Tamer Khashab, Salma Kaochar, Alexander D. Le, Samantha Cohen, Attiya B. Noor, Heidi Dowst, Neda Zarrin-Khameh, Michael A. Brooks, Guilherme Godoy, Maria A. Berezina, Anna E. Schwarzbach, Michael E. Scheurer, Martha P. Mims, and Nicholas Mitsiades
Background: AA men have higher PC incidence and mortality than white men. Healthcare access and other socioeconomic factors contribute to these disparities. The high cost of NGS can become an additional factor for disparity. Indeed, minority and uninsured pts were underrepresented in prior NGS studies and NGS-based Precision Oncology clinical trials.
Methods: Ben Taub Hospital (BTH) is a safety net hospital serving a racially/ethnically diverse pt population (91% minorities). We retrospectively analyzed NGS data obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor tissue at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes at 5,000x depth) for germline and/or somatic mutations detected in 117 BTH pts [61 self-identified AA and 56 white (including white Hispanic)] receiving treatment for locally advanced, biochemically recurrent or metastatic PC. We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC pts (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL).
Results: AA BTH PC pts exhibited high frequencies of BRCA2 (14.8%), SPOP (19.7%), AR (16.4%) and TP53 (49.1%) mutations (respective frequencies in white BTH pts were 9%, 7%, 3.6% and 12.5%). TMPRSS2 fusions were less frequent in AA than white pts. Upon treatment with active therapy (hormonal or taxane), the allele frequency of PC-derived ctDNA mutations in the liquid biopsy declined significantly and concordantly to the biochemical (PSA) response. In addition, two out of 61 (3.3%) AA BTH PCs had microsatellite instability [a frequency comparable to that seen in white BTH PC pts (3.6%) and in the nationwide Tempus Labs cohort (3.6% of AA PC pts)], and experienced prompt and durable clinical, biochemical and molecular responses to pembrolizumab, including disappearance of PC-derived mutant ctDNA. On the other hand, four AA PC pts who had progressed on abiraterone or enzalutamide with ctDNA findings of AR mutations previously reported as sensitive in vitro to the newest FDA-approved AR antagonist darolutamide, did not achieve clinical or biochemical response on darolutamide treatment and that was paralleled by lack of molecular (ctDNA fraction) response.
Conclusions: The high mutation frequency in key PC drivers in AA pts at our safety net hospital can be attributed to underlying disease biology or the more advanced disease at presentation in AA pts with socioeconomic factors delaying access to healthcare. Wide use of NGS testing is necessary to improve early access of underserved minority populations to novel targeted therapies and to biomarker-based Precision Oncology clinical trials. Liquid biopsy is a minimally invasive tool that allows longitudinal monitoring of response (or lack thereof) to treatment.
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