Association between smoking, tumor genetics, and outcomes in men with metastatic prostate cancer.

5052 Background: Smoking has been associated with increased metastatic prostate cancer (mPC) mortality, but the mechanisms behind this association are largely unknown. We hypothesized that smoking promotes genetic alterations associated with aggressive disease and/or the transformation to neuroendocrine prostate cancer (NEPC). Methods: We utilized the Prostate Cancer Precision Medicine Multi-institutional Collaborative Effort (PROMISE) clinical genomic database for this retrospective analysis. We examined associations between patient characteristics and tumor genetic data with smoking exposure at diagnosis (current, former, never and pack years) and with clinical outcomes, including overall survival (OS) from diagnosis, OS from metastasis, and NEPC status. Patients with unknown smoking status or incomplete/empty/insufficient NGS entries were excluded from analysis. Results: We identified 2353 men with mPC and next generation somatic tumor sequencing available for analysis in PROMISE, including 8.1% current, 39.5% former, and 52.4% never smokers. Current smokers were more likely to be younger, present with metastatic (M1 or N1) disease at diagnosis, and were less likely to have prior local therapy (all p<0.001). Current smoking was associated with worse OS from diagnosis (99.9 mo in current vs 137 mo in former, and 139.4 mo in never smokers; p=0.008), which remained significant after adjusting for disease characteristics (HR 1.27 95% CI 1.01-1.59). No differences in OS from metastasis were observed for amongst the three groups (current 68.1mo, former 60.3 mo, and never 64.2 mo; p=0.86) We also found no difference in the percentage of NEPC at initial diagnosis or at any time between current, former, and never smokers (p=0.8). However, positive associations were observed between smoking status and genetic alterations in SPOP (current: 15%, former 6.7%, never 3.8%; p= 0.018), FGFR1 (current 10%, former 0.4%, never 1.1% p=0.001), and ARID1A (current 5.1%, former 2.2%, never 0.4%; p=0.035) in mHSPC. No other associations between smoking status and genes of interest were identified. Conclusions: Active smoking is associated with worse overall and prostate cancer specific survival as compared to never/former smoking and was associated with specific tumor genetic alterations but not small cell/NEPC transformation. Association of tumor genetics with smoking status; alterations detected in hormone sensitive tissue only. Characteristic Current N = 39 1 Former N = 224 1 Never N = 264 1 p-value TP53 17 (44%) 79 (35%) 100 (38%) 0.58 RB1 3 (7.7%) 11 (4.9%) 17 (6.4%) 0.59 PTEN 8 (21%) 55 (25%) 60 (23%) 0.81 BRCA2 8 (21%) 20 (8.9%) 35 (13%) 0.07 MYC 3 (7.7%) 18 (8.0%) 11 (4.2%) 0.15 SPOP 6 (15%) 15 (6.7%) 10 (3.8%) 0.02 FGFR1 4 (10%) 1 (0.4%) 3 (1.1%) 0.001 ARID1A 2 (5.1%) 5 (2.2%) 1 (0.4%) 0.04 PIK3CA 2 (5.1%) 9 (4.0%) 13 (4.9%) 0.80 1 n (%).