Somatic Tumor Next-Generation Sequencing in US Veterans With Metastatic Prostate Cancer

Abstract

Importance: National guidelines recommend next-generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. Non-Hispanic Black men are poorly represented in precision oncology cohorts, and therefore differences in alterations frequencies between non-Hispanic Black and White men remain poorly characterized.

Objectives: To describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race and ethnicity and overall survival in US veterans.

Design, setting, and participants: This retrospective cohort study compared alteration frequencies between non-Hispanic Black and White men who underwent NGS testing from January 23, 2019, to November 2, 2023, adjusted by NGS analyte and clinicopathologic covariates. The analytic data file was locked on December 8, 2023. NGS testing was performed through the Department of Veterans Affairs (VA) National Precision Oncology Program, part of the largest near-equal access integrated health care system in the US.

Exposures: Pathogenic alterations identified by NGS testing with a commercially available NGS platform.

Main outcomes and measures: The primary outcome consisted of alteration frequencies in individual genes, actionable targets, and canonical prostate cancer pathways. Associations between alteration frequency and race and ethnicity as well as survival were also examined.

Results: A total of 5015 veterans with mPCa who underwent NGS were included (1784 non-Hispanic Black [35.6%] and 3231 non-Hispanic White [64.4%]; mean [SD] age, 67.4 [9.0] years). Non-Hispanic Black veterans were younger, had higher prostate-specific antigen levels at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared with non-Hispanic White veterans. Nine of the top 10 most commonly altered genes were the same in non-Hispanic Black and non-Hispanic White veterans; however, the frequencies of alterations varied by race and ethnicity. Non-Hispanic Black race and ethnicity was associated with higher odds of genomic alterations in SPOP (odds ratio [OR], 1.7; 95% CI, 1.2-2.6) as well as immunotherapy targets (OR, 1.7; 95% CI, 1.1-2.5) including high microsatellite instability status (OR, 3.1; 95% CI, 1.1-9.4). Furthermore, non-Hispanic Black race and ethnicity was associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR, 0.6; 95% CI, 0.4-0.7), androgen receptor axis (OR, 0.7; 95% CI, 0.5-0.9), and tumor suppressor genes (OR, 0.7; 95% CI, 0.5-0.8). Cox proportional hazards modeling stratified by race and ethnicity found that alterations in tumor suppressor genes, including TP53, were associated with shorter overall survival in both non-Hispanic Black (hazards ratio [HR], 1.54; 95% CI, 1.13-2.11) and non-Hispanic White (HR, 1.52; 95% CI, 1.25-1.85) veterans.

Conclusions and relevance: This retrospective clinical genomic profiling cohort study with a large total and proportional representation of non-Hispanic Black men with mPCa reported significant differences in alteration frequencies from key oncogenic pathways but similar survival rates in the near equal-access VA health care setting. This analysis suggests the utility of genomic testing for identifying candidates irrespective of race and ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.

Figure 1.. Association of Genomics, Race, and Survival in Patients With Metastatic Prostate Cancer

A, Rates of oncogenic alterations in genes from cancer-related pathways are shown in 3 different tissues (primary tumor, metastatic, and plasma samples), separated by patient self-identified race. Differences in rates of oncogenic alterations between non-Hispanic Black and non-Hispanic White patients were compared by Fisher exact test for each of the 3 tissue types. B, Percentage change in oncogenic alteration rates in constituent genes within pathways are compared in non-Hispanic Black and non-Hispanic White patients in the 3 tissue types. Positive percentages indicate changes were higher in non-Hispanic Black patients; negative percentages, lower. AR indicates androgen receptor; PCS PARPi, prostate cancer–specific Poly (adenosine diphosphate–ribose) polymerase inhibitor.

Figure 2.. Association of Race and Alteration Frequency in Patients With Metastatic Prostate Cancer

Multivariable logistic regression analysis was used 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 a statistically significant difference in rates was found between non-Hispanic Black and non-Hispanic White patients in univariate analyses. Numeric values for the odds ratios (ORs) and 95% CIs are found in eTable 7 in Supplement 1. AR indicates androgen receptor; MSI, microsatellite instability; OR, odds ratio; and PCS PARPi, prostate cancer–specific Poly (adenosine diphosphate–ribose) polymerase inhibitor.

Figure 3.. Association of Genomics, Race, and Survival in Patients With Metastatic Prostate Cancer

Cox proportional hazards modeling was used 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. Numeric values for the hazard ratios (HRs) and 95% CIs are found in eTable 8 in Supplement 1. AR indicates androgen receptor; MSI, microsatellite instability; and PCS PARPi, prostate cancer–specific Poly (adenosine diphosphate–ribose) polymerase inhibitor.