Identifying Genomic Differences Could Lead to Improved Precision Medicine Use, VA Study Says
A study reveals significant genomic differences in metastatic prostate cancer among veterans, highlighting the need for universal genomic testing for precision medicine.
Conceptual image for prostate cancer treatment: © Dr_Microbe - stock.adobe.com
A retrospective cohort study evaluating genomic differences in metastatic prostate cancer between non-Hispanic Black and non-Hispanic White veterans revealed distinct alteration frequencies but comparable survival outcomes within the Veterans’ Affairs (VA) health care system. The findings delineate the role of genomic testing for identifying candidates irrespective of race and ethnicity for precision medicine treatments.1
The study, which included 5015 veterans who underwent next-generation sequencing (NGS) through the National Precision Oncology Program between January 2019 and November 2023, found that while key oncogenic pathways, including CDK12, AR axis, and mismatch repair (MMR) deficiency, exhibited racial disparities, genomic testing remained clinically valuable for precision oncology across all racial groups.
In the study, patients self-identified race and cancer outcomes. Those with a given pathogenic alteration (cases) were compared with those without a given alteration (controls).
Tissue biospecimens, including prostate biopsies, radical prostatectomy specimens, and metastatic lesions, were sequenced using FoundationOne CDx or FoundationOne Liquid CDx. Alterations were analyzed across hallmark prostate cancer pathways, such as MMR deficiency genes, immunotherapy targets, DNA repair pathways (including PARP inhibitor targets), AKT/PI3K and AR-signaling pathways, and tumor suppressor genes.
Overall, the median age was 67 years (IQR, 61-73). In the non-Hispanic Black cohort (n = 1784), the median age was 64 years (IQR, 59-70) and in the non-Hispanic White cohort (n = 3231), the median age was 69 years (IQR 63-75). Non-Hispanic Black veterans were significantly younger at the time of diagnoses compared with non-Hispanic White veterans (mean age, 64.8 vs 68.8 years; P <.001), presented with higher prostate-specific antigen levels at diagnosis (997 ng/mL vs 1592 ng/mL with a PSA >20 ng/mL; P <.001), and were less likely to have been exposed to Agent Orange (293 vs 893; P <.001).1
An aggregate comparison of alteration frequency stratified by both race and tissue revealed that the most commonly altered genes were similar between non-Hispanic Black and non-Hispanic White veterans stratified by NGS analyte type, but the oncogenic alteration rates were significantly different between non-Hispanic Black and non-Hispanic White veterans for multiple genes.
AR axis alterations were more likely observed in non-Hispanic White samples derived from primary (46.5% vs 35.2%; P <.001) and metastatic (55.8% vs 39.9%; P <.001) tumor tissue. Investigators reported that a similar pattern was observed for alterations in the AKT/PI3K pathway.
In contrast, there was a significant increase of PARP inhibitor target alterations (33.8% vs 27.2%; P =.01) in sequenced plasma samples taken from non-Hispanic White men.
When looking at overall survival, the adjusted Cox proportional hazards model suggests that tumor suppressor alterations driven by TP53 alterations (HR, 1.52; 95% CI, 1.25-1.85), immunotherapy targets driven by mismatch repair deficiency and microsatellite instability high status (HR, 144; 95% CI, 1.02-2.02), and AR axis alterations (HR, 1.28; 95% CI, 1.05-1.56) increased the hazard of death in non-Hispanic White veterans, whereas tumor suppressor alterations driven by TP53 alterations (HR, 1.54; 95% CI, 1.13-2.11) and CDK12 alterations (HR, 2.04; 95% CI, 1.13-3.67) both increased the hazard of death in non-Hispanic Black veterans.
These findings underscore the importance of genomic profiling in metastatic prostate cancer management, particularly for non-Hispanic Black men. While racial differences in alteration frequencies exist, the study supports universal molecular testing to guide precision therapy. This is desperately needed, as non-Hispanic Black men have consistently been shown to exhibit more aggressive prostate cancer phenotypes as well as more than twice the incidence and prevalence of prostate cancer across all disease states compared with non-Hispanic White patients.
The authors noted the limitations of the study, notably the lack of matched germline data for the cohort. But importantly, they did not identify any genomic alterations or biomarkers that should not be tested in prostate cancer based on patient self-identified race.
