Oncogenic alteration rates, race, and prostate cancer specific mortality in Veterans with metastatic prostate cancer undergoing somatic tumor next generation sequencing.

5017Background: National guidelines recommend next generation sequencing (NGS) of tumors from patients diagnosed with metastatic prostate cancer (PCa) to identify potential actionable alterations. We sought to determine associations between alteration frequencies of PCa-related genes and pathways, self-identified race, and PCa specific mortality (PCSM) in Veterans. Methods: This comprehensive retrospective cohort study evaluated the association of somatic alterations with race in Veterans with metastatic PCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. NGS data was linked to clinicopathologic and social determinants of health (SDOH) data elements. Multivariate logistic regression permitted associations between race and genomic alteration frequencies, adjusted for specimen tested and clinical and SDOH co-variates. Cox proportional hazards models permitted associations of race, alteration frequencies, and PCSM, stratified by genomic alteration frequencies and adjusting for race, clinicopathologic features, and SDOH. Results: 5015 Veterans with metastatic PCa and self-identified race/ethnicity as non-Hispanic Black (NHB, n=1784) and non-Hispanic White (NHW, n= 3231) were included. NGS was conducted on primary tumors (n= 2359), metastases (n = 1011), and cfDNA (n = 1644). NHB Veterans were younger, had higher PSA at PCa diagnoses, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods. Upon adjusting for tissue sequenced and clinicopathologic variables, NHB race/ethnicity was significantly associated with a higher rate of genomic alterations in immunotherapy targets, SPOP and BRAF(p<0.05 for all).Furthermore, NHB race/ethnicity was significantly associated with lower rates of genomic alterations in the AKT/PI3K pathway, AR axis, and tumor suppressor genes including TP53and PTEN(p<0.05 for all). While alterations in TP53 (HR 1.5 [1.1-2.0], p=0.007), and tumor suppressor pathways (HR 1.3 [1.0-1.8], p=0.04) conferred a significantly higher risk of PCSM in all men on adjusted analysis, race was not independently associated with PCSM. Conclusions: In this diverse cohort of Veterans undergoing NGS for metastatic PCa in the equal access VA healthcare system, we observed significant differences in alteration rates of several oncogenic genes/pathways by race. While alterations in tumor suppressor genes were significantly associated with PCSM, race was not. Thus, there remains a critical need for integrating personalized approaches to patient selection for metastatic PCa treatments in order to improve disease-specific outcomes across diverse populations.

Duke Scholars

Author Michael John Kelley Medicine, Medical Oncology