PORTOS gene signature as a predictor of risk of adverse events after dose-escalated vs. lower-dose prostate radiation therapy in NRG/RTOG 0126.
Authors: Karen E. Hoffman, Sophia C. Kamran, Hyunnam Monica Ryu, James A. Proudfoot, Elai Davicioni, Paul L. Nguyen, Stephanie L. Pugh, Daniel Eidelberg Spratt, Jeff M. Michalski, Matthew Parliament, Ian S. Dayes, Rohann Correa, John M Robertson, Elizabeth Gore, Desiree E. Doncals, Eric Vigneault, Luis Souhami, Felix Y Feng, Phuoc T. Tran, Shuang Zhao
Journal: Journal of Clinical Oncology (2025)

375 Background: Dose-escalated radiation therapy is standard treatment for patients with prostate cancer. Dose-escalation improves cancer control but also increases the risk of treatment adverse effects. We hypothesized RNA-based tumor gene expression recapitulates normal tissue gene expression and therefore could identify patients at increased risk of adverse events after dose-escalated radiation. We specifically evaluated the 24-gene PORTOS score which characterizes response to DNA damage and radiation. Methods: PORTOS scores were calculated from biopsy samples obtained from 215 patients treated on the NRG/RTOG 0126 clinical trial that randomized patients with intermediate-risk prostate cancer between 70.2 Gy and 79.2 Gy delivered in 1.8 Gy fractions. In this trial, adverse events were categorized using RTOG criteria. Fine-Gray multivariable analysis of continuous and categorical PORTOS (tertiles) were used to calculate subdistribution hazard ratios (sHR), treating death without events as a competing risk, adjusting for age. Results: Median age was 70 years [IQR 65-74]. Fifty percent received 70.2 Gy (n=107), 50% received 79.2 Gy (n=108) and median follow up was 12.8 years. Patient and treatment characteristics were well balanced across treatment arms (all p&gt;0.05) and across PORTOS groups (all p&gt;0.05). Forty-five percent (n=97) of patients experienced grade 2 or higher adverse events after treatment. In patients receiving standard dose 70.2 Gy radiation, PORTOS was not associated with grade 2 or higher adverse events. However, in patients receiving dose-escalated 79.2 Gy radiation, higher PORTOS score was associated with a higher rate of grade 2 or higher adverse events (sHR = 1.12 [95% CI 1.03-1.22], p=0.01). There was a statistically significant interaction between continuous PORTOS scores and treatment arm for grade 2 or higher adverse events (p=0.01). Regarding treatment arm effects by PORTOS tertile, we observed that for patients with higher tertile PORTOS scores, dose-escalated radiation is more likely to cause grade 2 or higher adverse events compared to lower-dose radiation (sHR = 2.15 [1.04 - 4.44], p = 0.04; five-year cumulative incidence adverse events of 61% after 79.2 Gy vs. 36% after 70.2 Gy). In contrast, risk of grade 2 or higher adverse events was similar after treatment with dose-escalated vs. lower-dose radiation for patients with lower (p=0.41) or mid-tertile (p=0.78) PORTOS scores. Conclusions: HigherPORTOS scores were associated with an increased risk of adverse events after administration of dose-escalated radiation compared to standard-dose radiation. PORTOS is the first radiation sensitivity biomarker to be validated for toxicity with data from a phase III randomized trial and could be used to help personalize radiation therapy dose for patients to limit risk of treatment toxicity.