%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 110 0 R 280 0 R 331 0 R 377 0 R 379 0 R ] /Count 6 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 9 0 R /F3 10 0 R /F4 11 0 R >> /XObject << /I1 12 0 R /I2 13 0 R /I3 298 0 R /I4 335 0 R /I5 348 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20180721150708+00'00') /ModDate (D:20180721150708+00'00') /Title (A 22 Gene-expression Assay, Decipher \(GenomeDx Biosciences\) to Predict Five-year Risk of Metastatic Prostate Cancer in Men Treated with Radical Prostatectomy PLOS Currents Evidence on Genomic Tests) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 14 0 R 16 0 R 18 0 R 20 0 R 22 0 R 24 0 R 26 0 R 28 0 R 30 0 R 32 0 R 34 0 R 36 0 R 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 56 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R 78 0 R 80 0 R 82 0 R 84 0 R 86 0 R 88 0 R 90 0 R 92 0 R 94 0 R 96 0 R 98 0 R 100 0 R 102 0 R 104 0 R 106 0 R 108 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 25092 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 659.406 577.500 78.594 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(A 22 Gene-expression Assay, Decipher \(GenomeDx )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Biosciences\) to Predict Five-year Risk of Metastatic Prostate )] TJ ET BT 15.000 668.146 Td /F2 21.0 Tf [(Cancer in Men Treated with Radical Prostatectomy)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 650.140 Td /F3 9.8 Tf [(November 17, 2015)] TJ ET BT 96.510 650.140 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 101.385 650.140 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET BT 26.250 638.299 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 98.849 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 104.270 638.299 Td /F1 9.8 Tf [(Arnold L. Potosky)] TJ ET 0.271 0.267 0.267 rg BT 180.680 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.101 638.299 Td /F1 9.8 Tf [(David Penson)] TJ ET 0.271 0.267 0.267 rg BT 246.795 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 252.216 638.299 Td /F1 9.8 Tf [(Andrew N. Freedman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.394 Td /F1 9.8 Tf [(Marrone M, Potosky AL, Penson D, Freedman AN. A 22 Gene-expression Assay, Decipher \(GenomeDx Biosciences\) to )] TJ ET BT 26.250 614.490 Td /F1 9.8 Tf [(Predict Five-year Risk of Metastatic Prostate Cancer in Men Treated with Radical Prostatectomy. PLOS Currents Evidence on )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Genomic Tests. 2015 Nov 17 . Edition 1. doi: 10.1371/currents.eogt.761b81608129ed61b0b48d42c04f92a4.)] TJ ET q 15.000 31.834 577.500 568.370 re W n 0.271 0.267 0.267 rg BT 26.250 573.482 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 553.528 Td /F1 9.8 Tf [(Among the estimated 230,000 men diagnosed with prostate cancer in the US each year there has been a rise in the number of )] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(radical prostatectomies \(RP\). There is some debate over the value of immediate adjuvant therapy following RP in men with high-)] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(risk pathological features versus delayed salvage radiation therapy when signs of disease progression are observed. Thus, it )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(would be potentially useful to inform post-RP management strategies by more clearly identifying those patients at higher risk of )] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(progression and death from prostate cancer. A 22 gene-expression assay, Decipher \(GenomeDx Biosciences\), has been )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(developed in men treated with radical prostatectomy to predict the five-year risk of metastatic prostate cancer. Published and )] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(unpublished literature was evaluated to determine the analytic validity, clinical validity and clinical utility of Decipher. Limited )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(information is available on the analytic validity of Decipher. In both discovery and validation studies, Decipher was shown to )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(have good performance in discriminating men with metastasis from men without metastasis five years after surgery \(AUC 0.75 )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(to 0.90\). In terms of clinical utility, no evidence was found reporting improved outcomes \(lower prostate cancer specific mortality )] TJ ET BT 26.250 434.481 Td /F1 9.8 Tf [(and treatment related adverse effects\) from using this test to guide post-operative treatment. Four studies provided weak )] TJ ET BT 26.250 422.576 Td /F1 9.8 Tf [(indirect evidence of clinical utility in which 31% to 43% of post-operative treatment recommendations were changed in men with )] TJ ET BT 26.250 410.671 Td /F1 9.8 Tf [(high-risk prostate cancer based on test results, with 27% to 52% of treatment recommendations changing from any treatment to )] TJ ET BT 26.250 398.766 Td /F1 9.8 Tf [(no treatment.)] TJ ET BT 26.250 362.164 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 342.210 Td /F1 9.8 Tf [(No external sources of funding.)] TJ ET BT 26.250 313.107 Td /F4 12.0 Tf [(Clinical scenario)] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(In men diagnosed with prostate cancer in the US, prognosis is generally excellent following radical prostatectomy \(RP\) with 15-)] TJ ET BT 26.250 281.248 Td /F1 9.8 Tf [(year disease free survival of 93%.)] TJ ET 0.267 0.267 0.267 rg BT 172.559 282.755 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 177.377 281.248 Td /F1 9.8 Tf [( However, RP may be associated with significant complications and adverse-effects, )] TJ ET BT 26.250 269.343 Td /F1 9.8 Tf [(primarily sexual dysfunction and urinary incontinence. Furthermore, between 19% and 30% of men experience biochemical )] TJ ET BT 26.250 257.439 Td /F1 9.8 Tf [(recurrence \(rise in PSA over 0.2 ng/ml\) 5 to 10 years after surgery, and these men have a 37% risk of developing distant )] TJ ET BT 26.250 245.534 Td /F1 9.8 Tf [(metastasis within five years if not treated and have a 17% risk of dying from prostate cancer within six years of biochemical )] TJ ET BT 26.250 233.629 Td /F1 9.8 Tf [(recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 75.556 235.136 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 80.374 237.517 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 82.784 235.136 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 87.602 233.629 Td /F1 9.8 Tf [( The most appropriate course of treatment is based on standard risk assessment that incorporates clinical )] TJ ET BT 26.250 221.724 Td /F1 9.8 Tf [(characteristics such as cancer stage, grade, and size as well as histopathological features including PSA and Gleason score to )] TJ ET BT 26.250 209.820 Td /F1 9.8 Tf [(estimate risk of recurrence from nomograms.)] TJ ET 0.267 0.267 0.267 rg BT 220.216 211.327 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 225.035 209.820 Td /F1 9.8 Tf [( Current post-RP practice includes observation for low risk disease, adjuvant )] TJ ET BT 26.250 197.915 Td /F1 9.8 Tf [(therapy for adverse pathology and salvage therapy after biochemical recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 374.159 199.422 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 378.978 197.915 Td /F1 9.8 Tf [( However, not all men with high-risk prostate )] TJ ET BT 26.250 186.010 Td /F1 9.8 Tf [(cancer with adverse pathological features will require or will benefit from adjuvant therapy. Furthermore, the adverse events and )] TJ ET BT 26.250 174.105 Td /F1 9.8 Tf [(complications associated with postoperative adjuvant therapy are not insignificant and range from incontinence, bowel )] TJ ET BT 26.250 162.201 Td /F1 9.8 Tf [(complications as well as urogenital toxicities resulting from radiotherapy.)] TJ ET 0.267 0.267 0.267 rg BT 337.811 163.708 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 342.630 162.201 Td /F1 9.8 Tf [( Thus, there remains a need for increased accuracy in )] TJ ET BT 26.250 150.296 Td /F1 9.8 Tf [(estimating a mans prognosis \(risk of metastasis\) to ensure appropriate follow up care is given in a timely manner.)] TJ ET BT 26.250 113.693 Td /F4 12.0 Tf [(Test Description)] TJ ET BT 26.250 93.739 Td /F1 9.8 Tf [(Decipher \(GenomeDx Biosciences\) is a genomic test that was developed to predict the risk of metastatic prostate cancer )] TJ ET BT 26.250 81.834 Td /F1 9.8 Tf [(within five years of RP in men at high risk of recurrence \(extraprostatic extension, seminal vesicle invasion, positive margins, or )] TJ ET BT 26.250 69.930 Td /F1 9.8 Tf [(biochemical recurrence\).)] TJ ET 0.267 0.267 0.267 rg BT 132.983 71.437 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 137.802 69.930 Td /F1 9.8 Tf [( A genomic classifier score calculated from a gene-expression microarray analysis of 22 genes on )] TJ ET BT 26.250 58.025 Td /F1 9.8 Tf [(formalin-fixed, paraffin embedded \(FFPE\) prostate tumor tissue ranges between 0 and 1 and classifies patients as high risk \(1 in )] TJ ET BT 26.250 46.120 Td /F1 9.8 Tf [(5 risk of metastasis\), average risk, or low risk \(1 in 42 risk of metastasis\).)] TJ ET 0.267 0.267 0.267 rg BT 339.956 47.627 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 344.775 46.120 Td /F1 9.8 Tf [(No information was available on the specific genes )] TJ ET Q q 15.000 659.406 577.500 78.594 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(A 22 Gene-expression Assay, Decipher \(GenomeDx )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Biosciences\) to Predict Five-year Risk of Metastatic Prostate )] TJ ET BT 15.000 668.146 Td /F2 21.0 Tf [(Cancer in Men Treated with Radical Prostatectomy)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 650.140 Td /F3 9.8 Tf [(November 17, 2015)] TJ ET BT 96.510 650.140 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 101.385 650.140 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET BT 26.250 638.299 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 98.849 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 104.270 638.299 Td /F1 9.8 Tf [(Arnold L. Potosky)] TJ ET 0.271 0.267 0.267 rg BT 180.680 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.101 638.299 Td /F1 9.8 Tf [(David Penson)] TJ ET 0.271 0.267 0.267 rg BT 246.795 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 252.216 638.299 Td /F1 9.8 Tf [(Andrew N. Freedman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.394 Td /F1 9.8 Tf [(Marrone M, Potosky AL, Penson D, Freedman AN. A 22 Gene-expression Assay, Decipher \(GenomeDx Biosciences\) to )] TJ ET BT 26.250 614.490 Td /F1 9.8 Tf [(Predict Five-year Risk of Metastatic Prostate Cancer in Men Treated with Radical Prostatectomy. PLOS Currents Evidence on )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Genomic Tests. 2015 Nov 17 . Edition 1. doi: 10.1371/currents.eogt.761b81608129ed61b0b48d42c04f92a4.)] TJ ET q 15.000 31.834 577.500 568.370 re W n 0.271 0.267 0.267 rg BT 26.250 573.482 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 553.528 Td /F1 9.8 Tf [(Among the estimated 230,000 men diagnosed with prostate cancer in the US each year there has been a rise in the number of )] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(radical prostatectomies \(RP\). There is some debate over the value of immediate adjuvant therapy following RP in men with high-)] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(risk pathological features versus delayed salvage radiation therapy when signs of disease progression are observed. Thus, it )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(would be potentially useful to inform post-RP management strategies by more clearly identifying those patients at higher risk of )] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(progression and death from prostate cancer. A 22 gene-expression assay, Decipher \(GenomeDx Biosciences\), has been )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(developed in men treated with radical prostatectomy to predict the five-year risk of metastatic prostate cancer. Published and )] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(unpublished literature was evaluated to determine the analytic validity, clinical validity and clinical utility of Decipher. Limited )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(information is available on the analytic validity of Decipher. In both discovery and validation studies, Decipher was shown to )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(have good performance in discriminating men with metastasis from men without metastasis five years after surgery \(AUC 0.75 )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(to 0.90\). In terms of clinical utility, no evidence was found reporting improved outcomes \(lower prostate cancer specific mortality )] TJ ET BT 26.250 434.481 Td /F1 9.8 Tf [(and treatment related adverse effects\) from using this test to guide post-operative treatment. Four studies provided weak )] TJ ET BT 26.250 422.576 Td /F1 9.8 Tf [(indirect evidence of clinical utility in which 31% to 43% of post-operative treatment recommendations were changed in men with )] TJ ET BT 26.250 410.671 Td /F1 9.8 Tf [(high-risk prostate cancer based on test results, with 27% to 52% of treatment recommendations changing from any treatment to )] TJ ET BT 26.250 398.766 Td /F1 9.8 Tf [(no treatment.)] TJ ET BT 26.250 362.164 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 342.210 Td /F1 9.8 Tf [(No external sources of funding.)] TJ ET BT 26.250 313.107 Td /F4 12.0 Tf [(Clinical scenario)] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(In men diagnosed with prostate cancer in the US, prognosis is generally excellent following radical prostatectomy \(RP\) with 15-)] TJ ET BT 26.250 281.248 Td /F1 9.8 Tf [(year disease free survival of 93%.)] TJ ET 0.267 0.267 0.267 rg BT 172.559 282.755 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 177.377 281.248 Td /F1 9.8 Tf [( However, RP may be associated with significant complications and adverse-effects, )] TJ ET BT 26.250 269.343 Td /F1 9.8 Tf [(primarily sexual dysfunction and urinary incontinence. Furthermore, between 19% and 30% of men experience biochemical )] TJ ET BT 26.250 257.439 Td /F1 9.8 Tf [(recurrence \(rise in PSA over 0.2 ng/ml\) 5 to 10 years after surgery, and these men have a 37% risk of developing distant )] TJ ET BT 26.250 245.534 Td /F1 9.8 Tf [(metastasis within five years if not treated and have a 17% risk of dying from prostate cancer within six years of biochemical )] TJ ET BT 26.250 233.629 Td /F1 9.8 Tf [(recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 75.556 235.136 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 80.374 237.517 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 82.784 235.136 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 87.602 233.629 Td /F1 9.8 Tf [( The most appropriate course of treatment is based on standard risk assessment that incorporates clinical )] TJ ET BT 26.250 221.724 Td /F1 9.8 Tf [(characteristics such as cancer stage, grade, and size as well as histopathological features including PSA and Gleason score to )] TJ ET BT 26.250 209.820 Td /F1 9.8 Tf [(estimate risk of recurrence from nomograms.)] TJ ET 0.267 0.267 0.267 rg BT 220.216 211.327 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 225.035 209.820 Td /F1 9.8 Tf [( Current post-RP practice includes observation for low risk disease, adjuvant )] TJ ET BT 26.250 197.915 Td /F1 9.8 Tf [(therapy for adverse pathology and salvage therapy after biochemical recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 374.159 199.422 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 378.978 197.915 Td /F1 9.8 Tf [( However, not all men with high-risk prostate )] TJ ET BT 26.250 186.010 Td /F1 9.8 Tf [(cancer with adverse pathological features will require or will benefit from adjuvant therapy. Furthermore, the adverse events and )] TJ ET BT 26.250 174.105 Td /F1 9.8 Tf [(complications associated with postoperative adjuvant therapy are not insignificant and range from incontinence, bowel )] TJ ET BT 26.250 162.201 Td /F1 9.8 Tf [(complications as well as urogenital toxicities resulting from radiotherapy.)] TJ ET 0.267 0.267 0.267 rg BT 337.811 163.708 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 342.630 162.201 Td /F1 9.8 Tf [( Thus, there remains a need for increased accuracy in )] TJ ET BT 26.250 150.296 Td /F1 9.8 Tf [(estimating a mans prognosis \(risk of metastasis\) to ensure appropriate follow up care is given in a timely manner.)] TJ ET BT 26.250 113.693 Td /F4 12.0 Tf [(Test Description)] TJ ET BT 26.250 93.739 Td /F1 9.8 Tf [(Decipher \(GenomeDx Biosciences\) is a genomic test that was developed to predict the risk of metastatic prostate cancer )] TJ ET BT 26.250 81.834 Td /F1 9.8 Tf [(within five years of RP in men at high risk of recurrence \(extraprostatic extension, seminal vesicle invasion, positive margins, or )] TJ ET BT 26.250 69.930 Td /F1 9.8 Tf [(biochemical recurrence\).)] TJ ET 0.267 0.267 0.267 rg BT 132.983 71.437 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 137.802 69.930 Td /F1 9.8 Tf [( A genomic classifier score calculated from a gene-expression microarray analysis of 22 genes on )] TJ ET BT 26.250 58.025 Td /F1 9.8 Tf [(formalin-fixed, paraffin embedded \(FFPE\) prostate tumor tissue ranges between 0 and 1 and classifies patients as high risk \(1 in )] TJ ET BT 26.250 46.120 Td /F1 9.8 Tf [(5 risk of metastasis\), average risk, or low risk \(1 in 42 risk of metastasis\).)] TJ ET 0.267 0.267 0.267 rg BT 339.956 47.627 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 344.775 46.120 Td /F1 9.8 Tf [(No information was available on the specific genes )] TJ ET Q q 15.000 659.406 577.500 78.594 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(A 22 Gene-expression Assay, Decipher \(GenomeDx )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Biosciences\) to Predict Five-year Risk of Metastatic Prostate )] TJ ET BT 15.000 668.146 Td /F2 21.0 Tf [(Cancer in Men Treated with Radical Prostatectomy)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 650.140 Td /F3 9.8 Tf [(November 17, 2015)] TJ ET BT 96.510 650.140 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 101.385 650.140 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET BT 26.250 638.299 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 98.849 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 104.270 638.299 Td /F1 9.8 Tf [(Arnold L. Potosky)] TJ ET 0.271 0.267 0.267 rg BT 180.680 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.101 638.299 Td /F1 9.8 Tf [(David Penson)] TJ ET 0.271 0.267 0.267 rg BT 246.795 638.299 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 252.216 638.299 Td /F1 9.8 Tf [(Andrew N. Freedman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.394 Td /F1 9.8 Tf [(Marrone M, Potosky AL, Penson D, Freedman AN. A 22 Gene-expression Assay, Decipher \(GenomeDx Biosciences\) to )] TJ ET BT 26.250 614.490 Td /F1 9.8 Tf [(Predict Five-year Risk of Metastatic Prostate Cancer in Men Treated with Radical Prostatectomy. PLOS Currents Evidence on )] TJ ET BT 26.250 602.585 Td /F1 9.8 Tf [(Genomic Tests. 2015 Nov 17 . Edition 1. doi: 10.1371/currents.eogt.761b81608129ed61b0b48d42c04f92a4.)] TJ ET q 15.000 31.834 577.500 568.370 re W n 0.271 0.267 0.267 rg BT 26.250 573.482 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 553.528 Td /F1 9.8 Tf [(Among the estimated 230,000 men diagnosed with prostate cancer in the US each year there has been a rise in the number of )] TJ ET BT 26.250 541.623 Td /F1 9.8 Tf [(radical prostatectomies \(RP\). There is some debate over the value of immediate adjuvant therapy following RP in men with high-)] TJ ET BT 26.250 529.719 Td /F1 9.8 Tf [(risk pathological features versus delayed salvage radiation therapy when signs of disease progression are observed. Thus, it )] TJ ET BT 26.250 517.814 Td /F1 9.8 Tf [(would be potentially useful to inform post-RP management strategies by more clearly identifying those patients at higher risk of )] TJ ET BT 26.250 505.909 Td /F1 9.8 Tf [(progression and death from prostate cancer. A 22 gene-expression assay, Decipher \(GenomeDx Biosciences\), has been )] TJ ET BT 26.250 494.004 Td /F1 9.8 Tf [(developed in men treated with radical prostatectomy to predict the five-year risk of metastatic prostate cancer. Published and )] TJ ET BT 26.250 482.100 Td /F1 9.8 Tf [(unpublished literature was evaluated to determine the analytic validity, clinical validity and clinical utility of Decipher. Limited )] TJ ET BT 26.250 470.195 Td /F1 9.8 Tf [(information is available on the analytic validity of Decipher. In both discovery and validation studies, Decipher was shown to )] TJ ET BT 26.250 458.290 Td /F1 9.8 Tf [(have good performance in discriminating men with metastasis from men without metastasis five years after surgery \(AUC 0.75 )] TJ ET BT 26.250 446.385 Td /F1 9.8 Tf [(to 0.90\). In terms of clinical utility, no evidence was found reporting improved outcomes \(lower prostate cancer specific mortality )] TJ ET BT 26.250 434.481 Td /F1 9.8 Tf [(and treatment related adverse effects\) from using this test to guide post-operative treatment. Four studies provided weak )] TJ ET BT 26.250 422.576 Td /F1 9.8 Tf [(indirect evidence of clinical utility in which 31% to 43% of post-operative treatment recommendations were changed in men with )] TJ ET BT 26.250 410.671 Td /F1 9.8 Tf [(high-risk prostate cancer based on test results, with 27% to 52% of treatment recommendations changing from any treatment to )] TJ ET BT 26.250 398.766 Td /F1 9.8 Tf [(no treatment.)] TJ ET BT 26.250 362.164 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 342.210 Td /F1 9.8 Tf [(No external sources of funding.)] TJ ET BT 26.250 313.107 Td /F4 12.0 Tf [(Clinical scenario)] TJ ET BT 26.250 293.153 Td /F1 9.8 Tf [(In men diagnosed with prostate cancer in the US, prognosis is generally excellent following radical prostatectomy \(RP\) with 15-)] TJ ET BT 26.250 281.248 Td /F1 9.8 Tf [(year disease free survival of 93%.)] TJ ET 0.267 0.267 0.267 rg BT 172.559 282.755 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 177.377 281.248 Td /F1 9.8 Tf [( However, RP may be associated with significant complications and adverse-effects, )] TJ ET BT 26.250 269.343 Td /F1 9.8 Tf [(primarily sexual dysfunction and urinary incontinence. Furthermore, between 19% and 30% of men experience biochemical )] TJ ET BT 26.250 257.439 Td /F1 9.8 Tf [(recurrence \(rise in PSA over 0.2 ng/ml\) 5 to 10 years after surgery, and these men have a 37% risk of developing distant )] TJ ET BT 26.250 245.534 Td /F1 9.8 Tf [(metastasis within five years if not treated and have a 17% risk of dying from prostate cancer within six years of biochemical )] TJ ET BT 26.250 233.629 Td /F1 9.8 Tf [(recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 75.556 235.136 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 80.374 237.517 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 82.784 235.136 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 87.602 233.629 Td /F1 9.8 Tf [( The most appropriate course of treatment is based on standard risk assessment that incorporates clinical )] TJ ET BT 26.250 221.724 Td /F1 9.8 Tf [(characteristics such as cancer stage, grade, and size as well as histopathological features including PSA and Gleason score to )] TJ ET BT 26.250 209.820 Td /F1 9.8 Tf [(estimate risk of recurrence from nomograms.)] TJ ET 0.267 0.267 0.267 rg BT 220.216 211.327 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 225.035 209.820 Td /F1 9.8 Tf [( Current post-RP practice includes observation for low risk disease, adjuvant )] TJ ET BT 26.250 197.915 Td /F1 9.8 Tf [(therapy for adverse pathology and salvage therapy after biochemical recurrence.)] TJ ET 0.267 0.267 0.267 rg BT 374.159 199.422 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 378.978 197.915 Td /F1 9.8 Tf [( However, not all men with high-risk prostate )] TJ ET BT 26.250 186.010 Td /F1 9.8 Tf [(cancer with adverse pathological features will require or will benefit from adjuvant therapy. Furthermore, the adverse events and )] TJ ET BT 26.250 174.105 Td /F1 9.8 Tf [(complications associated with postoperative adjuvant therapy are not insignificant and range from incontinence, bowel )] TJ ET BT 26.250 162.201 Td /F1 9.8 Tf [(complications as well as urogenital toxicities resulting from radiotherapy.)] TJ ET 0.267 0.267 0.267 rg BT 337.811 163.708 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 342.630 162.201 Td /F1 9.8 Tf [( Thus, there remains a need for increased accuracy in )] TJ ET BT 26.250 150.296 Td /F1 9.8 Tf [(estimating a mans prognosis \(risk of metastasis\) to ensure appropriate follow up care is given in a timely manner.)] TJ ET BT 26.250 113.693 Td /F4 12.0 Tf [(Test Description)] TJ ET BT 26.250 93.739 Td /F1 9.8 Tf [(Decipher \(GenomeDx Biosciences\) is a genomic test that was developed to predict the risk of metastatic prostate cancer )] TJ ET BT 26.250 81.834 Td /F1 9.8 Tf [(within five years of RP in men at high risk of recurrence \(extraprostatic extension, seminal vesicle invasion, positive margins, or )] TJ ET BT 26.250 69.930 Td /F1 9.8 Tf [(biochemical recurrence\).)] TJ ET 0.267 0.267 0.267 rg BT 132.983 71.437 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 137.802 69.930 Td /F1 9.8 Tf [( A genomic classifier score calculated from a gene-expression microarray analysis of 22 genes on )] TJ ET BT 26.250 58.025 Td /F1 9.8 Tf [(formalin-fixed, paraffin embedded \(FFPE\) prostate tumor tissue ranges between 0 and 1 and classifies patients as high risk \(1 in )] TJ ET BT 26.250 46.120 Td /F1 9.8 Tf [(5 risk of metastasis\), average risk, or low risk \(1 in 42 risk of metastasis\).)] TJ ET 0.267 0.267 0.267 rg BT 339.956 47.627 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 344.775 46.120 Td /F1 9.8 Tf [(No information was available on the specific genes )] 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 Q endstream 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Decipher is available as a laboratory developed test through physicians or as part of clinical )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(investigations sponsored by GenomDx, which is licensed under the Clinical Laboratory Improvement Act \(CLIA\).)] TJ ET BT 26.250 718.969 Td /F4 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(In the US, prostate cancer is the most common cancer in men with estimates showing over 230,000 cases will be diagnosed in )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(2014 and just under 30,000 men will die from the disease.)] TJ ET 0.267 0.267 0.267 rg BT 276.084 688.617 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 280.903 687.110 Td /F1 9.8 Tf [( For men with high-risk prostate cancer based on post-RP )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(pathological findings the strongest predictors of prostate cancer metastasis and death are baseline Gleason score, time of )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(biochemical recurrence after RP, and PSA doubling-time.)] TJ ET 0.267 0.267 0.267 rg BT 273.344 664.808 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 278.163 667.189 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 280.572 664.808 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 285.391 663.300 Td /F1 9.8 Tf [( Within this high-risk group of men with prostate cancer the benefit )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(of adjuvant or salvage therapy varies, and the high costs and complications associated with adjuvant radiotherapy underscore )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(the need for improved prognostic markers.)] TJ ET 0.267 0.267 0.267 rg BT 209.404 640.998 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 26.250 602.888 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 582.934 Td /F1 9.8 Tf [(PubMed was searched \(14 July 2015\) to identify published reports of studies investigating the analytic validity, clinical validity )] TJ ET BT 26.250 571.029 Td /F1 9.8 Tf [(and clinical utility of Decipher. Supplemental searches for grey literature, guidelines, and coverage decisions included Google, )] TJ ET BT 26.250 559.125 Td /F1 9.8 Tf [(Genetic Testing Registry \(GTR\), guidelines.gov, and the Centers for Medicare and Medicaid using the terms Decipher genomic )] TJ ET BT 26.250 547.220 Td /F1 9.8 Tf [(classifier and Decipher. Websites for Decipher)] TJ ET 0.267 0.267 0.267 rg BT 235.924 548.727 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 240.742 547.220 Td /F1 9.8 Tf [( and GenomeDx)] TJ ET 0.267 0.267 0.267 rg BT 311.732 548.727 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 316.551 547.220 Td /F1 9.8 Tf [( were also reviewed to identified additional published and )] TJ ET BT 26.250 535.315 Td /F1 9.8 Tf [(unpublished information. No trial registries were searched, which is a possible limitation.)] TJ ET BT 26.250 515.910 Td /F1 9.8 Tf [(PubMed search strategy:)] TJ ET BT 26.250 496.506 Td /F1 9.8 Tf [(\(\(classifier[tiab]\) AND \(\(genomic*[tiab]\) OR \(genome*[tiab]\)\)\) AND \(\(prostate[tiab] OR prostatic[tiab] OR \(prostatic )] TJ ET BT 26.250 484.601 Td /F1 9.8 Tf [(neoplasm[mesh]\) OR \(biochemical recurrence[tiab]\)\))] TJ ET BT 26.250 465.196 Td /F4 9.8 Tf [(Published Reviews, Recommendations, and Guidelines)] TJ ET BT 26.250 445.791 Td /F1 9.8 Tf [(No published reviews, recommendations or guidelines describing the Decipher genomic classifier were identified from the )] TJ ET BT 26.250 433.887 Td /F1 9.8 Tf [(methods described above. One local coverage decision from Palmetto GBA was identified providing limited coverage for )] TJ ET BT 26.250 421.982 Td /F1 9.8 Tf [(Decipher in order to determine which patients at high-risk of recurrence following RP should receive radiation therapy vs. )] TJ ET BT 26.250 410.077 Td /F1 9.8 Tf [(continued observation.)] TJ ET 0.267 0.267 0.267 rg BT 124.345 411.584 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 26.250 390.672 Td /F4 9.8 Tf [(Analytic Validity)] TJ ET BT 26.250 371.268 Td /F1 9.8 Tf [(Data reported in a conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 192.624 372.775 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 202.261 371.268 Td /F1 9.8 Tf [( showed RNA was successfully extracted from 91% \(63/69\) FFPE biopsies and 100% )] TJ ET BT 26.250 359.363 Td /F1 9.8 Tf [(\(69/69\) of RP tissue samples, and 98% \(62/63\) and 99% \(68/69\) of the FFPE and RP samples passed gene-expression data )] TJ ET BT 26.250 347.458 Td /F1 9.8 Tf [(quality control, respectively. In this study, the correlation between matched biopsy FFPE tissue and RP tissue samples in the )] TJ ET BT 26.250 335.553 Td /F1 9.8 Tf [(genomic classifier scores predicting metastasis was 0.74 \(p=0.0003\).)] TJ ET BT 26.250 316.149 Td /F1 9.8 Tf [(Two other studies are listed on the Decipher website under Analytic Validity,)] TJ ET 0.267 0.267 0.267 rg BT 358.423 317.656 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 368.060 320.037 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 370.469 317.656 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 380.107 316.149 Td /F1 9.8 Tf [( but it is unclear whether the methods and )] TJ ET BT 26.250 304.244 Td /F1 9.8 Tf [(procedures described in these reports are integrated into the Decipher analytic pipeline.)] TJ ET BT 26.250 284.839 Td /F4 9.8 Tf [(Clinical Validity)] TJ ET BT 26.250 265.434 Td /F1 9.8 Tf [(Eight published studies were identified evaluating the clinical validity of the genomic classifier, based on its ability to predict )] TJ ET BT 26.250 253.530 Td /F1 9.8 Tf [(clinical metastasis)] TJ ET 0.267 0.267 0.267 rg BT 104.806 255.037 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 114.443 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 116.852 255.037 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 126.490 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 128.899 255.037 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 138.536 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 140.946 255.037 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 150.583 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 152.992 255.037 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 162.630 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 165.039 255.037 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 174.676 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 177.086 255.037 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 186.723 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 189.132 255.037 Td /F4 8.7 Tf [(20)] TJ ET 0.271 0.267 0.267 rg BT 198.770 253.530 Td /F1 9.8 Tf [(. The first study used data from a Mayo Clinic patient registry to compare men with )] TJ ET BT 26.250 241.625 Td /F1 9.8 Tf [(evidence of clinical metastasis following RP \(cases\) to men with no evidence of metastasis after RP \(controls\) with median )] TJ ET BT 26.250 229.720 Td /F1 9.8 Tf [(follow-up greater than five years. One publication reported results from the initial training and validation datasets in which )] TJ ET BT 26.250 217.815 Td /F1 9.8 Tf [(participants with no evidence of disease recurrence and those with biochemical recurrence \(PSA )] TJ ET BT 445.130 217.815 Td /F1 9.8 Tf [(>)] TJ ET BT 450.824 217.815 Td /F1 9.8 Tf [( 0.20 ng/ml within 30 days of )] TJ ET BT 26.250 205.911 Td /F1 9.8 Tf [(RP\) served as controls due to very limited differential expression between these two groups.)] TJ ET 0.267 0.267 0.267 rg BT 429.949 207.418 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 439.586 205.911 Td /F1 9.8 Tf [( Therefore, the genomic )] TJ ET BT 26.250 194.006 Td /F1 9.8 Tf [(classifier was developed to discriminate men who develop clinical metastasis from men who have no evidence of disease )] TJ ET BT 26.250 182.101 Td /F1 9.8 Tf [(recurrence \(clinical or biochemical\) within five years of RP. Two additional studies using data from the Mayo Clinic registry )] TJ ET BT 26.250 170.196 Td /F1 9.8 Tf [(described subsequent validation of the genomic classifier in men with biochemical recurrence after RP)] TJ ET 0.267 0.267 0.267 rg BT 466.794 171.704 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 476.431 170.196 Td /F1 9.8 Tf [( and in men with high-)] TJ ET BT 26.250 158.292 Td /F1 9.8 Tf [(risk prostate cancer \(pre-RP PSA > 20ng/mL, Gleason score )] TJ ET BT 290.416 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 296.111 158.292 Td /F1 9.8 Tf [( 8, pT3b, or Mayo Clinic nomogram score )] TJ ET BT 477.626 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 483.320 158.292 Td /F1 9.8 Tf [( 10\).)] TJ ET 0.267 0.267 0.267 rg BT 502.830 159.799 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 26.250 138.887 Td /F1 9.8 Tf [(Overall, the genomic classifier had good discriminatory ability \(e.g. ability to predict clinical metastasis\) in both the discovery and )] TJ ET BT 26.250 126.982 Td /F1 9.8 Tf [(validation studies \(Table 1\). Across the nine analyses, the area under the receiver operating curve \(AUC\) ranged between 0.75 )] TJ ET BT 26.250 115.077 Td /F1 9.8 Tf [(and 0.90. None of the studies examining the predictive accuracy of the genomic classifier explicitly reported whether the gene-)] TJ ET BT 26.250 103.173 Td /F1 9.8 Tf [(expression analysis was performed on tissue collected at the time of surgery or at the time of clinical end point \(e.g. metastasis\). )] TJ ET BT 26.250 91.268 Td /F1 9.8 Tf [(There was potential overlap in participants used to develop and validate the genomic classifier across four studies interrogating )] TJ ET BT 26.250 79.363 Td /F1 9.8 Tf [(a patient registry)] TJ ET 0.267 0.267 0.267 rg BT 98.322 80.870 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 107.959 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 110.369 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 120.006 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 122.415 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 132.053 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 134.462 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 144.099 79.363 Td /F1 9.8 Tf [(. In three full-text validation studies)] TJ ET 0.267 0.267 0.267 rg BT 294.210 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 303.848 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 306.257 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 315.894 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 318.304 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 327.941 79.363 Td /F1 9.8 Tf [( there were noticeable differences between cases and )] TJ ET BT 26.250 67.458 Td /F1 9.8 Tf [(controls in the frequency of high-risk pathological features, risk factors for metastasis, and adjuvant and salvage therapy \(Table )] TJ ET BT 26.250 55.554 Td /F1 9.8 Tf [(2\). The possibility of confounding due to these differences may have yielded an overestimate of the prognostic ability of the )] TJ ET BT 26.250 43.649 Td /F1 9.8 Tf [(genomic classifier. Another limitation is the change in risk of metastasis with more follow up time. The 5-year risk of metastasis )] TJ ET Q q 15.000 29.363 577.500 747.637 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(included in the 22-geen analysis. Decipher is available as a laboratory developed test through physicians or as part of clinical )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(investigations sponsored by GenomDx, which is licensed under the Clinical Laboratory Improvement Act \(CLIA\).)] TJ ET BT 26.250 718.969 Td /F4 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(In the US, prostate cancer is the most common cancer in men with estimates showing over 230,000 cases will be diagnosed in )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(2014 and just under 30,000 men will die from the disease.)] TJ ET 0.267 0.267 0.267 rg BT 276.084 688.617 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 280.903 687.110 Td /F1 9.8 Tf [( For men with high-risk prostate cancer based on post-RP )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(pathological findings the strongest predictors of prostate cancer metastasis and death are baseline Gleason score, time of )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(biochemical recurrence after RP, and PSA doubling-time.)] TJ ET 0.267 0.267 0.267 rg BT 273.344 664.808 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 278.163 667.189 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 280.572 664.808 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 285.391 663.300 Td /F1 9.8 Tf [( Within this high-risk group of men with prostate cancer the benefit )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(of adjuvant or salvage therapy varies, and the high costs and complications associated with adjuvant radiotherapy underscore )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(the need for improved prognostic markers.)] TJ ET 0.267 0.267 0.267 rg BT 209.404 640.998 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 26.250 602.888 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 582.934 Td /F1 9.8 Tf [(PubMed was searched \(14 July 2015\) to identify published reports of studies investigating the analytic validity, clinical validity )] TJ ET BT 26.250 571.029 Td /F1 9.8 Tf [(and clinical utility of Decipher. Supplemental searches for grey literature, guidelines, and coverage decisions included Google, )] TJ ET BT 26.250 559.125 Td /F1 9.8 Tf [(Genetic Testing Registry \(GTR\), guidelines.gov, and the Centers for Medicare and Medicaid using the terms Decipher genomic )] TJ ET BT 26.250 547.220 Td /F1 9.8 Tf [(classifier and Decipher. Websites for Decipher)] TJ ET 0.267 0.267 0.267 rg BT 235.924 548.727 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 240.742 547.220 Td /F1 9.8 Tf [( and GenomeDx)] TJ ET 0.267 0.267 0.267 rg BT 311.732 548.727 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 316.551 547.220 Td /F1 9.8 Tf [( were also reviewed to identified additional published and )] TJ ET BT 26.250 535.315 Td /F1 9.8 Tf [(unpublished information. No trial registries were searched, which is a possible limitation.)] TJ ET BT 26.250 515.910 Td /F1 9.8 Tf [(PubMed search strategy:)] TJ ET BT 26.250 496.506 Td /F1 9.8 Tf [(\(\(classifier[tiab]\) AND \(\(genomic*[tiab]\) OR \(genome*[tiab]\)\)\) AND \(\(prostate[tiab] OR prostatic[tiab] OR \(prostatic )] TJ ET BT 26.250 484.601 Td /F1 9.8 Tf [(neoplasm[mesh]\) OR \(biochemical recurrence[tiab]\)\))] TJ ET BT 26.250 465.196 Td /F4 9.8 Tf [(Published Reviews, Recommendations, and Guidelines)] TJ ET BT 26.250 445.791 Td /F1 9.8 Tf [(No published reviews, recommendations or guidelines describing the Decipher genomic classifier were identified from the )] TJ ET BT 26.250 433.887 Td /F1 9.8 Tf [(methods described above. One local coverage decision from Palmetto GBA was identified providing limited coverage for )] TJ ET BT 26.250 421.982 Td /F1 9.8 Tf [(Decipher in order to determine which patients at high-risk of recurrence following RP should receive radiation therapy vs. )] TJ ET BT 26.250 410.077 Td /F1 9.8 Tf [(continued observation.)] TJ ET 0.267 0.267 0.267 rg BT 124.345 411.584 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 26.250 390.672 Td /F4 9.8 Tf [(Analytic Validity)] TJ ET BT 26.250 371.268 Td /F1 9.8 Tf [(Data reported in a conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 192.624 372.775 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 202.261 371.268 Td /F1 9.8 Tf [( showed RNA was successfully extracted from 91% \(63/69\) FFPE biopsies and 100% )] TJ ET BT 26.250 359.363 Td /F1 9.8 Tf [(\(69/69\) of RP tissue samples, and 98% \(62/63\) and 99% \(68/69\) of the FFPE and RP samples passed gene-expression data )] TJ ET BT 26.250 347.458 Td /F1 9.8 Tf [(quality control, respectively. In this study, the correlation between matched biopsy FFPE tissue and RP tissue samples in the )] TJ ET BT 26.250 335.553 Td /F1 9.8 Tf [(genomic classifier scores predicting metastasis was 0.74 \(p=0.0003\).)] TJ ET BT 26.250 316.149 Td /F1 9.8 Tf [(Two other studies are listed on the Decipher website under Analytic Validity,)] TJ ET 0.267 0.267 0.267 rg BT 358.423 317.656 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 368.060 320.037 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 370.469 317.656 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 380.107 316.149 Td /F1 9.8 Tf [( but it is unclear whether the methods and )] TJ ET BT 26.250 304.244 Td /F1 9.8 Tf [(procedures described in these reports are integrated into the Decipher analytic pipeline.)] TJ ET BT 26.250 284.839 Td /F4 9.8 Tf [(Clinical Validity)] TJ ET BT 26.250 265.434 Td /F1 9.8 Tf [(Eight published studies were identified evaluating the clinical validity of the genomic classifier, based on its ability to predict )] TJ ET BT 26.250 253.530 Td /F1 9.8 Tf [(clinical metastasis)] TJ ET 0.267 0.267 0.267 rg BT 104.806 255.037 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 114.443 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 116.852 255.037 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 126.490 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 128.899 255.037 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 138.536 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 140.946 255.037 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 150.583 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 152.992 255.037 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 162.630 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 165.039 255.037 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 174.676 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 177.086 255.037 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 186.723 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 189.132 255.037 Td /F4 8.7 Tf [(20)] TJ ET 0.271 0.267 0.267 rg BT 198.770 253.530 Td /F1 9.8 Tf [(. The first study used data from a Mayo Clinic patient registry to compare men with )] TJ ET BT 26.250 241.625 Td /F1 9.8 Tf [(evidence of clinical metastasis following RP \(cases\) to men with no evidence of metastasis after RP \(controls\) with median )] TJ ET BT 26.250 229.720 Td /F1 9.8 Tf [(follow-up greater than five years. One publication reported results from the initial training and validation datasets in which )] TJ ET BT 26.250 217.815 Td /F1 9.8 Tf [(participants with no evidence of disease recurrence and those with biochemical recurrence \(PSA )] TJ ET BT 445.130 217.815 Td /F1 9.8 Tf [(>)] TJ ET BT 450.824 217.815 Td /F1 9.8 Tf [( 0.20 ng/ml within 30 days of )] TJ ET BT 26.250 205.911 Td /F1 9.8 Tf [(RP\) served as controls due to very limited differential expression between these two groups.)] TJ ET 0.267 0.267 0.267 rg BT 429.949 207.418 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 439.586 205.911 Td /F1 9.8 Tf [( Therefore, the genomic )] TJ ET BT 26.250 194.006 Td /F1 9.8 Tf [(classifier was developed to discriminate men who develop clinical metastasis from men who have no evidence of disease )] TJ ET BT 26.250 182.101 Td /F1 9.8 Tf [(recurrence \(clinical or biochemical\) within five years of RP. Two additional studies using data from the Mayo Clinic registry )] TJ ET BT 26.250 170.196 Td /F1 9.8 Tf [(described subsequent validation of the genomic classifier in men with biochemical recurrence after RP)] TJ ET 0.267 0.267 0.267 rg BT 466.794 171.704 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 476.431 170.196 Td /F1 9.8 Tf [( and in men with high-)] TJ ET BT 26.250 158.292 Td /F1 9.8 Tf [(risk prostate cancer \(pre-RP PSA > 20ng/mL, Gleason score )] TJ ET BT 290.416 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 296.111 158.292 Td /F1 9.8 Tf [( 8, pT3b, or Mayo Clinic nomogram score )] TJ ET BT 477.626 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 483.320 158.292 Td /F1 9.8 Tf [( 10\).)] TJ ET 0.267 0.267 0.267 rg BT 502.830 159.799 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 26.250 138.887 Td /F1 9.8 Tf [(Overall, the genomic classifier had good discriminatory ability \(e.g. ability to predict clinical metastasis\) in both the discovery and )] TJ ET BT 26.250 126.982 Td /F1 9.8 Tf [(validation studies \(Table 1\). Across the nine analyses, the area under the receiver operating curve \(AUC\) ranged between 0.75 )] TJ ET BT 26.250 115.077 Td /F1 9.8 Tf [(and 0.90. None of the studies examining the predictive accuracy of the genomic classifier explicitly reported whether the gene-)] TJ ET BT 26.250 103.173 Td /F1 9.8 Tf [(expression analysis was performed on tissue collected at the time of surgery or at the time of clinical end point \(e.g. metastasis\). )] TJ ET BT 26.250 91.268 Td /F1 9.8 Tf [(There was potential overlap in participants used to develop and validate the genomic classifier across four studies interrogating )] TJ ET BT 26.250 79.363 Td /F1 9.8 Tf [(a patient registry)] TJ ET 0.267 0.267 0.267 rg BT 98.322 80.870 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 107.959 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 110.369 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 120.006 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 122.415 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 132.053 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 134.462 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 144.099 79.363 Td /F1 9.8 Tf [(. In three full-text validation studies)] TJ ET 0.267 0.267 0.267 rg BT 294.210 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 303.848 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 306.257 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 315.894 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 318.304 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 327.941 79.363 Td /F1 9.8 Tf [( there were noticeable differences between cases and )] TJ ET BT 26.250 67.458 Td /F1 9.8 Tf [(controls in the frequency of high-risk pathological features, risk factors for metastasis, and adjuvant and salvage therapy \(Table )] TJ ET BT 26.250 55.554 Td /F1 9.8 Tf [(2\). The possibility of confounding due to these differences may have yielded an overestimate of the prognostic ability of the )] TJ ET BT 26.250 43.649 Td /F1 9.8 Tf [(genomic classifier. Another limitation is the change in risk of metastasis with more follow up time. The 5-year risk of metastasis )] TJ ET Q q 15.000 29.363 577.500 747.637 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(included in the 22-geen analysis. Decipher is available as a laboratory developed test through physicians or as part of clinical )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(investigations sponsored by GenomDx, which is licensed under the Clinical Laboratory Improvement Act \(CLIA\).)] TJ ET BT 26.250 718.969 Td /F4 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(In the US, prostate cancer is the most common cancer in men with estimates showing over 230,000 cases will be diagnosed in )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(2014 and just under 30,000 men will die from the disease.)] TJ ET 0.267 0.267 0.267 rg BT 276.084 688.617 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 280.903 687.110 Td /F1 9.8 Tf [( For men with high-risk prostate cancer based on post-RP )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(pathological findings the strongest predictors of prostate cancer metastasis and death are baseline Gleason score, time of )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(biochemical recurrence after RP, and PSA doubling-time.)] TJ ET 0.267 0.267 0.267 rg BT 273.344 664.808 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 278.163 667.189 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 280.572 664.808 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 285.391 663.300 Td /F1 9.8 Tf [( Within this high-risk group of men with prostate cancer the benefit )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(of adjuvant or salvage therapy varies, and the high costs and complications associated with adjuvant radiotherapy underscore )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(the need for improved prognostic markers.)] TJ ET 0.267 0.267 0.267 rg BT 209.404 640.998 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 26.250 602.888 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 582.934 Td /F1 9.8 Tf [(PubMed was searched \(14 July 2015\) to identify published reports of studies investigating the analytic validity, clinical validity )] TJ ET BT 26.250 571.029 Td /F1 9.8 Tf [(and clinical utility of Decipher. Supplemental searches for grey literature, guidelines, and coverage decisions included Google, )] TJ ET BT 26.250 559.125 Td /F1 9.8 Tf [(Genetic Testing Registry \(GTR\), guidelines.gov, and the Centers for Medicare and Medicaid using the terms Decipher genomic )] TJ ET BT 26.250 547.220 Td /F1 9.8 Tf [(classifier and Decipher. Websites for Decipher)] TJ ET 0.267 0.267 0.267 rg BT 235.924 548.727 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 240.742 547.220 Td /F1 9.8 Tf [( and GenomeDx)] TJ ET 0.267 0.267 0.267 rg BT 311.732 548.727 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 316.551 547.220 Td /F1 9.8 Tf [( were also reviewed to identified additional published and )] TJ ET BT 26.250 535.315 Td /F1 9.8 Tf [(unpublished information. No trial registries were searched, which is a possible limitation.)] TJ ET BT 26.250 515.910 Td /F1 9.8 Tf [(PubMed search strategy:)] TJ ET BT 26.250 496.506 Td /F1 9.8 Tf [(\(\(classifier[tiab]\) AND \(\(genomic*[tiab]\) OR \(genome*[tiab]\)\)\) AND \(\(prostate[tiab] OR prostatic[tiab] OR \(prostatic )] TJ ET BT 26.250 484.601 Td /F1 9.8 Tf [(neoplasm[mesh]\) OR \(biochemical recurrence[tiab]\)\))] TJ ET BT 26.250 465.196 Td /F4 9.8 Tf [(Published Reviews, Recommendations, and Guidelines)] TJ ET BT 26.250 445.791 Td /F1 9.8 Tf [(No published reviews, recommendations or guidelines describing the Decipher genomic classifier were identified from the )] TJ ET BT 26.250 433.887 Td /F1 9.8 Tf [(methods described above. One local coverage decision from Palmetto GBA was identified providing limited coverage for )] TJ ET BT 26.250 421.982 Td /F1 9.8 Tf [(Decipher in order to determine which patients at high-risk of recurrence following RP should receive radiation therapy vs. )] TJ ET BT 26.250 410.077 Td /F1 9.8 Tf [(continued observation.)] TJ ET 0.267 0.267 0.267 rg BT 124.345 411.584 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 26.250 390.672 Td /F4 9.8 Tf [(Analytic Validity)] TJ ET BT 26.250 371.268 Td /F1 9.8 Tf [(Data reported in a conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 192.624 372.775 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 202.261 371.268 Td /F1 9.8 Tf [( showed RNA was successfully extracted from 91% \(63/69\) FFPE biopsies and 100% )] TJ ET BT 26.250 359.363 Td /F1 9.8 Tf [(\(69/69\) of RP tissue samples, and 98% \(62/63\) and 99% \(68/69\) of the FFPE and RP samples passed gene-expression data )] TJ ET BT 26.250 347.458 Td /F1 9.8 Tf [(quality control, respectively. In this study, the correlation between matched biopsy FFPE tissue and RP tissue samples in the )] TJ ET BT 26.250 335.553 Td /F1 9.8 Tf [(genomic classifier scores predicting metastasis was 0.74 \(p=0.0003\).)] TJ ET BT 26.250 316.149 Td /F1 9.8 Tf [(Two other studies are listed on the Decipher website under Analytic Validity,)] TJ ET 0.267 0.267 0.267 rg BT 358.423 317.656 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 368.060 320.037 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 370.469 317.656 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 380.107 316.149 Td /F1 9.8 Tf [( but it is unclear whether the methods and )] TJ ET BT 26.250 304.244 Td /F1 9.8 Tf [(procedures described in these reports are integrated into the Decipher analytic pipeline.)] TJ ET BT 26.250 284.839 Td /F4 9.8 Tf [(Clinical Validity)] TJ ET BT 26.250 265.434 Td /F1 9.8 Tf [(Eight published studies were identified evaluating the clinical validity of the genomic classifier, based on its ability to predict )] TJ ET BT 26.250 253.530 Td /F1 9.8 Tf [(clinical metastasis)] TJ ET 0.267 0.267 0.267 rg BT 104.806 255.037 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 114.443 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 116.852 255.037 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 126.490 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 128.899 255.037 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 138.536 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 140.946 255.037 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 150.583 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 152.992 255.037 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 162.630 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 165.039 255.037 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 174.676 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 177.086 255.037 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 186.723 257.418 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 189.132 255.037 Td /F4 8.7 Tf [(20)] TJ ET 0.271 0.267 0.267 rg BT 198.770 253.530 Td /F1 9.8 Tf [(. The first study used data from a Mayo Clinic patient registry to compare men with )] TJ ET BT 26.250 241.625 Td /F1 9.8 Tf [(evidence of clinical metastasis following RP \(cases\) to men with no evidence of metastasis after RP \(controls\) with median )] TJ ET BT 26.250 229.720 Td /F1 9.8 Tf [(follow-up greater than five years. One publication reported results from the initial training and validation datasets in which )] TJ ET BT 26.250 217.815 Td /F1 9.8 Tf [(participants with no evidence of disease recurrence and those with biochemical recurrence \(PSA )] TJ ET BT 445.130 217.815 Td /F1 9.8 Tf [(>)] TJ ET BT 450.824 217.815 Td /F1 9.8 Tf [( 0.20 ng/ml within 30 days of )] TJ ET BT 26.250 205.911 Td /F1 9.8 Tf [(RP\) served as controls due to very limited differential expression between these two groups.)] TJ ET 0.267 0.267 0.267 rg BT 429.949 207.418 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 439.586 205.911 Td /F1 9.8 Tf [( Therefore, the genomic )] TJ ET BT 26.250 194.006 Td /F1 9.8 Tf [(classifier was developed to discriminate men who develop clinical metastasis from men who have no evidence of disease )] TJ ET BT 26.250 182.101 Td /F1 9.8 Tf [(recurrence \(clinical or biochemical\) within five years of RP. Two additional studies using data from the Mayo Clinic registry )] TJ ET BT 26.250 170.196 Td /F1 9.8 Tf [(described subsequent validation of the genomic classifier in men with biochemical recurrence after RP)] TJ ET 0.267 0.267 0.267 rg BT 466.794 171.704 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 476.431 170.196 Td /F1 9.8 Tf [( and in men with high-)] TJ ET BT 26.250 158.292 Td /F1 9.8 Tf [(risk prostate cancer \(pre-RP PSA > 20ng/mL, Gleason score )] TJ ET BT 290.416 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 296.111 158.292 Td /F1 9.8 Tf [( 8, pT3b, or Mayo Clinic nomogram score )] TJ ET BT 477.626 158.292 Td /F1 9.8 Tf [(>)] TJ ET BT 483.320 158.292 Td /F1 9.8 Tf [( 10\).)] TJ ET 0.267 0.267 0.267 rg BT 502.830 159.799 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 26.250 138.887 Td /F1 9.8 Tf [(Overall, the genomic classifier had good discriminatory ability \(e.g. ability to predict clinical metastasis\) in both the discovery and )] TJ ET BT 26.250 126.982 Td /F1 9.8 Tf [(validation studies \(Table 1\). Across the nine analyses, the area under the receiver operating curve \(AUC\) ranged between 0.75 )] TJ ET BT 26.250 115.077 Td /F1 9.8 Tf [(and 0.90. None of the studies examining the predictive accuracy of the genomic classifier explicitly reported whether the gene-)] TJ ET BT 26.250 103.173 Td /F1 9.8 Tf [(expression analysis was performed on tissue collected at the time of surgery or at the time of clinical end point \(e.g. metastasis\). )] TJ ET BT 26.250 91.268 Td /F1 9.8 Tf [(There was potential overlap in participants used to develop and validate the genomic classifier across four studies interrogating )] TJ ET BT 26.250 79.363 Td /F1 9.8 Tf [(a patient registry)] TJ ET 0.267 0.267 0.267 rg BT 98.322 80.870 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 107.959 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 110.369 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 120.006 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 122.415 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 132.053 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 134.462 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 144.099 79.363 Td /F1 9.8 Tf [(. In three full-text validation studies)] TJ ET 0.267 0.267 0.267 rg BT 294.210 80.870 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 303.848 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 306.257 80.870 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 315.894 83.251 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 318.304 80.870 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 327.941 79.363 Td /F1 9.8 Tf [( there were noticeable differences between cases and )] TJ ET BT 26.250 67.458 Td /F1 9.8 Tf [(controls in the frequency of high-risk pathological features, risk factors for metastasis, and adjuvant and salvage therapy \(Table )] TJ ET BT 26.250 55.554 Td /F1 9.8 Tf [(2\). The possibility of confounding due to these differences may have yielded an overestimate of the prognostic ability of the )] TJ ET BT 26.250 43.649 Td /F1 9.8 Tf [(genomic classifier. Another limitation is the change in risk of metastasis with more follow up time. 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In terms of prostate cancer-specific mortality, one study reported an AUC of 0.78 \(95% CI: 0.68 to 0.87\) among high-risk )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(patients)] TJ ET 0.267 0.267 0.267 rg BT 60.395 733.269 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 70.032 731.762 Td /F1 9.8 Tf [(. In a group of men treated with adjuvant radiation therapy, the AUC for metastasis was 0.83 \(95% CI: 0.27 to 0.89\).)] TJ ET 0.267 0.267 0.267 rg BT 568.072 733.269 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 26.250 712.357 Td /F1 9.8 Tf [(A conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 121.088 713.864 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 130.726 712.357 Td /F1 9.8 Tf [( reported that the genomic classifier could predict metastasis in a subset of prostate cancer tumors with )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(ETS gene overexpression, PTEN-loss, or both very well. Among the tumors with ETS gene overexpression and PTEN loss the )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(genomic classifier had an AUC of 0.82 and 0.85, respectively. In tumors with both ETS overexpression and PTEN loss, the AUC )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(was 0.85.)] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(The cumulative incidence of metastasis five years after RP was 2.4%, 6.0%, and 22.5% for the low, intermediate, and high risk )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(groups defined by the genomic classifier respectively)] TJ ET 0.267 0.267 0.267 rg BT 254.381 646.841 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 264.018 645.333 Td /F1 9.8 Tf [( and 0%, 12%, 17% eight years after RP)] TJ ET 0.267 0.267 0.267 rg BT 438.523 646.841 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 448.161 645.333 Td /F1 9.8 Tf [( and 12%, 31% and 47% 10 )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(years after RP for the same three risk groups respectively)] TJ ET 0.267 0.267 0.267 rg BT 274.963 634.936 Td /F4 8.7 Tf [(20)] TJ ET 0.271 0.267 0.267 rg BT 284.600 633.429 Td /F1 9.8 Tf [(.)] TJ ET 0.965 0.965 0.965 rg 26.250 14.548 555.000 609.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 623.548 m 581.250 623.548 l 581.250 622.798 l 26.250 622.798 l f q 450.000 0 0 593.250 35.250 20.548 cm /I3 Do Q q 35.250 14.548 537.000 0.000 re W n Q Q q 450.000 0 0 593.250 35.250 20.548 cm /I3 Do Q q 0.000 0.000 0.000 rg 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 Q endstream endobj 282 0 obj << /Type /Annot /Subtype /Link /A 283 0 R /Border [0 0 0] /H /I /Rect [ 565.3958 768.1817 575.0331 777.0000 ] >> endobj 283 0 obj << /Type /Action >> endobj 284 0 obj << /Type /Annot /Subtype /Link /A 285 0 R /Border [0 0 0] /H /I /Rect [ 60.3945 732.4674 70.0318 741.2858 ] >> endobj 285 0 obj << /Type /Action >> endobj 286 0 obj << /Type /Annot /Subtype /Link /A 287 0 R /Border [0 0 0] /H /I /Rect [ 568.0716 732.4674 577.7089 741.2858 ] >> endobj 287 0 obj << /Type /Action >> endobj 288 0 obj << /Type /Annot /Subtype /Link /A 289 0 R /Border [0 0 0] /H /I /Rect [ 121.0883 713.0627 130.7256 721.8810 ] >> endobj 289 0 obj << /Type /Action >> endobj 290 0 obj << /Type /Annot /Subtype /Link /A 291 0 R /Border [0 0 0] /H /I /Rect [ 254.3805 646.0389 264.0178 654.8573 ] >> endobj 291 0 obj << /Type /Action >> endobj 292 0 obj << /Type /Annot /Subtype /Link /A 293 0 R /Border [0 0 0] /H /I /Rect [ 438.5233 646.0389 448.1607 654.8573 ] >> endobj 293 0 obj << /Type /Action >> endobj 294 0 obj << /Type /Annot /Subtype /Link /A 295 0 R /Border [0 0 0] /H /I /Rect [ 274.9628 634.1342 284.6001 642.9525 ] >> endobj 295 0 obj << /Type /Action >> endobj 296 0 obj << /Type /Annot /Subtype /Link /A 297 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 20.5477 485.2500 613.7977 ] >> endobj 297 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2015/11/Table1.jpg) >> endobj 298 0 obj << /Type /XObject /Subtype /Image /Width 600 /Height 791 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 127089>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   X" }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?Qjtkq|myhj#,q22HPx;'7ywSxEľCqu,13ɆdxdVޥoڋQLT=kϤ=8lbymb7I0Q[85D߅k3 Ώm.7g([nd0'x˔r)bҼ9misyI{$IP"?~m2v-v?>Koǎ5 ɫ۩پ˗3ּ;_-kZOţkRxN^K]=|bWʌ; VA8?eW:h}[[]TrG0"` uř~X,%6մ;Tb;msՁD:n// ŦjEōV GXr}i8,ϚCSt?oT׵,)D>. ~@-XV5}?Q%֣Юٚu3M$m7g.%>Ծ/Fli4T Kr4_1,K ukTPxQNaቕ-jP;)Y!=sim'mψNJx~no4[gIa%U(~~Þ/u?67ˡ]XM9Ko$#)RM#:|I."S jB~χ q[V~]7x3Y5"ϣw7Π$Kp<aǯmj_tv:珦;Y˵'bGy3 y'OIVc/ jpFD&]CSfaGAgmV9H6 >c}A/FnQ "ݙmШ6GſKj[A&~ݡU;=r1 ==wMmMmM͹n$V ["ivza4b[}>+FТ _+0u^G|^kT Mb#-2Yͻ,aln9>eO FVO=B[[CDzKW[$T&&WTf!c AwW,4[-xij0ٺ:6yu,G5O~$l ݻKĆ02ݼe]JA\B<9a:xfU{hnaY[2Fb+0`pyKuj>ӼE_jҭocs$JŐr:V+rq(<.MNl oB|:^=_~|U|] I-n5K+{?PM_%kt%lp'_^,5;~;KOQon&En ?dFY<~0 =#M_xua#M[ԐB `T9EƿŬK<2h%ەb$ٟI|a<B[odcOEXLԧ+M4=4Trпei]j6,:V~,lH.a<4B3(,Y$ۯ#hW?_aj蚽Ҭw1Hs*BI軉Z73-CZ|Gw#Kk;إuV&3 } |?(:uPd ^8U&\2KrYrΗ_翲OcYh?,PB.gV*$FģGEdNZC㵲,ڼWO{eeG&2Vd25{O]kkލYK Jbc:'m"~^ t{+GZ0׺]DbC 2E|ݤ]h?aվ'^jee$hR,1 V+?:i$؋D;m9.q_هnuu2^jiNi#0F ]bʌ}gxþ+M{L.|,/#KI72QF6Qc[|א|!mYW7zrdknmwl O!A;h)xbg#Ԍ lVRQ88e8 9kWOWOk&(&(k&(&(k&(&(k&(&(k&(&(k&(&(Z^BM*d,ҐIV'PAv WO9kWOWO9kWOWO9Y)xb9c"I҂l', 7@/4s\, 7G, 7@/4s\, 7G, 7@/4s\, 7G, 7@/4s\, 7QKI&ѼͲ5kiAvlcڀ:h湯Y^?o"Y^?o":^h湯Y^?o"Y^?o":^h湯Y^?o"Y^?o":^h湯Y^?o"73(3Z)A::R2j3F 4dW1īMQO\7G@>h4`j3F 4gڌQF <уF g2sM\ae>f4fQF >`у@ M]>}?W_)r#Ff!UFI' v}ϵr^࿊q?UxmB4ٗ98% $q]zڕƟosMj8ܰGeB@ lt4k4fhSRׯk,6ԍgb{(' UAia}/KsS޺|3F}_2|>]lI}7iK&Il4 g,G1.OЬ S^KB?4i6i;\ @>ϵ|OOO|Omye.=N|3<2G9\xec|Fo7|+ihhxZxYZDF"fYLd\9 iڌΫg jV75Jپo@ӦUg{D-4.ˀw\)~~*j\4_h1[ [Uw7dI4AIŔVl( .(W1^? 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There is only limited evidence of clinical utility from four publications)] TJ ET 0.267 0.267 0.267 rg BT 365.989 280.547 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 375.626 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 378.035 280.547 Td /F4 8.7 Tf [(24)] TJ ET 0.271 0.267 0.267 rg BT 387.673 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 390.082 280.547 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 399.719 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 402.129 280.547 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 411.766 279.039 Td /F1 9.8 Tf [( and one conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 538.048 280.547 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 267.135 Td /F1 9.8 Tf [(comparing physicians treatment recommendations before and after knowledge of the results from the genomic classifier. Study )] TJ ET BT 26.250 255.230 Td /F1 9.8 Tf [(investigators recruited physicians to review the medical records of selected patients from an actual practice with high-risk )] TJ ET BT 26.250 243.325 Td /F1 9.8 Tf [(prostate cancer in the adjuvant setting \(no evidence of biochemical recurrence after RP\) and salvage setting \(evidence of )] TJ ET BT 26.250 231.420 Td /F1 9.8 Tf [(biochemical recurrence after RP\). Physicians were asked to make treatment recommendations based on their reviews. The )] TJ ET BT 26.250 219.516 Td /F1 9.8 Tf [(overall change in treatment recommendations, after asking physicians to consider the scores from the genomic classifier, )] TJ ET BT 26.250 207.611 Td /F1 9.8 Tf [(ranged between 31% and 43% in the adjuvant setting and 53% in the salvage setting \(Table 3\). The change from no treatment )] TJ ET BT 26.250 195.706 Td /F1 9.8 Tf [(\(observation\) to any therapy ranged from 8% to 38%, and from any treatment to no treatment ranged from 27% to 52%. All )] TJ ET BT 26.250 183.801 Td /F1 9.8 Tf [(study reports included case histories of high-risk prostate cancer in which the most significant change in treatment )] TJ ET BT 26.250 171.897 Td /F1 9.8 Tf [(recommendations was from any adjuvant therapy to no treatment. These studies provide indirect evidence that only suggests )] TJ ET BT 26.250 159.992 Td /F1 9.8 Tf [(some potential for the genomic classifier to achieve clinical utility.)] TJ ET 0.965 0.965 0.965 rg 26.250 2.361 555.000 147.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 150.111 m 581.250 150.111 l 581.250 149.361 l 26.250 149.361 l f q 450.000 0 0 132.000 35.250 8.361 cm /I5 Do Q q 35.250 2.361 537.000 0.000 re W n Q Q q 15.000 2.361 577.500 774.639 re W n 0.965 0.965 0.965 rg 26.250 744.514 555.000 32.486 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 744.514 m 581.250 744.514 l 581.250 745.264 l 26.250 745.264 l f q 35.250 755.764 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F1 9.8 Tf [(Table 1: Performance characteristics of the genomic classifier)] TJ ET Q 0.965 0.965 0.965 rg 26.250 339.277 555.000 397.736 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 737.014 m 581.250 737.014 l 581.250 736.264 l 26.250 736.264 l f 26.250 339.277 m 581.250 339.277 l 581.250 340.027 l 26.250 340.027 l f q 450.000 0 0 349.500 35.250 377.764 cm /I4 Do Q q 35.250 350.527 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 360.775 Td /F1 9.8 Tf [(Table 2: Participant characteristics in clinical validation studies)] TJ ET Q BT 26.250 322.254 Td /F4 9.8 Tf [(Clinical Utility)] TJ ET BT 26.250 302.849 Td /F1 9.8 Tf [(No direct evidence for clinical utility for the genomic classifier is currently available showing changes in selection of primary or )] TJ ET BT 26.250 290.944 Td /F1 9.8 Tf [(adjuvant treatment based on the genomic classifier or showing that the genomic classifier can successfully predict treatment )] TJ ET BT 26.250 279.039 Td /F1 9.8 Tf [(outcomes. There is only limited evidence of clinical utility from four publications)] TJ ET 0.267 0.267 0.267 rg BT 365.989 280.547 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 375.626 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 378.035 280.547 Td /F4 8.7 Tf [(24)] TJ ET 0.271 0.267 0.267 rg BT 387.673 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 390.082 280.547 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 399.719 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 402.129 280.547 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 411.766 279.039 Td /F1 9.8 Tf [( and one conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 538.048 280.547 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 267.135 Td /F1 9.8 Tf [(comparing physicians treatment recommendations before and after knowledge of the results from the genomic classifier. Study )] TJ ET BT 26.250 255.230 Td /F1 9.8 Tf [(investigators recruited physicians to review the medical records of selected patients from an actual practice with high-risk )] TJ ET BT 26.250 243.325 Td /F1 9.8 Tf [(prostate cancer in the adjuvant setting \(no evidence of biochemical recurrence after RP\) and salvage setting \(evidence of )] TJ ET BT 26.250 231.420 Td /F1 9.8 Tf [(biochemical recurrence after RP\). Physicians were asked to make treatment recommendations based on their reviews. The )] TJ ET BT 26.250 219.516 Td /F1 9.8 Tf [(overall change in treatment recommendations, after asking physicians to consider the scores from the genomic classifier, )] TJ ET BT 26.250 207.611 Td /F1 9.8 Tf [(ranged between 31% and 43% in the adjuvant setting and 53% in the salvage setting \(Table 3\). The change from no treatment )] TJ ET BT 26.250 195.706 Td /F1 9.8 Tf [(\(observation\) to any therapy ranged from 8% to 38%, and from any treatment to no treatment ranged from 27% to 52%. All )] TJ ET BT 26.250 183.801 Td /F1 9.8 Tf [(study reports included case histories of high-risk prostate cancer in which the most significant change in treatment )] TJ ET BT 26.250 171.897 Td /F1 9.8 Tf [(recommendations was from any adjuvant therapy to no treatment. These studies provide indirect evidence that only suggests )] TJ ET BT 26.250 159.992 Td /F1 9.8 Tf [(some potential for the genomic classifier to achieve clinical utility.)] TJ ET 0.965 0.965 0.965 rg 26.250 2.361 555.000 147.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 150.111 m 581.250 150.111 l 581.250 149.361 l 26.250 149.361 l f q 450.000 0 0 132.000 35.250 8.361 cm /I5 Do Q q 35.250 2.361 537.000 0.000 re W n Q Q q 15.000 2.361 577.500 774.639 re W n 0.965 0.965 0.965 rg 26.250 744.514 555.000 32.486 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 744.514 m 581.250 744.514 l 581.250 745.264 l 26.250 745.264 l f q 35.250 755.764 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F1 9.8 Tf [(Table 1: Performance characteristics of the genomic classifier)] TJ ET Q 0.965 0.965 0.965 rg 26.250 339.277 555.000 397.736 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 737.014 m 581.250 737.014 l 581.250 736.264 l 26.250 736.264 l f 26.250 339.277 m 581.250 339.277 l 581.250 340.027 l 26.250 340.027 l f q 450.000 0 0 349.500 35.250 377.764 cm /I4 Do Q q 35.250 350.527 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 360.775 Td /F1 9.8 Tf [(Table 2: Participant characteristics in clinical validation studies)] TJ ET Q BT 26.250 322.254 Td /F4 9.8 Tf [(Clinical Utility)] TJ ET BT 26.250 302.849 Td /F1 9.8 Tf [(No direct evidence for clinical utility for the genomic classifier is currently available showing changes in selection of primary or )] TJ ET BT 26.250 290.944 Td /F1 9.8 Tf [(adjuvant treatment based on the genomic classifier or showing that the genomic classifier can successfully predict treatment )] TJ ET BT 26.250 279.039 Td /F1 9.8 Tf [(outcomes. There is only limited evidence of clinical utility from four publications)] TJ ET 0.267 0.267 0.267 rg BT 365.989 280.547 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 375.626 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 378.035 280.547 Td /F4 8.7 Tf [(24)] TJ ET 0.271 0.267 0.267 rg BT 387.673 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 390.082 280.547 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 399.719 282.928 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 402.129 280.547 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 411.766 279.039 Td /F1 9.8 Tf [( and one conference abstract)] TJ ET 0.267 0.267 0.267 rg BT 538.048 280.547 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 267.135 Td /F1 9.8 Tf [(comparing physicians treatment recommendations before and after knowledge of the results from the genomic classifier. Study )] TJ ET BT 26.250 255.230 Td /F1 9.8 Tf [(investigators recruited physicians to review the medical records of selected patients from an actual practice with high-risk )] TJ ET BT 26.250 243.325 Td /F1 9.8 Tf [(prostate cancer in the adjuvant setting \(no evidence of biochemical recurrence after RP\) and salvage setting \(evidence of )] TJ ET BT 26.250 231.420 Td /F1 9.8 Tf [(biochemical recurrence after RP\). Physicians were asked to make treatment recommendations based on their reviews. The )] TJ ET BT 26.250 219.516 Td /F1 9.8 Tf [(overall change in treatment recommendations, after asking physicians to consider the scores from the genomic classifier, )] TJ ET BT 26.250 207.611 Td /F1 9.8 Tf [(ranged between 31% and 43% in the adjuvant setting and 53% in the salvage setting \(Table 3\). The change from no treatment )] TJ ET BT 26.250 195.706 Td /F1 9.8 Tf [(\(observation\) to any therapy ranged from 8% to 38%, and from any treatment to no treatment ranged from 27% to 52%. All )] TJ ET BT 26.250 183.801 Td /F1 9.8 Tf [(study reports included case histories of high-risk prostate cancer in which the most significant change in treatment )] TJ ET BT 26.250 171.897 Td /F1 9.8 Tf [(recommendations was from any adjuvant therapy to no treatment. These studies provide indirect evidence that only suggests )] TJ ET BT 26.250 159.992 Td /F1 9.8 Tf [(some potential for the genomic classifier to achieve clinical utility.)] TJ ET 0.965 0.965 0.965 rg 26.250 2.361 555.000 147.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 150.111 m 581.250 150.111 l 581.250 149.361 l 26.250 149.361 l f q 450.000 0 0 132.000 35.250 8.361 cm /I5 Do Q q 35.250 2.361 537.000 0.000 re W n Q Q q 450.000 0 0 349.500 35.250 377.764 cm /I4 Do Q q 450.000 0 0 132.000 35.250 8.361 cm /I5 Do 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 333 0 obj << /Type /Annot /Subtype /Link /A 334 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 377.7637 485.2500 727.2637 ] >> endobj 334 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2015/11/Table2.jpg) >> endobj 335 0 obj << /Type /XObject /Subtype /Image /Width 600 /Height 466 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 88813>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   X" }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?Qǵ/Fh&= Z^yyoH6f15!蛏Ad@(_O^_Xj7rXdk_&F_"iB˄,FJ }5?c/ x̞% RpnnExG]g 4^Ky|kJ.%>֟7],O oY𯌡φk\hZLq$($Ȫ%g*-߉AyWXXC2qm>ab~~Z]:o[qZ(/E]ľi$iJS1G,XAzZhwh$BhnbTfHbE\A;F|XЯumijٯ Yy^T'K腷[>7H,|i^klM6ZgGO0i\7ƗMt^e%ƍXYL`W`AP98oЧğ jI{BЩ%e(\^F`ӵO[]nN3˨MX^Fon.XE\#mE,@:h߆s =/lDR]7jdOH#Hhqi7M)-FiHa3:(\e";Q8RG9OZ^#OO[Qx M"d "R;1rw3؇D:K{ndk9noqlwoeWRnyV@ΝT|/4BWiaoc\=bHbt. 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The genomic classifier was shown to have good discrimination in detecting men at risk for )] TJ ET BT 26.250 666.528 Td /F1 9.8 Tf [(metastatic prostate cancer five years after surgery \(AUC 0.75 to 0.90\). However, these estimates may be biased given )] TJ ET BT 26.250 654.624 Td /F1 9.8 Tf [(differences in important prognostic characteristics between cases and controls. Independent validation in patients with high-risk )] TJ ET BT 26.250 642.719 Td /F1 9.8 Tf [(prostate cancer may provide more reliable estimates of the prognostic ability of the genomic classifier. At this time it is unclear )] TJ ET BT 26.250 630.814 Td /F1 9.8 Tf [(what the most appropriate clinical actions are based on test results. No studies yet published have reported the ability of the )] TJ ET BT 26.250 618.909 Td /F1 9.8 Tf [(genomic classifier to predict significant clinical outcomes from any of the available adjuvant therapies. In order to demonstrate )] TJ ET BT 26.250 607.005 Td /F1 9.8 Tf [(clinical utility additional evidence is needed showing improved outcomes \(clinical metastasis or prostate cancer-specific )] TJ ET BT 26.250 595.100 Td /F1 9.8 Tf [(mortality\) in men whose post-operative treatment was guided by the genomic classifier compared to standard practice.)] TJ ET BT 26.250 558.497 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 538.543 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist. The findings and conclusions are those of authors, including NIH )] TJ ET BT 26.250 526.638 Td /F1 9.8 Tf [(co-authors, and do not necessarily represent the views of the National Institutes of Health \(NIH\). The information provided in )] TJ ET BT 26.250 514.734 Td /F1 9.8 Tf [(this manuscript does not constitute an endorsement of any of the commercially available tests described in this report by NIH )] TJ ET BT 26.250 502.829 Td /F1 9.8 Tf [(nor the Department of Health and Human Services of the U.S. government.)] TJ ET BT 26.250 466.226 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 438.772 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 438.772 Td /F1 9.8 Tf [(Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham JA, Yossepowitch O, Rabah )] TJ ET BT 26.250 426.867 Td /F1 9.8 Tf [(DM, Kattan MW, Yu C, Klein EA, Stephenson AJ. Predicting 15-year prostate cancer specific mortality after radical )] TJ ET BT 26.250 414.963 Td /F1 9.8 Tf [(prostatectomy. J Urol. 2011 Mar;185\(3\):869-75. PubMed PMID:21239008.)] TJ ET BT 26.250 395.558 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 395.558 Td /F1 9.8 Tf [(Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA )] TJ ET BT 26.250 383.653 Td /F1 9.8 Tf [(elevation following radical prostatectomy. JAMA. 1999 May 5;281\(17\):1591-7. PubMed PMID:10235151.)] TJ ET BT 26.250 364.248 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 364.248 Td /F1 9.8 Tf [(Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW. Risk of prostate cancer-specific )] TJ ET BT 26.250 352.344 Td /F1 9.8 Tf [(mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005 Jul 27;294\(4\):433-9. PubMed )] TJ ET BT 26.250 340.439 Td /F1 9.8 Tf [(PMID:16046649.)] TJ ET BT 26.250 321.034 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 321.034 Td /F1 9.8 Tf [(NCCN Guidelines for patients - prostate cancer.1.2014.)] TJ ET BT 26.250 301.629 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 301.629 Td /F1 9.8 Tf [(Nielsen ME, Trock BJ, Walsh PC. Salvage or adjuvant radiation therapy: counseling patients on the benefits. J Natl Compr )] TJ ET BT 26.250 289.725 Td /F1 9.8 Tf [(Canc Netw. 2010 Feb;8\(2\):228-37. PubMed PMID:20141679.)] TJ ET BT 26.250 270.320 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 270.320 Td /F1 9.8 Tf [(Decipher prostate cancer classifier. https://deciphertest.com/. Accessed July, 2015)] TJ ET BT 26.250 250.915 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 250.915 Td /F1 9.8 Tf [(Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64\(1\):9-29. PubMed )] TJ ET BT 26.250 239.010 Td /F1 9.8 Tf [(PMID:24399786.)] TJ ET BT 26.250 219.606 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 219.606 Td /F1 9.8 Tf [(GenomeDx Biosciences. https://genomedx.com/. Accessed July, 2015.)] TJ ET BT 26.250 200.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 200.201 Td /F1 9.8 Tf [(Centers for Medicare & Medicaid Services. MolDX: Decpiher Prostate Cancer Classifier Assay. Local coverage document )] TJ ET BT 26.250 188.296 Td /F1 9.8 Tf [(\(L35650\). Medicare Coverage Database \(https://www.cms.gov/medicare-coverage-database/overview-and-quick-)] TJ ET BT 26.250 176.391 Td /F1 9.8 Tf [(search.aspx?CoverageSelection=Local&ArticleType=All&PolicyType=Final&s=All&KeyWord=decipher&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAAAAAAAAAAA%3d%3d&=&\). )] TJ ET BT 26.250 164.487 Td /F1 9.8 Tf [(Accessed August 2015)] TJ ET BT 26.250 145.082 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 145.082 Td /F1 9.8 Tf [(Knudsen B, Simko JP, Lam LL, et al. Transcriptome-wide analysis of matched biopsy and prostatectomy to measure )] TJ ET BT 26.250 133.177 Td /F1 9.8 Tf [(genomic classifiers of prostate cancer progression and field effect. J Clin Oncol. 2014;32\(suppl 4\).)] TJ ET BT 26.250 113.772 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 113.772 Td /F1 9.8 Tf [(Abdueva D, Wing M, Schaub B, Triche T, Davicioni E. Quantitative expression profiling in formalin-fixed paraffin-embedded )] TJ ET BT 26.250 101.868 Td /F1 9.8 Tf [(samples by affymetrix microarrays. J Mol Diagn. 2010 Jul;12\(4\):409-17. PubMed PMID:20522636.)] TJ ET BT 26.250 82.463 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 82.463 Td /F1 9.8 Tf [(Erho N, Buerki C, Triche TJ, Davicioni E, Vergara IA. Transcriptome-wide detection of differentially expressed coding and )] TJ ET BT 26.250 70.558 Td /F1 9.8 Tf [(non-coding transcripts and their clinical significance in prostate cancer. J Oncol. 2012;2012:541353. PubMed PMID:22956952.)] TJ ET BT 26.250 51.153 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 51.153 Td /F1 9.8 Tf [(Cooperberg MR, Davicioni E, Crisan A, Jenkins RB, Ghadessi M, Karnes RJ. Combined value of validated clinical and )] TJ ET Q q 15.000 36.868 577.500 740.132 re W n 0.965 0.965 0.965 rg 26.250 744.514 555.000 32.486 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 744.514 m 581.250 744.514 l 581.250 745.264 l 26.250 745.264 l f q 35.250 755.764 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F1 9.8 Tf [(Table 3: Change in treatment recommendation in high-risk prostate cancer based on knowledge of the genomic classifier)] TJ ET Q BT 26.250 710.292 Td /F4 12.0 Tf [(Conclusions)] TJ ET BT 26.250 690.338 Td /F1 9.8 Tf [(The recently introduced genomic classifier was developed to identify men with increased risk for metastatic prostate cancer )] TJ ET BT 26.250 678.433 Td /F1 9.8 Tf [(following radical prostatectomy. The genomic classifier was shown to have good discrimination in detecting men at risk for )] TJ ET BT 26.250 666.528 Td /F1 9.8 Tf [(metastatic prostate cancer five years after surgery \(AUC 0.75 to 0.90\). However, these estimates may be biased given )] TJ ET BT 26.250 654.624 Td /F1 9.8 Tf [(differences in important prognostic characteristics between cases and controls. Independent validation in patients with high-risk )] TJ ET BT 26.250 642.719 Td /F1 9.8 Tf [(prostate cancer may provide more reliable estimates of the prognostic ability of the genomic classifier. At this time it is unclear )] TJ ET BT 26.250 630.814 Td /F1 9.8 Tf [(what the most appropriate clinical actions are based on test results. No studies yet published have reported the ability of the )] TJ ET BT 26.250 618.909 Td /F1 9.8 Tf [(genomic classifier to predict significant clinical outcomes from any of the available adjuvant therapies. In order to demonstrate )] TJ ET BT 26.250 607.005 Td /F1 9.8 Tf [(clinical utility additional evidence is needed showing improved outcomes \(clinical metastasis or prostate cancer-specific )] TJ ET BT 26.250 595.100 Td /F1 9.8 Tf [(mortality\) in men whose post-operative treatment was guided by the genomic classifier compared to standard practice.)] TJ ET BT 26.250 558.497 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 538.543 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist. The findings and conclusions are those of authors, including NIH )] TJ ET BT 26.250 526.638 Td /F1 9.8 Tf [(co-authors, and do not necessarily represent the views of the National Institutes of Health \(NIH\). The information provided in )] TJ ET BT 26.250 514.734 Td /F1 9.8 Tf [(this manuscript does not constitute an endorsement of any of the commercially available tests described in this report by NIH )] TJ ET BT 26.250 502.829 Td /F1 9.8 Tf [(nor the Department of Health and Human Services of the U.S. government.)] TJ ET BT 26.250 466.226 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 438.772 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 438.772 Td /F1 9.8 Tf [(Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham JA, Yossepowitch O, Rabah )] TJ ET BT 26.250 426.867 Td /F1 9.8 Tf [(DM, Kattan MW, Yu C, Klein EA, Stephenson AJ. Predicting 15-year prostate cancer specific mortality after radical )] TJ ET BT 26.250 414.963 Td /F1 9.8 Tf [(prostatectomy. J Urol. 2011 Mar;185\(3\):869-75. PubMed PMID:21239008.)] TJ ET BT 26.250 395.558 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 395.558 Td /F1 9.8 Tf [(Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA )] TJ ET BT 26.250 383.653 Td /F1 9.8 Tf [(elevation following radical prostatectomy. JAMA. 1999 May 5;281\(17\):1591-7. PubMed PMID:10235151.)] TJ ET BT 26.250 364.248 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 364.248 Td /F1 9.8 Tf [(Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW. Risk of prostate cancer-specific )] TJ ET BT 26.250 352.344 Td /F1 9.8 Tf [(mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005 Jul 27;294\(4\):433-9. PubMed )] TJ ET BT 26.250 340.439 Td /F1 9.8 Tf [(PMID:16046649.)] TJ ET BT 26.250 321.034 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 321.034 Td /F1 9.8 Tf [(NCCN Guidelines for patients - prostate cancer.1.2014.)] TJ ET BT 26.250 301.629 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 301.629 Td /F1 9.8 Tf [(Nielsen ME, Trock BJ, Walsh PC. Salvage or adjuvant radiation therapy: counseling patients on the benefits. J Natl Compr )] TJ ET BT 26.250 289.725 Td /F1 9.8 Tf [(Canc Netw. 2010 Feb;8\(2\):228-37. PubMed PMID:20141679.)] TJ ET BT 26.250 270.320 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 270.320 Td /F1 9.8 Tf [(Decipher prostate cancer classifier. https://deciphertest.com/. Accessed July, 2015)] TJ ET BT 26.250 250.915 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 250.915 Td /F1 9.8 Tf [(Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64\(1\):9-29. PubMed )] TJ ET BT 26.250 239.010 Td /F1 9.8 Tf [(PMID:24399786.)] TJ ET BT 26.250 219.606 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 219.606 Td /F1 9.8 Tf [(GenomeDx Biosciences. https://genomedx.com/. Accessed July, 2015.)] TJ ET BT 26.250 200.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 200.201 Td /F1 9.8 Tf [(Centers for Medicare & Medicaid Services. MolDX: Decpiher Prostate Cancer Classifier Assay. Local coverage document )] TJ ET BT 26.250 188.296 Td /F1 9.8 Tf [(\(L35650\). Medicare Coverage Database \(https://www.cms.gov/medicare-coverage-database/overview-and-quick-)] TJ ET BT 26.250 176.391 Td /F1 9.8 Tf [(search.aspx?CoverageSelection=Local&ArticleType=All&PolicyType=Final&s=All&KeyWord=decipher&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAAAAAAAAAAA%3d%3d&=&\). )] TJ ET BT 26.250 164.487 Td /F1 9.8 Tf [(Accessed August 2015)] TJ ET BT 26.250 145.082 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 145.082 Td /F1 9.8 Tf [(Knudsen B, Simko JP, Lam LL, et al. Transcriptome-wide analysis of matched biopsy and prostatectomy to measure )] TJ ET BT 26.250 133.177 Td /F1 9.8 Tf [(genomic classifiers of prostate cancer progression and field effect. J Clin Oncol. 2014;32\(suppl 4\).)] TJ ET BT 26.250 113.772 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 113.772 Td /F1 9.8 Tf [(Abdueva D, Wing M, Schaub B, Triche T, Davicioni E. Quantitative expression profiling in formalin-fixed paraffin-embedded )] TJ ET BT 26.250 101.868 Td /F1 9.8 Tf [(samples by affymetrix microarrays. J Mol Diagn. 2010 Jul;12\(4\):409-17. PubMed PMID:20522636.)] TJ ET BT 26.250 82.463 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 82.463 Td /F1 9.8 Tf [(Erho N, Buerki C, Triche TJ, Davicioni E, Vergara IA. Transcriptome-wide detection of differentially expressed coding and )] TJ ET BT 26.250 70.558 Td /F1 9.8 Tf [(non-coding transcripts and their clinical significance in prostate cancer. J Oncol. 2012;2012:541353. PubMed PMID:22956952.)] TJ ET BT 26.250 51.153 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 51.153 Td /F1 9.8 Tf [(Cooperberg MR, Davicioni E, Crisan A, Jenkins RB, Ghadessi M, Karnes RJ. Combined value of validated clinical and )] TJ ET Q q 15.000 36.868 577.500 740.132 re W n 0.965 0.965 0.965 rg 26.250 744.514 555.000 32.486 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 744.514 m 581.250 744.514 l 581.250 745.264 l 26.250 745.264 l f q 35.250 755.764 537.000 21.236 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F1 9.8 Tf [(Table 3: Change in treatment recommendation in high-risk prostate cancer based on knowledge of the genomic classifier)] TJ ET Q BT 26.250 710.292 Td /F4 12.0 Tf [(Conclusions)] TJ ET BT 26.250 690.338 Td /F1 9.8 Tf [(The recently introduced genomic classifier was developed to identify men with increased risk for metastatic prostate cancer )] TJ ET BT 26.250 678.433 Td /F1 9.8 Tf [(following radical prostatectomy. The genomic classifier was shown to have good discrimination in detecting men at risk for )] TJ ET BT 26.250 666.528 Td /F1 9.8 Tf [(metastatic prostate cancer five years after surgery \(AUC 0.75 to 0.90\). However, these estimates may be biased given )] TJ ET BT 26.250 654.624 Td /F1 9.8 Tf [(differences in important prognostic characteristics between cases and controls. Independent validation in patients with high-risk )] TJ ET BT 26.250 642.719 Td /F1 9.8 Tf [(prostate cancer may provide more reliable estimates of the prognostic ability of the genomic classifier. At this time it is unclear )] TJ ET BT 26.250 630.814 Td /F1 9.8 Tf [(what the most appropriate clinical actions are based on test results. No studies yet published have reported the ability of the )] TJ ET BT 26.250 618.909 Td /F1 9.8 Tf [(genomic classifier to predict significant clinical outcomes from any of the available adjuvant therapies. In order to demonstrate )] TJ ET BT 26.250 607.005 Td /F1 9.8 Tf [(clinical utility additional evidence is needed showing improved outcomes \(clinical metastasis or prostate cancer-specific )] TJ ET BT 26.250 595.100 Td /F1 9.8 Tf [(mortality\) in men whose post-operative treatment was guided by the genomic classifier compared to standard practice.)] TJ ET BT 26.250 558.497 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 538.543 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist. The findings and conclusions are those of authors, including NIH )] TJ ET BT 26.250 526.638 Td /F1 9.8 Tf [(co-authors, and do not necessarily represent the views of the National Institutes of Health \(NIH\). The information provided in )] TJ ET BT 26.250 514.734 Td /F1 9.8 Tf [(this manuscript does not constitute an endorsement of any of the commercially available tests described in this report by NIH )] TJ ET BT 26.250 502.829 Td /F1 9.8 Tf [(nor the Department of Health and Human Services of the U.S. government.)] TJ ET BT 26.250 466.226 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 438.772 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 438.772 Td /F1 9.8 Tf [(Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham JA, Yossepowitch O, Rabah )] TJ ET BT 26.250 426.867 Td /F1 9.8 Tf [(DM, Kattan MW, Yu C, Klein EA, Stephenson AJ. Predicting 15-year prostate cancer specific mortality after radical )] TJ ET BT 26.250 414.963 Td /F1 9.8 Tf [(prostatectomy. J Urol. 2011 Mar;185\(3\):869-75. PubMed PMID:21239008.)] TJ ET BT 26.250 395.558 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 395.558 Td /F1 9.8 Tf [(Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA )] TJ ET BT 26.250 383.653 Td /F1 9.8 Tf [(elevation following radical prostatectomy. JAMA. 1999 May 5;281\(17\):1591-7. PubMed PMID:10235151.)] TJ ET BT 26.250 364.248 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 364.248 Td /F1 9.8 Tf [(Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW. Risk of prostate cancer-specific )] TJ ET BT 26.250 352.344 Td /F1 9.8 Tf [(mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005 Jul 27;294\(4\):433-9. PubMed )] TJ ET BT 26.250 340.439 Td /F1 9.8 Tf [(PMID:16046649.)] TJ ET BT 26.250 321.034 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 321.034 Td /F1 9.8 Tf [(NCCN Guidelines for patients - prostate cancer.1.2014.)] TJ ET BT 26.250 301.629 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 301.629 Td /F1 9.8 Tf [(Nielsen ME, Trock BJ, Walsh PC. Salvage or adjuvant radiation therapy: counseling patients on the benefits. J Natl Compr )] TJ ET BT 26.250 289.725 Td /F1 9.8 Tf [(Canc Netw. 2010 Feb;8\(2\):228-37. PubMed PMID:20141679.)] TJ ET BT 26.250 270.320 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 270.320 Td /F1 9.8 Tf [(Decipher prostate cancer classifier. https://deciphertest.com/. Accessed July, 2015)] TJ ET BT 26.250 250.915 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 250.915 Td /F1 9.8 Tf [(Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64\(1\):9-29. PubMed )] TJ ET BT 26.250 239.010 Td /F1 9.8 Tf [(PMID:24399786.)] TJ ET BT 26.250 219.606 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 219.606 Td /F1 9.8 Tf [(GenomeDx Biosciences. https://genomedx.com/. Accessed July, 2015.)] TJ ET BT 26.250 200.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 200.201 Td /F1 9.8 Tf [(Centers for Medicare & Medicaid Services. MolDX: Decpiher Prostate Cancer Classifier Assay. Local coverage document )] TJ ET BT 26.250 188.296 Td /F1 9.8 Tf [(\(L35650\). Medicare Coverage Database \(https://www.cms.gov/medicare-coverage-database/overview-and-quick-)] TJ ET BT 26.250 176.391 Td /F1 9.8 Tf [(search.aspx?CoverageSelection=Local&ArticleType=All&PolicyType=Final&s=All&KeyWord=decipher&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAAAAAAAAAAA%3d%3d&=&\). )] TJ ET BT 26.250 164.487 Td /F1 9.8 Tf [(Accessed August 2015)] TJ ET BT 26.250 145.082 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 145.082 Td /F1 9.8 Tf [(Knudsen B, Simko JP, Lam LL, et al. Transcriptome-wide analysis of matched biopsy and prostatectomy to measure )] TJ ET BT 26.250 133.177 Td /F1 9.8 Tf [(genomic classifiers of prostate cancer progression and field effect. J Clin Oncol. 2014;32\(suppl 4\).)] TJ ET BT 26.250 113.772 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 113.772 Td /F1 9.8 Tf [(Abdueva D, Wing M, Schaub B, Triche T, Davicioni E. Quantitative expression profiling in formalin-fixed paraffin-embedded )] TJ ET BT 26.250 101.868 Td /F1 9.8 Tf [(samples by affymetrix microarrays. J Mol Diagn. 2010 Jul;12\(4\):409-17. PubMed PMID:20522636.)] TJ ET BT 26.250 82.463 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 82.463 Td /F1 9.8 Tf [(Erho N, Buerki C, Triche TJ, Davicioni E, Vergara IA. Transcriptome-wide detection of differentially expressed coding and )] TJ ET BT 26.250 70.558 Td /F1 9.8 Tf [(non-coding transcripts and their clinical significance in prostate cancer. J Oncol. 2012;2012:541353. PubMed PMID:22956952.)] TJ ET BT 26.250 51.153 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 51.153 Td /F1 9.8 Tf [(Cooperberg MR, Davicioni E, Crisan A, Jenkins RB, Ghadessi M, Karnes RJ. Combined value of validated clinical and )] TJ ET Q q 0.000 0.000 0.000 rg 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 Q endstream endobj 379 0 obj << /Type /Page /Parent 3 0 R /Contents 380 0 R >> endobj 380 0 obj << /Length 22880 >> stream 0.271 0.267 0.267 rg q 15.000 73.667 577.500 703.333 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. Eur Urol. 2015 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Feb;67\(2\):326-33. PubMed PMID:24998118.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Den RB, Feng FY, Showalter TN, Mishra MV, Trabulsi EJ, Lallas CD, Gomella LG, Kelly WK, Birbe RC, McCue PA, )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Ghadessi M, Yousefi K, Davicioni E, Knudsen KE, Dicker AP. Genomic prostate cancer classifier predicts biochemical failure )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89\(5\):1038-46. )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(PubMed PMID:25035207.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 681.048 Td /F1 9.8 Tf [(Den RB, Yousefi K, Trabulsi EJ, Abdollah F, Choeurng V, Feng FY, Dicker AP, Lallas CD, Gomella LG, Davicioni E, Karnes )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(RJ. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(therapy. J Clin Oncol. 2015 Mar 10;33\(8\):944-51. PubMed PMID:25667284.)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 637.833 Td /F1 9.8 Tf [(Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, Bergstralh EJ, Kollmeyer T, Fink S, Haddad Z, Zimmermann )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(B, Sierocinski T, Ballman KV, Triche TJ, Black PC, Karnes RJ, Klee G, Davicioni E, Jenkins RB. Discovery and validation of a )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013;8\(6\):e66855. )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(PubMed PMID:23826159.)] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 582.714 Td /F1 9.8 Tf [(Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, Crisan A, Erho N, Vergara IA, Lam LL, Carlson R, )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Thompson DJ, Haddad Z, Zimmermann B, Sierocinski T, Triche TJ, Kollmeyer T, Ballman KV, Black PC, Klee GG, Jenkins RB. )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(2013 Dec;190\(6\):2047-53. PubMed PMID:23770138.)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 527.595 Td /F1 9.8 Tf [(Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ, Li J, Kattan MW, Magi-Galluzzi C, Davicioni E. A )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(cancer patients managed by radical prostatectomy without adjuvant therapy. Eur Urol. 2015 Apr;67\(4\):778-86. PubMed )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(PMID:25466945.)] TJ ET BT 26.250 472.476 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 472.476 Td /F1 9.8 Tf [(Ross AE, Feng FY, Ghadessi M, Erho N, Crisan A, Buerki C, Sundi D, Mitra AP, Vergara IA, Thompson DJ, Triche TJ, )] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Davicioni E, Bergstralh EJ, Jenkins RB, Karnes RJ, Schaeffer EM. A genomic classifier predicting metastatic disease )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(progression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic Dis. 2014 Mar;17\(1\):64-9. )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(PubMed PMID:24145624.)] TJ ET BT 26.250 417.357 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 417.357 Td /F1 9.8 Tf [(Ross AE, Johnson MH, Yousefi K, Davicioni E, Netto GJ, Marchionni L, Fedor HL, Glavaris S, Choeurng V, Buerki C, Erho )] TJ ET BT 26.250 405.453 Td /F1 9.8 Tf [(N, Lam LL, Humphreys EB, Faraj S, Bezerra SM, Han M, Partin AW, Trock BJ, Schaeffer EM. Tissue-based Genomics )] TJ ET BT 26.250 393.548 Td /F1 9.8 Tf [(Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men. Eur Urol. 2015 )] TJ ET BT 26.250 381.643 Td /F1 9.8 Tf [(Jun 6. PubMed PMID:26058959.)] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 362.238 Td /F1 9.8 Tf [(Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC. Biochemical \(prostate specific antigen\) recurrence )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(probability following radical prostatectomy for clinically localized prostate cancer. J Urol. 2003 Feb;169\(2\):517-23. PubMed )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(PMID:12544300.)] TJ ET BT 26.250 319.024 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 319.024 Td /F1 9.8 Tf [(Alshalalfa M, Vergara IA, Erho N, Davicioni E, Jenkins RB, Kollmeyer T. Evaluation of a genomic classifier \(Decipher\) in )] TJ ET BT 26.250 307.119 Td /F1 9.8 Tf [(subsets of primary tumors with common prostate cancer genomic alterations. AACR Annual Meeting; April 5-9, 2014; San )] TJ ET BT 26.250 295.215 Td /F1 9.8 Tf [(Diego, CA)] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 275.810 Td /F1 9.8 Tf [(Badani K, Thompson DJ, Buerki C, Davicioni E, Garrison J, Ghadessi M, Mitra AP, Wood PJ, Hornberger J. Impact of a )] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(genomic classifier of metastatic risk on postoperative treatment recommendations for prostate cancer patients: a report from the )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(DECIDE study group. Oncotarget. 2013 Apr;4\(4\):600-9. PubMed PMID:23592338.)] TJ ET BT 26.250 232.596 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 232.596 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Brown G, Holmes D, Kella N, Albala D, Singh A, Buerki C, Davicioni E, Hornberger J. Effect of a )] TJ ET BT 26.250 220.691 Td /F1 9.8 Tf [(genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int. 2015 )] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(Mar;115\(3\):419-29. PubMed PMID:24784420.)] TJ ET BT 26.250 189.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 189.381 Td /F1 9.8 Tf [(Michalopoulos SN, Kella N, Payne R, Yohannes P, Singh A, Hettinger C, Yousefi K, Hornberger J. Influence of a genomic )] TJ ET BT 26.250 177.477 Td /F1 9.8 Tf [(classifier on post-operative treatment decisions in high-risk prostate cancer patients: results from the PRO-ACT study. Curr Med )] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Res Opin. 2014 Aug;30\(8\):1547-56. PubMed PMID:24803160.)] TJ ET BT 26.250 146.167 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 146.167 Td /F1 9.8 Tf [(Nguyen PL, Shin H, Yousefi K, Thompson DJ, Hornberger J, Hyatt AS, Badani KK, Morgan TM, Feng FY. Impact of a )] TJ ET BT 26.250 134.262 Td /F1 9.8 Tf [(Genomic Classifier of Metastatic Risk on Postprostatectomy Treatment Recommendations by Radiation Oncologists and )] TJ ET BT 26.250 122.358 Td /F1 9.8 Tf [(Urologists. Urology. 2015 Jul;86\(1\):35-40. PubMed PMID:26142578.)] TJ ET BT 26.250 102.953 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 102.953 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Buerki C, Singh A. Effect of a genomic classifier on adjuvant radiation recommendations after )] TJ ET BT 26.250 91.048 Td /F1 9.8 Tf [(prostate cancer surgery. J Clin Oncol. 2014;32\(suppl 4\).)] TJ ET Q q 15.000 73.667 577.500 703.333 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. Eur Urol. 2015 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Feb;67\(2\):326-33. PubMed PMID:24998118.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Den RB, Feng FY, Showalter TN, Mishra MV, Trabulsi EJ, Lallas CD, Gomella LG, Kelly WK, Birbe RC, McCue PA, )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Ghadessi M, Yousefi K, Davicioni E, Knudsen KE, Dicker AP. Genomic prostate cancer classifier predicts biochemical failure )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89\(5\):1038-46. )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(PubMed PMID:25035207.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 681.048 Td /F1 9.8 Tf [(Den RB, Yousefi K, Trabulsi EJ, Abdollah F, Choeurng V, Feng FY, Dicker AP, Lallas CD, Gomella LG, Davicioni E, Karnes )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(RJ. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(therapy. J Clin Oncol. 2015 Mar 10;33\(8\):944-51. PubMed PMID:25667284.)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 637.833 Td /F1 9.8 Tf [(Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, Bergstralh EJ, Kollmeyer T, Fink S, Haddad Z, Zimmermann )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(B, Sierocinski T, Ballman KV, Triche TJ, Black PC, Karnes RJ, Klee G, Davicioni E, Jenkins RB. Discovery and validation of a )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013;8\(6\):e66855. )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(PubMed PMID:23826159.)] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 582.714 Td /F1 9.8 Tf [(Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, Crisan A, Erho N, Vergara IA, Lam LL, Carlson R, )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Thompson DJ, Haddad Z, Zimmermann B, Sierocinski T, Triche TJ, Kollmeyer T, Ballman KV, Black PC, Klee GG, Jenkins RB. )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(2013 Dec;190\(6\):2047-53. PubMed PMID:23770138.)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 527.595 Td /F1 9.8 Tf [(Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ, Li J, Kattan MW, Magi-Galluzzi C, Davicioni E. A )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(cancer patients managed by radical prostatectomy without adjuvant therapy. Eur Urol. 2015 Apr;67\(4\):778-86. PubMed )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(PMID:25466945.)] TJ ET BT 26.250 472.476 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 472.476 Td /F1 9.8 Tf [(Ross AE, Feng FY, Ghadessi M, Erho N, Crisan A, Buerki C, Sundi D, Mitra AP, Vergara IA, Thompson DJ, Triche TJ, )] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Davicioni E, Bergstralh EJ, Jenkins RB, Karnes RJ, Schaeffer EM. A genomic classifier predicting metastatic disease )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(progression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic Dis. 2014 Mar;17\(1\):64-9. )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(PubMed PMID:24145624.)] TJ ET BT 26.250 417.357 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 417.357 Td /F1 9.8 Tf [(Ross AE, Johnson MH, Yousefi K, Davicioni E, Netto GJ, Marchionni L, Fedor HL, Glavaris S, Choeurng V, Buerki C, Erho )] TJ ET BT 26.250 405.453 Td /F1 9.8 Tf [(N, Lam LL, Humphreys EB, Faraj S, Bezerra SM, Han M, Partin AW, Trock BJ, Schaeffer EM. Tissue-based Genomics )] TJ ET BT 26.250 393.548 Td /F1 9.8 Tf [(Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men. Eur Urol. 2015 )] TJ ET BT 26.250 381.643 Td /F1 9.8 Tf [(Jun 6. PubMed PMID:26058959.)] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 362.238 Td /F1 9.8 Tf [(Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC. Biochemical \(prostate specific antigen\) recurrence )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(probability following radical prostatectomy for clinically localized prostate cancer. J Urol. 2003 Feb;169\(2\):517-23. PubMed )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(PMID:12544300.)] TJ ET BT 26.250 319.024 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 319.024 Td /F1 9.8 Tf [(Alshalalfa M, Vergara IA, Erho N, Davicioni E, Jenkins RB, Kollmeyer T. Evaluation of a genomic classifier \(Decipher\) in )] TJ ET BT 26.250 307.119 Td /F1 9.8 Tf [(subsets of primary tumors with common prostate cancer genomic alterations. AACR Annual Meeting; April 5-9, 2014; San )] TJ ET BT 26.250 295.215 Td /F1 9.8 Tf [(Diego, CA)] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 275.810 Td /F1 9.8 Tf [(Badani K, Thompson DJ, Buerki C, Davicioni E, Garrison J, Ghadessi M, Mitra AP, Wood PJ, Hornberger J. Impact of a )] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(genomic classifier of metastatic risk on postoperative treatment recommendations for prostate cancer patients: a report from the )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(DECIDE study group. Oncotarget. 2013 Apr;4\(4\):600-9. PubMed PMID:23592338.)] TJ ET BT 26.250 232.596 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 232.596 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Brown G, Holmes D, Kella N, Albala D, Singh A, Buerki C, Davicioni E, Hornberger J. Effect of a )] TJ ET BT 26.250 220.691 Td /F1 9.8 Tf [(genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int. 2015 )] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(Mar;115\(3\):419-29. PubMed PMID:24784420.)] TJ ET BT 26.250 189.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 189.381 Td /F1 9.8 Tf [(Michalopoulos SN, Kella N, Payne R, Yohannes P, Singh A, Hettinger C, Yousefi K, Hornberger J. Influence of a genomic )] TJ ET BT 26.250 177.477 Td /F1 9.8 Tf [(classifier on post-operative treatment decisions in high-risk prostate cancer patients: results from the PRO-ACT study. Curr Med )] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Res Opin. 2014 Aug;30\(8\):1547-56. PubMed PMID:24803160.)] TJ ET BT 26.250 146.167 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 146.167 Td /F1 9.8 Tf [(Nguyen PL, Shin H, Yousefi K, Thompson DJ, Hornberger J, Hyatt AS, Badani KK, Morgan TM, Feng FY. Impact of a )] TJ ET BT 26.250 134.262 Td /F1 9.8 Tf [(Genomic Classifier of Metastatic Risk on Postprostatectomy Treatment Recommendations by Radiation Oncologists and )] TJ ET BT 26.250 122.358 Td /F1 9.8 Tf [(Urologists. Urology. 2015 Jul;86\(1\):35-40. PubMed PMID:26142578.)] TJ ET BT 26.250 102.953 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 102.953 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Buerki C, Singh A. Effect of a genomic classifier on adjuvant radiation recommendations after )] TJ ET BT 26.250 91.048 Td /F1 9.8 Tf [(prostate cancer surgery. J Clin Oncol. 2014;32\(suppl 4\).)] TJ ET Q q 15.000 73.667 577.500 703.333 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. Eur Urol. 2015 )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Feb;67\(2\):326-33. PubMed PMID:24998118.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Den RB, Feng FY, Showalter TN, Mishra MV, Trabulsi EJ, Lallas CD, Gomella LG, Kelly WK, Birbe RC, McCue PA, )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Ghadessi M, Yousefi K, Davicioni E, Knudsen KE, Dicker AP. Genomic prostate cancer classifier predicts biochemical failure )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89\(5\):1038-46. )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(PubMed PMID:25035207.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 681.048 Td /F1 9.8 Tf [(Den RB, Yousefi K, Trabulsi EJ, Abdollah F, Choeurng V, Feng FY, Dicker AP, Lallas CD, Gomella LG, Davicioni E, Karnes )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(RJ. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(therapy. J Clin Oncol. 2015 Mar 10;33\(8\):944-51. PubMed PMID:25667284.)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 637.833 Td /F1 9.8 Tf [(Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, Bergstralh EJ, Kollmeyer T, Fink S, Haddad Z, Zimmermann )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(B, Sierocinski T, Ballman KV, Triche TJ, Black PC, Karnes RJ, Klee G, Davicioni E, Jenkins RB. Discovery and validation of a )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013;8\(6\):e66855. )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(PubMed PMID:23826159.)] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 582.714 Td /F1 9.8 Tf [(Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, Crisan A, Erho N, Vergara IA, Lam LL, Carlson R, )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Thompson DJ, Haddad Z, Zimmermann B, Sierocinski T, Triche TJ, Kollmeyer T, Ballman KV, Black PC, Klee GG, Jenkins RB. )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(2013 Dec;190\(6\):2047-53. PubMed PMID:23770138.)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 527.595 Td /F1 9.8 Tf [(Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ, Li J, Kattan MW, Magi-Galluzzi C, Davicioni E. A )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(cancer patients managed by radical prostatectomy without adjuvant therapy. Eur Urol. 2015 Apr;67\(4\):778-86. PubMed )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(PMID:25466945.)] TJ ET BT 26.250 472.476 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 472.476 Td /F1 9.8 Tf [(Ross AE, Feng FY, Ghadessi M, Erho N, Crisan A, Buerki C, Sundi D, Mitra AP, Vergara IA, Thompson DJ, Triche TJ, )] TJ ET BT 26.250 460.572 Td /F1 9.8 Tf [(Davicioni E, Bergstralh EJ, Jenkins RB, Karnes RJ, Schaeffer EM. A genomic classifier predicting metastatic disease )] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(progression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic Dis. 2014 Mar;17\(1\):64-9. )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(PubMed PMID:24145624.)] TJ ET BT 26.250 417.357 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 417.357 Td /F1 9.8 Tf [(Ross AE, Johnson MH, Yousefi K, Davicioni E, Netto GJ, Marchionni L, Fedor HL, Glavaris S, Choeurng V, Buerki C, Erho )] TJ ET BT 26.250 405.453 Td /F1 9.8 Tf [(N, Lam LL, Humphreys EB, Faraj S, Bezerra SM, Han M, Partin AW, Trock BJ, Schaeffer EM. Tissue-based Genomics )] TJ ET BT 26.250 393.548 Td /F1 9.8 Tf [(Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men. Eur Urol. 2015 )] TJ ET BT 26.250 381.643 Td /F1 9.8 Tf [(Jun 6. PubMed PMID:26058959.)] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 362.238 Td /F1 9.8 Tf [(Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC. Biochemical \(prostate specific antigen\) recurrence )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(probability following radical prostatectomy for clinically localized prostate cancer. J Urol. 2003 Feb;169\(2\):517-23. PubMed )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(PMID:12544300.)] TJ ET BT 26.250 319.024 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 319.024 Td /F1 9.8 Tf [(Alshalalfa M, Vergara IA, Erho N, Davicioni E, Jenkins RB, Kollmeyer T. Evaluation of a genomic classifier \(Decipher\) in )] TJ ET BT 26.250 307.119 Td /F1 9.8 Tf [(subsets of primary tumors with common prostate cancer genomic alterations. AACR Annual Meeting; April 5-9, 2014; San )] TJ ET BT 26.250 295.215 Td /F1 9.8 Tf [(Diego, CA)] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 275.810 Td /F1 9.8 Tf [(Badani K, Thompson DJ, Buerki C, Davicioni E, Garrison J, Ghadessi M, Mitra AP, Wood PJ, Hornberger J. Impact of a )] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(genomic classifier of metastatic risk on postoperative treatment recommendations for prostate cancer patients: a report from the )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(DECIDE study group. Oncotarget. 2013 Apr;4\(4\):600-9. PubMed PMID:23592338.)] TJ ET BT 26.250 232.596 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 232.596 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Brown G, Holmes D, Kella N, Albala D, Singh A, Buerki C, Davicioni E, Hornberger J. Effect of a )] TJ ET BT 26.250 220.691 Td /F1 9.8 Tf [(genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int. 2015 )] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(Mar;115\(3\):419-29. PubMed PMID:24784420.)] TJ ET BT 26.250 189.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 189.381 Td /F1 9.8 Tf [(Michalopoulos SN, Kella N, Payne R, Yohannes P, Singh A, Hettinger C, Yousefi K, Hornberger J. Influence of a genomic )] TJ ET BT 26.250 177.477 Td /F1 9.8 Tf [(classifier on post-operative treatment decisions in high-risk prostate cancer patients: results from the PRO-ACT study. Curr Med )] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Res Opin. 2014 Aug;30\(8\):1547-56. PubMed PMID:24803160.)] TJ ET BT 26.250 146.167 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 146.167 Td /F1 9.8 Tf [(Nguyen PL, Shin H, Yousefi K, Thompson DJ, Hornberger J, Hyatt AS, Badani KK, Morgan TM, Feng FY. Impact of a )] TJ ET BT 26.250 134.262 Td /F1 9.8 Tf [(Genomic Classifier of Metastatic Risk on Postprostatectomy Treatment Recommendations by Radiation Oncologists and )] TJ ET BT 26.250 122.358 Td /F1 9.8 Tf [(Urologists. Urology. 2015 Jul;86\(1\):35-40. PubMed PMID:26142578.)] TJ ET BT 26.250 102.953 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 102.953 Td /F1 9.8 Tf [(Badani KK, Thompson DJ, Buerki C, Singh A. Effect of a genomic classifier on adjuvant radiation recommendations after )] TJ ET BT 26.250 91.048 Td /F1 9.8 Tf [(prostate cancer surgery. 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