Oncogenic Alterations, Race, and Survival in US Veterans with Metastatic Prostate Cancer Undergoing Somatic Tumor Next Generation Sequencing

Abstract

Purpose: National guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans.

Patients and methods: This retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival.

Results: 5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in SPOP (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including TP53 were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]).

Conclusion: In the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.

Figure 1:

Association of genomics, race and survival in metastatic prostate cancer patients. a. Rates of oncogenic alterations in genes from cancer-related pathways in three different tissues (primary tumors, metastatic lesions and plaslmasamples), separated by patient self-identified race in individuals with metastatic prostate cancer. Differences in rates of oncogenic alterations between NHB and NHW patients were compared by Fisher’s exact test for each of the three tissue types. b.Percent change in oncogenic alteration rates in pathways their constituent genes within those pathways in NHB compared to NHW patients in three tissue types. NHB = non-Hispanic Black; NHW = non-Hispanic White, AR = androgen receptor, PCS = prostate cancer specific, PARPi= PARP inhibitor.

Figure 2:

Association of race and alteration frequency in metastatic prostate cancer patients. Multivariate logistic regression analysis to evaluate the association of oncogenic alterations in pathways and genes in those pathways with self-identified race, controlling for multiple clinical factors. Pathways and genes were tested if statistically significantly difference in rates between Blacks and Whites in univariate analyses. NHB = non-Hispanic Black; NHW = non-Hispanic White, AR = androgen receptor, MSI = microsatellite instability, PCS = prostate cancer specific, PARPi = PARP inhibitor, OR = Odds Ratio.

Figure 3:

Association of genomics, race and survival in metastatic prostate cancer patients. Cox proportional hazards modeling to test the association of oncogenic alterations in pathways and genes in those pathways with overall survival, controlling for clinical factors and stratified by race, NHB = non-Hispanic Black; NHW = non-Hispanic White, AR = androgen receptor, MSI = microsatellite instability, PCS = prostate cancer specific, PARPi = PARP inhibitor, HR = Hazard Ratio.