Investigation of a prostate cancer radiation response signature in the breast cancer SweBCG91RT randomized trial

PURPOSE: PORTOS is a 24-gene radiation response signature developed and validated in multiple randomized trials in prostate cancer. Given its basis in general radiation and DNA damage response pathways, we sought to evaluate whether PORTOS could also predict RT benefit in breast cancer. METHODS: PORTOS scores were calculated from gene expression profiles of 765 tumor samples from SweBCG91RT, a randomized trial of adjuvant whole-breast RT versus observation following breast-conserving surgery in node-negative stage I-IIA breast cancer. The primary endpoint was 10-year cumulative incidence (CI) of any recurrence, which closely mirrored the prostate cancer endpoints PORTOS was validated on. Patient-reported breast pain and tumor-infiltrating leukocytes (TILs) were also analyzed. RESULTS: A significant interaction (P = 0.049) between PORTOS and RT was observed for 10-year CI of any recurrence. Patients in the top 75% of PORTOS scores derived substantial benefit from RT (subdistribution hazard ratio (SHR) = 0.46, P < 0.001), compared to those in the bottom 25% (SHR = 0.73, P = 0.24). Higher PORTOS scores were also associated with increased risk of RT-related breast pain, though the interaction P-value was not significant (interaction P = 0.07). PORTOS was weakly anti-correlated with tumor size, histologic grade, and TILs, and provided orthogonal information to previously validated signatures ARTIC and POLAR. CONCLUSION: PORTOS predicts benefit from RT for any recurrence in early-stage breast cancer, mirroring its performance in prostate cancer. It is the first radiation response biomarker to demonstrate predictive value for both efficacy and toxicity across randomized trials in multiple tumor types.