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.