Tumor suppressor genes, treatments, and survival in US veterans with prostate cancer

Abstract Background Tumor suppressor gene (TSG) alterations prognosticate inferior survival in metastatic hormone-sensitive prostate cancer (mHSPC) and may affect response to therapy. We evaluated association of TSG alterations with overall survival (OS) in mHSPC, stratified by initial treatment. Methods We identified veterans with de-novo mHSPC diagnosed from 2017-2023 within the Veterans Health Administration. TSG alterations included loss-of-function alterations in RB1, TP53, and PTEN identified by somatic sequencing through the National Precision Oncology Program. Treatments within 4 months of diagnosis included androgen deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs). Kaplan-Meier and Cox models evaluated relationships between TSG alterations, clinical factors, and OS. Results Among 1842 veterans who met criteria, 865 had sequencing within six months. TSG alterations were found in 935 veterans, with the most common alterations being TP53 (36.7%), PTEN (23.4%), and RB1 (4.5%). In veterans sequenced within 6 months, RB1, TP53, and PTEN alterations were associated with mortality with a hazard ratio (95% CI) of 2.86 (1.94-4.21) (p 0.001), 1.64 (1.30-2.05) (p 0.001), and 1.52 (1.20-1.91) (p 0.001), respectively. In the same cohort, median OS (95% CI) was 40.7 months (37.5-NR) with no alterations, 34.1 months (30.3-37.3) with one, and 19.7 months (16.5-25.5) with ≥2 TSG alterations. In veterans with ≥1 alteration and sequencing within six months, combination therapy with ARPIs was associated with decreased mortality, aHR (95% CI) of 0.65 (0.48-0.88, p = 0.005). Conclusions TSG alterations were associated with inferior OS in veterans with mHSPC. In this real-world observational study, ARPI-based combination therapy in veterans with TSG alterations was associated with the longest survival.