Prevalence of microsatellite instability and monitoring response to immune checkpoint inhibition utilizing liquid biopsy among African American men with advanced prostate cancer.
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

16 Background: African American (AA) men have higher prostate cancer (PC) incidence and PC-specific mortality than non-AA men. Socioeconomic/healthcare access and environmental factors contribute to the disparity in clinical outcomes. Moreover, AA PC exhibits increased inflammatory and immune response signaling, which may contribute to its aggressive behavior, but also allow for therapeutic intervention. Microsatellite instability (MSI) is a tissue-agnostic biomarker predictive of response to immune-checkpoint inhibition (pembrolizumab) that can be assessed by NGS testing of tumor tissue or circulating tumor DNA (ctDNA, liquid biopsy). The latter is particularly relevant for patients with PC, a disease which frequently metastasizes to bone and other deep sites, making conventional tissue biopsies invasive, painful and potentially risky. Methods: We retrospectively analyzed NGS results obtained via Tempus|xT tissue assay and/or Tempus|xF liquid biopsy assay for MSI, as well as clinical data (response to pembrolizumab), from 100 PC patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic disease at Ben Taub Hospital (BTH, a safety net hospital in Houston serving a patient population of which 91% are racial/ethnic minorities). We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC patients (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: MSI-High status (MSI-H) was detected using xT and/or xF assays in 4/100 (4%) of patients in the BTH cohort and in 62/2090 (3%) of metastatic PC patients in the nationwide Tempus Labs cohort. Specifically, within the AA PC patient population, MSI-H was detected in 2/53 (3.7%) in the BTH cohort and in 8/225 (3.6%) in the nationwide Tempus Labs cohort. For those patients who had both tissue and liquid biopsy testing, there was 100% concordance in MSI-H detection between the two assays. Genomically-driven treatment of two MSI-H AA CRPC patients with pembrolizumab resulted in prompt and durable clinical, biochemical and molecular responses, with precipitous decline in PSA levels to below detection limit, complete radiographic response of metastatic lymphadenopathy, radiographic non-progression of visceral disease (per iRECIST and PC Working Group 3 criteria) and disappearance of PC-derived ctDNA mutations in the liquid biopsy. Conclusions: MSI-H status is present in advanced AA PC at a frequency comparable to non-AA PC. Liquid biopsy (xF assay) is a minimally invasive tool that allows detection of MSI-H in PC patients, as well as longitudinal monitoring of response to treatment with pembrolizumab. Liquid biopsy conversion from positive to negative may provide reassurance that any residual lesions seen on imaging represent treated/inactive disease.