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Meta-Analysis
. 2023 Jul 1;116(3):521-529.
doi: 10.1016/j.ijrobp.2022.12.035. Epub 2022 Dec 31.

Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials

Paul L Nguyen  1 , Huei-Chung Rebecca Huang  2 , Daniel E Spratt  3 , Elai Davicioni  4 , Howard M Sandler  5 , William U Shipley  6 , Jason A Efstathiou  6 , Jeffry P Simko  7 , Alan Pollack  8 , Adam P Dicker  9 , Mack Roach  7 , Seth A Rosenthal  10 , Kenneth L Zeitzer  11 , Lucas C Mendez  12 , Alan C Hartford  13 , William A Hall  14 , Anand B Desai  15 , Rachel A Rabinovitch  16 , Christopher A Peters  17 , Joseph P Rodgers  18 , Phuoc Tran  19 , Felix Y Feng  20
Affiliations
Meta-Analysis

Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials

Paul L Nguyen et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 high-risk definitive radiation therapy trials.

Methods and materials: A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer-specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses.

Results: GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio [sHR], 1.29; 95% confidence interval [CI], 1.18-1.41; P < .001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P < .001), and OS (hazard ratio [HR], 1.16; 95% CI, 1.08-1.22; P < .001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk.

Conclusions: This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making.

Trial registration: ClinicalTrials.gov NCT00767286 NCT00769548 NCT00004054.

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Conflict of interest statement

Drs Desai, Peters, Rabinovitch, Roach, Rodgers, Rosenthal Shipley and Zeitzer have nothing to declare. Dr Mendez-declares Payments directed to the institution to run clinical trials in prostate and gynecologic malignancies ACURA-CARO, Ride for Dad and AMOSO. Dr. Sandler declares Member, clinical trial steering committee at Janssen, Member, Board of Directors at ASTRO. Low value stock from inactive medical advisory board Radiogel. Dr. Hall declares Institutional Research, Meeting and Travel support from Elekta. Dr. Tran declares Grants or contracts from Astellas, Bayer and RefleXion Medical, Patent 9114158- Compounds and Methods of Use in Ablative Radiotherapy licensed to Natsar Pharm, Consulting fees from Noxopharm, Janssen-Taris Biomedical, Myovant and AstraZeneca, Support for attending meetings and/or travel RefleXion Medical, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for NRG GU Translational Science Chair, ASTRO and RSNA. Dr. Davicioni declares Stock or stock options and Employee (formerly Decipher Biosciences, manufacturers of Decipher GC test) Veracyte, Inc. Dr. Dicker declares Grants or contracts from NCI, ASCO and NRG Oncology, Consulting fees from Janssen, Oncohost, Oranomed and CVS, Application No.PCT/US19/37487, Title: Doped BEO compounds for optically stimulated luminescence (OSL) and thermoluminescence (TL) radiation dosimetry, Stock or stock options Oncohost. Dr. Hartford member of the committee NRG Oncology Genitourinary Cancer Committee. Dr. Huang is Employed by Decipher, Veracyte. Stock or stock options Owned equity of Decipher, Veracyte. Dr. Efstathiou declares Consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech and Participation on a Data Safety Monitoring Board or Advisory Board for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare. Dr. Feng declares in the past 36 months, I have consulted for: Janssen, Bayer, PFS Genomics (this termed in April 2021 since the company has been acquired), Myovant Sciences, Roivant, Astellas, Foundation Medicine, Varian, Bristol Meyers Squibb, Exact Sciences, BlueStar Genomics, Novartis, and Tempus. I have also received stock options from SerImmune from serving on their scientific advisory board in 2020. This was a one-time advisory board meeting. I am a co-founder and advisor of Artera, a company focused on digital pathology biomarkers in prostate cancer. I am Chair of the Genitourinary Cancer Committee for NRG Oncology. My role is to help investigators design proposals for clinical trials, that are then evaluated by the NCI for funding. All funding decisions are made by the NCI – not by NRG or by myself. Dr. Nguyen funding NIH R01CA240582, Institutional Grants with Janssen, Bayer, Astellas, Consulting fees Janssen, Boston Scientific, Blue Earth, Astellas, Bayer, Cota, Myovant. Dr. Spratt declares Consulting fees from Boston Scientific, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bayer, Blue Earth, GammaTile, Janssen, Novartis, Varian. Dr. Pollack declares Grants P30CA240139 from the National Cancer Institute, and a University of Miami Sylvester Comprehensive Cancer Center Professorship (AP). Past co-Chair of the RTOG/NRG GU Translational Research Program. Dr. Simko declares GenomeDX, Inc. paid fees to my institution (UCSF) to complete this work. Grant to my institution from NCI.

Figures

Figure 1
Figure 1
CONSORT diagram of NRG GU-TS006.
Figure 2
Figure 2
Box plots of the continuous GC score distribution with A) the final QC pass cohort (n=265), B) within each of the three phase III trials, and C) by Gleason Score.
Figure 3
Figure 3
Univariable prognostic effect of GC on distant metastasis (DM), prostate cancer specific mortality (PCSM), and overall survival (OS) within each and the pooled cohort of three RTOG trials.
Figure 4
Figure 4
Cumulative incidence estimates of distant metastasis, prostate cancer specific mortality, and Kaplan-Meier estimates of overall survival by GC Low (<0.23), Intermediate (0.23-0.32) High (>0.32) risk groups.
See this image and copyright information in PMC

Comment in

References

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