Genomic landscape of advanced prostate cancer in racial minority populations: Real-world experience in a safety-net hospital oncology clinic.
Authors: Khashab Tamer , Le Alexander D , Cohen Samantha , Kaochar Salma , Dowst Heidi , Noor Attiya Batool , Zarrin-Khameh Neda , Brooks Michael Austin , Godoy Guilherme , Berezina Maria A , Schwarzbach Anna Ewa , Scheurer Michael E. , Mims Martha P. , Mitsiades Nicholas 
Published: March 2021

14 Background: The largest US cancer health disparity exists in prostate cancer (PC), with African American (AA) men having: ~1.6-1.8-fold higher risk of developing PC; younger age and more advanced stage at diagnosis; increased risk of recurrence after radical prostatectomy; and up to 2.5-fold higher mortality rate relative to men of other ancestries. Access to healthcare and other socioeconomic and environmental factors contribute to the disparity in clinical outcomes. However, genetic factors may also be involved, and their role and prevalence need to be better defined, especially in real-world clinical settings, as the high cost of next-generation sequencing (NGS) may have resulted in underrepresentation of uninsured and minority patients in prior studies. Methods: We retrospectively analyzed NGS data obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations detected in 100 patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic PC at Ben Taub Hospital (BTH), a safety net hospital in Harris County/Houston serving a patient population of which 91% are racial/ethnic minorities. For confirmation, we analyzed de-identified NGS data from a nationwide cohort of 1,211 metastatic PC patients (213 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: We found higher frequencies of AR (18.9%), TP53 (41.5%), SPOP (20.7%) and homologous recombination repair (HRR) pathway gene mutations, in particular BRCA2 (17%), in our AA BTH cohort, as compared to PC patients of other races/ethnicities. The latter finding was confirmed in the nationwide Tempus Labs cohort, with 91/213 (42.7%) AA patients exhibiting mutation in at least one of 14 HRR pathway genes associated with PC sensitivity to PARP inhibitors, compared to 347/998 (34.7%) non-AA patients (P < 0.05). This difference was mainly driven by higher frequency of BRCA2 (16.9%), CDK12 (8%) and PALB2 (5.2%) mutations in AA patients. In both cohorts, TMPRSS2 fusions were much less common in AA PC patients. Conclusions: The observed high frequency of mutations in key PC drivers in AA patients may reflect differences in disease biology between racial/ethnic groups or the more advanced disease presentation of AA patients due to socioeconomic factors delaying access to healthcare. Our study provides a real-world snapshot of the genomic landscape of advanced PC in a safety net hospital serving large racial/ethnic minority populations and highlights the role that NGS testing can play to improve their access to treatment with novel targeted therapies and to biomarker-based Precision Oncology clinical trials.