253 Td /F1 9.8 Tf  [(mutations were significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments )] TJ ET
BT 26.250 502.348 Td /F1 9.8 Tf  [(\(sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57\). )] TJ ET
0.267 0.267 0.267 rg
BT 370.123 502.348 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.943 Td /F1 9.8 Tf  [(A recent meta-analysis of 22 studies including persons with metastatic colorectal cancer treated with cetuximab found that )] TJ ET
BT 26.250 471.039 Td /F1 9.8 Tf  [(progression free and overall survival in persons with wildtype KRAS tumors was better compared to persons with mutated )] TJ ET
BT 26.250 459.134 Td /F1 9.8 Tf  [(KRAS tumors. )] TJ ET
0.267 0.267 0.267 rg
BT 90.727 459.134 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.729 Td /F1 9.8 Tf  [(The data are mixed whether KRAS mutation is indicative of worse prognosis independent of therapy. At present, KRAS )] TJ ET
BT 26.250 427.824 Td /F1 9.8 Tf  [(mutational analysis is not recommended for risk assessment.)] TJ ET
BT 26.250 408.420 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 408.420 Td /F4 9.8 Tf  [( :)] TJ ET
BT 26.250 389.015 Td /F1 9.8 Tf  [(NCCN and BCBS TEC conclude that tumor testing for KRAS mutation offers clinical utility, and testing is available outside of )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(research settings in clinical practice. However, we did not identify studies reporting physician and patient acceptance or )] TJ ET
BT 26.250 365.205 Td /F1 9.8 Tf  [(population-based health outcomes data from use in clinical practice.)] TJ ET
BT 26.250 328.603 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 308.649 Td /F1 9.8 Tf  [(The lab-based tests are regulated under the Clinical Laboratory Improvement Amendments \(CLIA\), and FDA premarket )] TJ ET
BT 26.250 296.744 Td /F1 9.8 Tf  [(approval is not required. )] TJ ET
0.267 0.267 0.267 rg
BT 133.549 296.744 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 260.141 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 222.989 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 203.035 Td /F1 9.8 Tf  [(This project was funded in part by the National Cancer Institute, grant # P01CA130818.)] TJ ET
BT 26.250 166.433 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 146.478 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 109.876 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 82.422 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 82.422 Td /F1 9.8 Tf  [(Normanno, N., et al., Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol, )] TJ ET
BT 26.250 70.517 Td /F1 9.8 Tf  [(2009. 6\(9\): p. 519-27.)] TJ ET
BT 26.250 51.112 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 51.112 Td /F1 9.8 Tf  [(KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. Technol Eval Cent )] TJ ET
Q
q
15.000 36.826 577.500 740.174 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 730.324 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 730.324 Td /F4 9.8 Tf  [( :)] TJ ET
BT 26.250 710.919 Td /F1 9.8 Tf  [(KRAS gene mutation analysis is commercially available through several labs. However, the labs themselves have not provided )] TJ ET
BT 26.250 699.015 Td /F1 9.8 Tf  [(information on analytic performance. )] TJ ET
0.267 0.267 0.267 rg
BT 186.647 699.015 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 679.610 Td /F1 9.8 Tf  [(A recent, industry sponsored study compared different KRAS testing assays from 5 labs \(Agencourt, Gentris, Genzyme, )] TJ ET
BT 26.250 667.705 Td /F1 9.8 Tf  [(HistoGeneX, and Invitek\) against the Amgen DNA Sequencing Laboratory direct sequencing assay. KRAS was classified as )] TJ ET
BT 26.250 655.800 Td /F1 9.8 Tf  [(either wild type or mutant. Techniques were in agreement if both assays identified wild type or a mutant. Agreement was )] TJ ET
BT 26.250 643.896 Td /F1 9.8 Tf  [(assessed by ? statistics. Agreement for each assay were reported as: HistoGeneX \(kappa=0.95\), Genzyme \(kappa=0.94\), )] TJ ET
BT 26.250 631.991 Td /F1 9.8 Tf  [(Agencourt \(kappa=0.94\), Gentris \(kappa=0.75\), and Invitek \(kappa=0.13\). )] TJ ET
0.267 0.267 0.267 rg
BT 346.820 631.991 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 612.586 Td /F6 9.8 Tf  [(Clinical Validity in Metastatic Colorectal Cancer)] TJ ET
BT 246.239 612.586 Td /F1 9.8 Tf  [( : )] TJ ET
BT 26.250 593.181 Td /F1 9.8 Tf  [(Retrospective, subset analyses of tumor tissue samples from small clinical trials have demonstrated that tumor KRAS gene )] TJ ET
BT 26.250 581.277 Td /F1 9.8 Tf  [(mutations are associated with lack of response to both of the EGFR-targeted monoclonal antibodies approved for use in )] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(colorectal cancer, cetuximab and panitumumab. )] TJ ET
0.267 0.267 0.267 rg
BT 235.963 569.372 Td /F1 9.8 Tf  [([8])] TJ ET
BT 246.805 569.372 Td /F1 9.8 Tf  [([9])] TJ ET
BT 257.647 569.372 Td /F1 9.8 Tf  [([10])] TJ ET
BT 273.910 569.372 Td /F1 9.8 Tf  [([11])] TJ ET
BT 290.173 569.372 Td /F1 9.8 Tf  [([12])] TJ ET
BT 306.436 569.372 Td /F1 9.8 Tf  [([13])] TJ ET
BT 322.699 569.372 Td /F1 9.8 Tf  [([14])] TJ ET
BT 338.962 569.372 Td /F1 9.8 Tf  [([15])] TJ ET
BT 355.225 569.372 Td /F1 9.8 Tf  [([16])] TJ ET
BT 371.488 569.372 Td /F1 9.8 Tf  [([17])] TJ ET
BT 387.751 569.372 Td /F1 9.8 Tf  [([18])] TJ ET
BT 404.014 569.372 Td /F1 9.8 Tf  [([19])] TJ ET
BT 420.277 569.372 Td /F1 9.8 Tf  [([20])] TJ ET
BT 436.540 569.372 Td /F1 9.8 Tf  [([21])] TJ ET
BT 452.803 569.372 Td /F1 9.8 Tf  [([22])] TJ ET
BT 469.066 569.372 Td /F1 9.8 Tf  [([23])] TJ ET
BT 485.329 569.372 Td /F1 9.8 Tf  [([24])] TJ ET
BT 501.592 569.372 Td /F1 9.8 Tf  [([25])] TJ ET
BT 517.855 569.372 Td /F1 9.8 Tf  [([26])] TJ ET
BT 534.118 569.372 Td /F1 9.8 Tf  [([27])] TJ ET
BT 550.381 569.372 Td /F1 9.8 Tf  [([28])] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [([29])] TJ ET
BT 42.513 557.467 Td /F1 9.8 Tf  [([30])] TJ ET
BT 58.776 557.467 Td /F1 9.8 Tf  [([31])] TJ ET
BT 75.039 557.467 Td /F1 9.8 Tf  [([32])] TJ ET
BT 91.302 557.467 Td /F1 9.8 Tf  [([33])] TJ ET
BT 107.565 557.467 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 123.828 557.467 Td /F1 9.8 Tf  [( The strength of this association has been substantiated in retrospective analyses of patients treated in )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(six, large randomized studies. )] TJ ET
0.267 0.267 0.267 rg
BT 157.924 545.562 Td /F1 9.8 Tf  [([35])] TJ ET
BT 174.187 545.562 Td /F1 9.8 Tf  [([36])] TJ ET
BT 190.450 545.562 Td /F1 9.8 Tf  [([37])] TJ ET
BT 206.713 545.562 Td /F1 9.8 Tf  [([38])] TJ ET
BT 222.976 545.562 Td /F1 9.8 Tf  [([39])] TJ ET
BT 239.239 545.562 Td /F1 9.8 Tf  [([40])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 526.158 Td /F1 9.8 Tf  [(A review of 8 studies \(306 of 817 patients with tumors mutant for the KRAS gene\) conducted by Linardou et al found that KRAS )] TJ ET
BT 26.250 514.253 Td /F1 9.8 Tf  [(mutations were significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments )] TJ ET
BT 26.250 502.348 Td /F1 9.8 Tf  [(\(sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57\). )] TJ ET
0.267 0.267 0.267 rg
BT 370.123 502.348 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.943 Td /F1 9.8 Tf  [(A recent meta-analysis of 22 studies including persons with metastatic colorectal cancer treated with cetuximab found that )] TJ ET
BT 26.250 471.039 Td /F1 9.8 Tf  [(progression free and overall survival in persons with wildtype KRAS tumors was better compared to persons with mutated )] TJ ET
BT 26.250 459.134 Td /F1 9.8 Tf  [(KRAS tumors. )] TJ ET
0.267 0.267 0.267 rg
BT 90.727 459.134 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 439.729 Td /F1 9.8 Tf  [(The data are mixed whether KRAS mutation is indicative of worse prognosis independent of therapy. At present, KRAS )] TJ ET
BT 26.250 427.824 Td /F1 9.8 Tf  [(mutational analysis is not recommended for risk assessment.)] TJ ET
BT 26.250 408.420 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 408.420 Td /F4 9.8 Tf  [( :)] TJ ET
BT 26.250 389.015 Td /F1 9.8 Tf  [(NCCN and BCBS TEC conclude that tumor testing for KRAS mutation offers clinical utility, and testing is available outside of )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(research settings in clinical practice. However, we did not identify studies reporting physician and patient acceptance or )] TJ ET
BT 26.250 365.205 Td /F1 9.8 Tf  [(population-based health outcomes data from use in clinical practice.)] TJ ET
BT 26.250 328.603 Td /F4 12.0 Tf  [(Links)] TJ ET
BT 26.250 308.649 Td /F1 9.8 Tf  [(The lab-based tests are regulated under the Clinical Laboratory Improvement Amendments \(CLIA\), and FDA premarket )] TJ ET
BT 26.250 296.744 Td /F1 9.8 Tf  [(approval is not required. )] TJ ET
0.267 0.267 0.267 rg
BT 133.549 296.744 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 260.141 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 222.989 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 203.035 Td /F1 9.8 Tf  [(This project was funded in part by the National Cancer Institute, grant # P01CA130818.)] TJ ET
BT 26.250 166.433 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 146.478 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 109.876 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 82.422 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 82.422 Td /F1 9.8 Tf  [(Normanno, N., et al., Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol, )] TJ ET
BT 26.250 70.517 Td /F1 9.8 Tf  [(2009. 6\(9\): p. 519-27.)] TJ ET
BT 26.250 51.112 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 51.112 Td /F1 9.8 Tf  [(KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. Technol Eval Cent )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(2)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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BT 26.250 521.142 Td /F1 9.8 Tf  [(patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol, 2009. 27\(7\): p. 1122-9.)] TJ ET
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BT 26.250 270.666 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients receiving cetuximab-based treatment. BMC Cancer, 2008. 8: p. 169.)] TJ ET
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BT 26.250 239.357 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol, 2007. 25\(22\): p. 3230-7.)] TJ ET
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BT 43.553 219.952 Td /F1 9.8 Tf  [(Laurent-Puig, P., et al., Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-)] TJ ET
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BT 26.250 126.024 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 126.024 Td /F1 9.8 Tf  [(Loupakis, F., et al., PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit )] TJ ET
BT 26.250 114.119 Td /F1 9.8 Tf  [(from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol, 2009. 27\(16\): p. 2622-9.)] TJ ET
BT 26.250 94.714 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 94.714 Td /F1 9.8 Tf  [(Loupakis, F., et al., KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS )] TJ ET
BT 26.250 82.809 Td /F1 9.8 Tf  [(codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer, 2009. 101\(4\): p. 715-21.)] TJ ET
BT 26.250 63.405 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 63.405 Td /F1 9.8 Tf  [(Lurje, G., et al., Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-)] TJ ET
BT 26.250 51.500 Td /F1 9.8 Tf  [(free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res, )] TJ ET
Q
q
15.000 37.214 577.500 739.786 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Asses Program Exec Summ, 2009. 23\(6\): p. 1-3.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 748.071 Td /F1 9.8 Tf  [(National Cancer Institute. SEER Stat Fact Sheets: Colon and Rectum. 2010 [cited 2010 April 26];)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 739.586 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 721.035 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 721.035 Td /F1 9.8 Tf  [(NCCN Updates Guidelines for Colorectal Cancer ; NCCN announces new updates to the NCCN Guidelines for Colon and )] TJ ET
BT 26.250 709.131 Td /F1 9.8 Tf  [(Rectal Cancers . The updates include recommendations to the pre-treatment work-up and use of anti- cancer agents in patients )] TJ ET
BT 26.250 697.226 Td /F1 9.8 Tf  [(with metastatic colorectal cancer depending on the status of the tumor's KRAS gene. The changes are based on recent studies )] TJ ET
BT 26.250 685.321 Td /F1 9.8 Tf  [(demonstrating that the tumor KRAS gene status is highly predictive of outcome with certain therapies, in Business Wire. 2008.)] TJ ET
BT 26.250 665.916 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 665.916 Td /F1 9.8 Tf  [(National Comprehensive Cancer Network. Colon Cancer. NCCN Clinical Practice Guidelines in Oncology 2009 [cited 2009 )] TJ ET
BT 26.250 654.012 Td /F1 9.8 Tf  [(October 21];)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 645.526 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 626.976 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 626.976 Td /F1 9.8 Tf  [(Allegra, C.J., et al., American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in )] TJ ET
BT 26.250 615.071 Td /F1 9.8 Tf  [(patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody )] TJ ET
BT 26.250 603.166 Td /F1 9.8 Tf  [(therapy. J Clin Oncol, 2009. 27\(12\): p. 2091-6)] TJ ET
BT 26.250 583.761 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 583.761 Td /F1 9.8 Tf  [(Oliner, K., et al., A comparability study of 5 commercial KRAS tests. Diagn Pathol. 5\(1\): p. 23)] TJ ET
BT 26.250 564.357 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 564.357 Td /F1 9.8 Tf  [(Benvenuti, S., et al., Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal )] TJ ET
BT 26.250 552.452 Td /F1 9.8 Tf  [(cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res, 2007. 67\(6\): p. 2643-8.)] TJ ET
BT 26.250 533.047 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 533.047 Td /F1 9.8 Tf  [(Bibeau, F., et al., Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of )] TJ ET
BT 26.250 521.142 Td /F1 9.8 Tf  [(patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol, 2009. 27\(7\): p. 1122-9.)] TJ ET
BT 26.250 501.738 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 501.738 Td /F1 9.8 Tf  [(Cappuzzo, F., et al., Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J )] TJ ET
BT 26.250 489.833 Td /F1 9.8 Tf  [(Cancer, 2008. 99\(1\): p. 83-9.)] TJ ET
BT 26.250 470.428 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 470.428 Td /F1 9.8 Tf  [(De Roock, W., et al., KRAS wild-type state predicts survival and is associated to early radiological response in metastatic )] TJ ET
BT 26.250 458.523 Td /F1 9.8 Tf  [(colorectal cancer treated with cetuximab. Ann Oncol, 2008. 19\(3\): p. 508-15.)] TJ ET
BT 26.250 439.119 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 439.119 Td /F1 9.8 Tf  [(Di Fiore, F., et al., Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus )] TJ ET
BT 26.250 427.214 Td /F1 9.8 Tf  [(chemotherapy. Br J Cancer, 2007. 96\(8\): p. 1166-9.)] TJ ET
BT 26.250 407.809 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 407.809 Td /F1 9.8 Tf  [(Di Nicolantonio, F., et al., Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal )] TJ ET
BT 26.250 395.904 Td /F1 9.8 Tf  [(cancer. J Clin Oncol, 2008. 26\(35\): p. 5705-12.)] TJ ET
BT 26.250 376.500 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 376.500 Td /F1 9.8 Tf  [(Frattini, M., et al., PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer, )] TJ ET
BT 26.250 364.595 Td /F1 9.8 Tf  [(2007. 97\(8\): p. 1139-45.)] TJ ET
BT 26.250 345.190 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 345.190 Td /F1 9.8 Tf  [(Freeman, D.J., et al., Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal )] TJ ET
BT 26.250 333.285 Td /F1 9.8 Tf  [(cancer receiving panitumumab alone. Clin Colorectal Cancer, 2008. 7\(3\): p. 184-90.)] TJ ET
BT 26.250 313.881 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 313.881 Td /F1 9.8 Tf  [(Garm Spindler, K.L., et al., The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab )] TJ ET
BT 26.250 301.976 Td /F1 9.8 Tf  [(and irinotecan in metastatic colorectal cancer. Ann Oncol, 2009. 20\(5\): p. 879-84.)] TJ ET
BT 26.250 282.571 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 282.571 Td /F1 9.8 Tf  [(Goncalves, A., et al., A polymorphism of EGFR extracellular domain is associated with progression free-survival in )] TJ ET
BT 26.250 270.666 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients receiving cetuximab-based treatment. BMC Cancer, 2008. 8: p. 169.)] TJ ET
BT 26.250 251.262 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 251.262 Td /F1 9.8 Tf  [(Khambata-Ford, S., et al., Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in )] TJ ET
BT 26.250 239.357 Td /F1 9.8 Tf  [(metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol, 2007. 25\(22\): p. 3230-7.)] TJ ET
BT 26.250 219.952 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 219.952 Td /F1 9.8 Tf  [(Laurent-Puig, P., et al., Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-)] TJ ET
BT 26.250 208.047 Td /F1 9.8 Tf  [(type KRAS metastatic colon cancer. J Clin Oncol, 2009. 27\(35\): p. 5924-30.)] TJ ET
BT 26.250 188.643 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 188.643 Td /F1 9.8 Tf  [(Lievre, A., et al., KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated )] TJ ET
BT 26.250 176.738 Td /F1 9.8 Tf  [(with cetuximab. J Clin Oncol, 2008. 26\(3\): p. 374-9.)] TJ ET
BT 26.250 157.333 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 157.333 Td /F1 9.8 Tf  [(Lievre, A., et al., KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res, )] TJ ET
BT 26.250 145.428 Td /F1 9.8 Tf  [(2006. 66\(8\): p. 3992-5.)] TJ ET
BT 26.250 126.024 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 126.024 Td /F1 9.8 Tf  [(Loupakis, F., et al., PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit )] TJ ET
BT 26.250 114.119 Td /F1 9.8 Tf  [(from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol, 2009. 27\(16\): p. 2622-9.)] TJ ET
BT 26.250 94.714 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 94.714 Td /F1 9.8 Tf  [(Loupakis, F., et al., KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS )] TJ ET
BT 26.250 82.809 Td /F1 9.8 Tf  [(codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer, 2009. 101\(4\): p. 715-21.)] TJ ET
BT 26.250 63.405 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 63.405 Td /F1 9.8 Tf  [(Lurje, G., et al., Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-)] TJ ET
BT 26.250 51.500 Td /F1 9.8 Tf  [(free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res, )] TJ ET
Q
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BT 291.710 19.825 Td /F1 11.0 Tf  [(3)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(2008. 14\(23\): p. 7884-95.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Molinari, F., et al., Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(metastatic sites may be clinically relevant. Br J Cancer, 2009. 100\(7\): p. 1087-94.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Moroni, M., et al., Gene copy number for epidermal growth factor receptor \(EGFR\) and clinical response to antiEGFR )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(treatment in colorectal cancer: a cohort study. Lancet Oncol, 2005. 6\(5\): p. 279-86.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Oden-Gangloff, A., et al., TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(based chemotherapy. Br J Cancer, 2009. 100\(8\): p. 1330-5.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Perrone, F., et al., PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(cancer patients. Ann Oncol, 2009. 20\(1\): p. 84-90.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Personeni, N., et al., Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res, 2008. 14\(18\): p. 5869-76.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Prenen, H., et al., PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res, 2009. 15\(9\): p. 3184-8.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Sartore-Bianchi, A., et al., PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(monoclonal antibodies. Cancer Res, 2009. 69\(5\): p. 1851-7.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Sohn, B.S., et al., The role of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan therapy in irinotecan-)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(refractory Korean metastatic colorectal cancer patients. Oncology, 2009. 77\(3-4\): p. 224-30.)] TJ ET
BT 26.250 497.595 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 497.595 Td /F1 9.8 Tf  [(Souglakos, J., et al., Prognostic and predictive value of common mutations for treatment response and survival in patients )] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(with metastatic colorectal cancer. Br J Cancer, 2009. 101\(3\): p. 465-72.)] TJ ET
BT 26.250 466.286 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 466.286 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 251\(2\): p. 254-60.)] TJ ET
BT 26.250 434.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 434.976 Td /F1 9.8 Tf  [(Amado, R.G., et al., Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J )] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(Clin Oncol, 2008. 26\(10\): p. 1626-34.)] TJ ET
BT 26.250 403.667 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 403.667 Td /F1 9.8 Tf  [(Bokemeyer, C., et al., Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of )] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 663-71.)] TJ ET
BT 26.250 372.357 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 372.357 Td /F1 9.8 Tf  [(Hecht, J.R., et al., A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with )] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 672-80.)] TJ ET
BT 26.250 341.048 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 341.048 Td /F1 9.8 Tf  [(Karapetis, C.S., et al., K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med, 2008. )] TJ ET
BT 26.250 329.143 Td /F1 9.8 Tf  [(359\(17\): p. 1757-65.)] TJ ET
BT 26.250 309.738 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 309.738 Td /F1 9.8 Tf  [(Tol, J., et al., Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med, 2009. 360\(6\): p. )] TJ ET
BT 26.250 297.834 Td /F1 9.8 Tf  [(563-72.)] TJ ET
BT 26.250 278.429 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 278.429 Td /F1 9.8 Tf  [(Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med, )] TJ ET
BT 26.250 266.524 Td /F1 9.8 Tf  [(2009. 360\(14\): p. 1408-17)] TJ ET
BT 26.250 247.119 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 247.119 Td /F1 9.8 Tf  [(Linardou, H., et al., Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted )] TJ ET
BT 26.250 235.215 Td /F1 9.8 Tf  [(agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal )] TJ ET
BT 26.250 223.310 Td /F1 9.8 Tf  [(cancer. Lancet Oncol, 2008. 9\(10\): p. 962-72)] TJ ET
BT 26.250 203.905 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 203.905 Td /F1 9.8 Tf  [(Qiu, L.X. et al., Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with )] TJ ET
BT 26.250 192.000 Td /F1 9.8 Tf  [(cetuximab: A meta-analysis of 22 studies. Eur J Cancer, 2010. \(in press\). doi:10.1016/j.ejca.2010.05.022)] TJ ET
BT 26.250 172.596 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 172.596 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 160.691 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg, 2010. 251\(2\): p. 254-60)] TJ ET
Q
q
15.000 143.310 577.500 633.690 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(2008. 14\(23\): p. 7884-95.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Molinari, F., et al., Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(metastatic sites may be clinically relevant. Br J Cancer, 2009. 100\(7\): p. 1087-94.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Moroni, M., et al., Gene copy number for epidermal growth factor receptor \(EGFR\) and clinical response to antiEGFR )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(treatment in colorectal cancer: a cohort study. Lancet Oncol, 2005. 6\(5\): p. 279-86.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Oden-Gangloff, A., et al., TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(based chemotherapy. Br J Cancer, 2009. 100\(8\): p. 1330-5.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Perrone, F., et al., PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(cancer patients. Ann Oncol, 2009. 20\(1\): p. 84-90.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Personeni, N., et al., Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res, 2008. 14\(18\): p. 5869-76.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Prenen, H., et al., PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res, 2009. 15\(9\): p. 3184-8.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Sartore-Bianchi, A., et al., PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(monoclonal antibodies. Cancer Res, 2009. 69\(5\): p. 1851-7.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Sohn, B.S., et al., The role of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan therapy in irinotecan-)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(refractory Korean metastatic colorectal cancer patients. Oncology, 2009. 77\(3-4\): p. 224-30.)] TJ ET
BT 26.250 497.595 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 497.595 Td /F1 9.8 Tf  [(Souglakos, J., et al., Prognostic and predictive value of common mutations for treatment response and survival in patients )] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(with metastatic colorectal cancer. Br J Cancer, 2009. 101\(3\): p. 465-72.)] TJ ET
BT 26.250 466.286 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 466.286 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 251\(2\): p. 254-60.)] TJ ET
BT 26.250 434.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 434.976 Td /F1 9.8 Tf  [(Amado, R.G., et al., Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J )] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(Clin Oncol, 2008. 26\(10\): p. 1626-34.)] TJ ET
BT 26.250 403.667 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 403.667 Td /F1 9.8 Tf  [(Bokemeyer, C., et al., Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of )] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 663-71.)] TJ ET
BT 26.250 372.357 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 372.357 Td /F1 9.8 Tf  [(Hecht, J.R., et al., A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with )] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 672-80.)] TJ ET
BT 26.250 341.048 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 341.048 Td /F1 9.8 Tf  [(Karapetis, C.S., et al., K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med, 2008. )] TJ ET
BT 26.250 329.143 Td /F1 9.8 Tf  [(359\(17\): p. 1757-65.)] TJ ET
BT 26.250 309.738 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 309.738 Td /F1 9.8 Tf  [(Tol, J., et al., Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med, 2009. 360\(6\): p. )] TJ ET
BT 26.250 297.834 Td /F1 9.8 Tf  [(563-72.)] TJ ET
BT 26.250 278.429 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 278.429 Td /F1 9.8 Tf  [(Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med, )] TJ ET
BT 26.250 266.524 Td /F1 9.8 Tf  [(2009. 360\(14\): p. 1408-17)] TJ ET
BT 26.250 247.119 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 247.119 Td /F1 9.8 Tf  [(Linardou, H., et al., Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted )] TJ ET
BT 26.250 235.215 Td /F1 9.8 Tf  [(agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal )] TJ ET
BT 26.250 223.310 Td /F1 9.8 Tf  [(cancer. Lancet Oncol, 2008. 9\(10\): p. 962-72)] TJ ET
BT 26.250 203.905 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 203.905 Td /F1 9.8 Tf  [(Qiu, L.X. et al., Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with )] TJ ET
BT 26.250 192.000 Td /F1 9.8 Tf  [(cetuximab: A meta-analysis of 22 studies. Eur J Cancer, 2010. \(in press\). doi:10.1016/j.ejca.2010.05.022)] TJ ET
BT 26.250 172.596 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 172.596 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 160.691 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg, 2010. 251\(2\): p. 254-60)] TJ ET
Q
q
15.000 143.310 577.500 633.690 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(2008. 14\(23\): p. 7884-95.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Molinari, F., et al., Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(metastatic sites may be clinically relevant. Br J Cancer, 2009. 100\(7\): p. 1087-94.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(Moroni, M., et al., Gene copy number for epidermal growth factor receptor \(EGFR\) and clinical response to antiEGFR )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(treatment in colorectal cancer: a cohort study. Lancet Oncol, 2005. 6\(5\): p. 279-86.)] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 685.452 Td /F1 9.8 Tf  [(Oden-Gangloff, A., et al., TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(based chemotherapy. Br J Cancer, 2009. 100\(8\): p. 1330-5.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(Perrone, F., et al., PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(cancer patients. Ann Oncol, 2009. 20\(1\): p. 84-90.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Personeni, N., et al., Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res, 2008. 14\(18\): p. 5869-76.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Prenen, H., et al., PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res, 2009. 15\(9\): p. 3184-8.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Sartore-Bianchi, A., et al., PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(monoclonal antibodies. Cancer Res, 2009. 69\(5\): p. 1851-7.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Sohn, B.S., et al., The role of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan therapy in irinotecan-)] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(refractory Korean metastatic colorectal cancer patients. Oncology, 2009. 77\(3-4\): p. 224-30.)] TJ ET
BT 26.250 497.595 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 497.595 Td /F1 9.8 Tf  [(Souglakos, J., et al., Prognostic and predictive value of common mutations for treatment response and survival in patients )] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(with metastatic colorectal cancer. Br J Cancer, 2009. 101\(3\): p. 465-72.)] TJ ET
BT 26.250 466.286 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 466.286 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 251\(2\): p. 254-60.)] TJ ET
BT 26.250 434.976 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 434.976 Td /F1 9.8 Tf  [(Amado, R.G., et al., Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J )] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(Clin Oncol, 2008. 26\(10\): p. 1626-34.)] TJ ET
BT 26.250 403.667 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 403.667 Td /F1 9.8 Tf  [(Bokemeyer, C., et al., Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of )] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 663-71.)] TJ ET
BT 26.250 372.357 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 372.357 Td /F1 9.8 Tf  [(Hecht, J.R., et al., A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with )] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol, 2009. 27\(5\): p. 672-80.)] TJ ET
BT 26.250 341.048 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 341.048 Td /F1 9.8 Tf  [(Karapetis, C.S., et al., K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med, 2008. )] TJ ET
BT 26.250 329.143 Td /F1 9.8 Tf  [(359\(17\): p. 1757-65.)] TJ ET
BT 26.250 309.738 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 309.738 Td /F1 9.8 Tf  [(Tol, J., et al., Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med, 2009. 360\(6\): p. )] TJ ET
BT 26.250 297.834 Td /F1 9.8 Tf  [(563-72.)] TJ ET
BT 26.250 278.429 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 278.429 Td /F1 9.8 Tf  [(Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med, )] TJ ET
BT 26.250 266.524 Td /F1 9.8 Tf  [(2009. 360\(14\): p. 1408-17)] TJ ET
BT 26.250 247.119 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 247.119 Td /F1 9.8 Tf  [(Linardou, H., et al., Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted )] TJ ET
BT 26.250 235.215 Td /F1 9.8 Tf  [(agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal )] TJ ET
BT 26.250 223.310 Td /F1 9.8 Tf  [(cancer. Lancet Oncol, 2008. 9\(10\): p. 962-72)] TJ ET
BT 26.250 203.905 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 203.905 Td /F1 9.8 Tf  [(Qiu, L.X. et al., Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with )] TJ ET
BT 26.250 192.000 Td /F1 9.8 Tf  [(cetuximab: A meta-analysis of 22 studies. Eur J Cancer, 2010. \(in press\). doi:10.1016/j.ejca.2010.05.022)] TJ ET
BT 26.250 172.596 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 172.596 Td /F1 9.8 Tf  [(Yen, L.C., et al., Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent )] TJ ET
BT 26.250 160.691 Td /F1 9.8 Tf  [(predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg, 2010. 251\(2\): p. 254-60)] 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

Q
endstream
endobj
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