TY - JOUR
T1 - Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer
T2 - a matched, retrospective analysis
AU - Zhao, Shuang G.
AU - Chang, S. Laura
AU - Spratt, Daniel E.
AU - Erho, Nicholas
AU - Yu, Menggang
AU - Ashab, Hussam Al Deen
AU - Alshalalfa, Mohammed
AU - Speers, Corey
AU - Tomlins, Scott A.
AU - Davicioni, Elai
AU - Dicker, Adam P.
AU - Carroll, Peter R.
AU - Cooperberg, Matthew R.
AU - Freedland, Stephen J.
AU - Karnes, R. Jeffrey
AU - Ross, Ashley E.
AU - Schaeffer, Edward M.
AU - Den, Robert B.
AU - Nguyen, Paul L.
AU - Feng, Felix Y.
N1 - Funding Information:
SGZ reports grants from Prostate Cancer Foundation and travel expenses from GenomeDx Biosciences, outside the submitted work; and has a patent PORTOS provisional filing United States Patent and Trademark Office (USPTO) pending. SLC reports employment at PFS Genomics, outside the submitted work; and has a patent PORTOS provisional filing USPTO pending. DES reports grants from Prostate Cancer Foundation, during the conduct of the study. NE reports employment at GenomeDx Biosciences, during the conduct of the study. HA-DA reports employment at GenomeDx Biosciences, during the conduct of the study. MA reports employment at GenomeDx Biosciences, during the conduct of the study. SAT reports personal fees from Ventana Medical Systems, Janssen, and Abbvie; grants and personal fees from Medivation and Astellas; travel support from Thermo Fisher; grants from GenomeDx; personal fees and equity in Strata Oncology; and has a patent on ETS gene fusions in prostate cancer with royalties paid to the University of Michigan from Hologic and Ventana Medical Systems, outside of the submitted work. SAT is included in the royalties distribution stream from the University of Michigan. ED reports employment at GenomeDx Biosciences, during the conduct of the study; and has a patent PORTOS provisional filing USPTO pending. MRC reports grants and personal fees from Myriad Genetics; grants from Genomic Health and GenomeDx Biosciences; and personal fees from Dendreon, Astellas, Bayer, and Janssen, outside the submitted work. SJF reports grants and personal fees from GenomeDx, during the conduct of the study. RJK reports grants and royalties from GenomeDx Biosciences, outside the submitted work. AER reports grants and personal fees from GenomeDx Biosciences, during the conduct of the study. EMS reports consulting for GenomeDx Biosciences, outside the submitted work. RBD reports grants from GenomeDx Biosciences, during the conduct of the study. PLN reports personal fees from Medivation, Ferring, and GenomeDx Biosciences, outside the submitted work. FYF reports non-financial support from GenomeDx Biosciences, during the conduct of the study; grants from Varian, personal fees from Medivation and Astellas; grants and personal fees from Celgene, outside the submitted work; has a patent PORTOS provisional filing USPTO pending; and is a founder and serves as president for PFS Genomics. MY, CS, APD, and PRC declare no competing interests.
Funding Information:
GenomeDx provided access to data from samples. The authors were funded by the Prostate Cancer Foundation, the Evans Foundation, the V Foundation for Cancer Research, the A Alfred Taubman Medical Research Institute at the University of Michigan, GenomeDx Biosciences, and a Patient-Centered Outcomes Research Institute (PCORI) Award (ME-1409–21219). The views in this publication are solely the responsibility of the authors and do not necessarily represent the views of the PCORI, its Board of Governors or Methodology Committee. We thank Steven Kronenberg for assistance with figure preparation.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Background Postoperative radiotherapy has an important role in the treatment of prostate cancer, but personalised patient selection could improve outcomes and spare unnecessary toxicity. We aimed to develop and validate a gene expression signature to predict which patients would benefit most from postoperative radiotherapy. Methods Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate adenocarcinoma who had radical prostatectomy (with or without postoperative radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician's discretion. In each cohort, patients who had postoperative radiotherapy were matched with patients who had not had radiotherapy using Gleason score, prostate-specific antigen concentration, surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, and androgen deprivation therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant metastasis. Findings In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had radiotherapy had a lower incidence of distant metastasis than did patients who did not have radiotherapy, with a 10-year metastasis rate of 5% (95% CI 0–14) in patients who had radiotherapy (n=20) and 63% (34–80) in patients who did not have radiotherapy (n=19; hazard ratio [HR] 0·12 [95% CI 0·03–0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative radiotherapy (n=78) had a greater incidence of distant metastasis at 10 years than did their untreated counterparts (n=79; 57% [44–67] vs 31% [20–41]; HR 2·5 [1·6–4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had radiotherapy had a lower incidence of distant metastasis compared with those who did not have radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0–10] in the radiotherapy group [n=57] vs 35% [95% CI 7–54] in the no radiotherapy group [n=25] had metastasis at 10 years; HR 0·15 [95% CI 0·04–0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19–43] in the radiotherapy group [n=108] vs 32% [95% CI 22–40] in the no radiotherapy group [n=140]; HR 0·92 [95% CI 0·56–1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to radiotherapy (pinteraction>0·05 for all). Interpretation Patients with a high PORTOS who had postoperative radiotherapy were less likely to have metastasis at 10 years than those who did not have radiotherapy, suggesting that treatment with postoperative radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts. Funding None.
AB - Background Postoperative radiotherapy has an important role in the treatment of prostate cancer, but personalised patient selection could improve outcomes and spare unnecessary toxicity. We aimed to develop and validate a gene expression signature to predict which patients would benefit most from postoperative radiotherapy. Methods Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate adenocarcinoma who had radical prostatectomy (with or without postoperative radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician's discretion. In each cohort, patients who had postoperative radiotherapy were matched with patients who had not had radiotherapy using Gleason score, prostate-specific antigen concentration, surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, and androgen deprivation therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant metastasis. Findings In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had radiotherapy had a lower incidence of distant metastasis than did patients who did not have radiotherapy, with a 10-year metastasis rate of 5% (95% CI 0–14) in patients who had radiotherapy (n=20) and 63% (34–80) in patients who did not have radiotherapy (n=19; hazard ratio [HR] 0·12 [95% CI 0·03–0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative radiotherapy (n=78) had a greater incidence of distant metastasis at 10 years than did their untreated counterparts (n=79; 57% [44–67] vs 31% [20–41]; HR 2·5 [1·6–4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had radiotherapy had a lower incidence of distant metastasis compared with those who did not have radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0–10] in the radiotherapy group [n=57] vs 35% [95% CI 7–54] in the no radiotherapy group [n=25] had metastasis at 10 years; HR 0·15 [95% CI 0·04–0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19–43] in the radiotherapy group [n=108] vs 32% [95% CI 22–40] in the no radiotherapy group [n=140]; HR 0·92 [95% CI 0·56–1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to radiotherapy (pinteraction>0·05 for all). Interpretation Patients with a high PORTOS who had postoperative radiotherapy were less likely to have metastasis at 10 years than those who did not have radiotherapy, suggesting that treatment with postoperative radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts. Funding None.
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U2 - 10.1016/S1470-2045(16)30491-0
DO - 10.1016/S1470-2045(16)30491-0
M3 - Article
C2 - 27743920
AN - SCOPUS:84995560647
VL - 17
SP - 1612
EP - 1620
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 11
ER -