ASCO GU 2021: Prevalence of Microsatellite Instability and Monitoring Response to Immune Checkpoint Inhibition Utilizing Liquid Biopsy Among African American Men with Advanced Prostate Cancer

(UroToday.com) As the most common non-cutaneous cancer of men in the United States, prostate cancer affects the African-American population with higher incidence and higher prostate-cancer specific mortality than men, not of African ancestry. The reasons for the higher burden of disease and disparate outcomes have been attributed, in part, due to social, economic, environmental, and biological influences. The biological factors are still opaque, with retrospective data to suggest an improved response to certain therapies, including sipuleucel-T1, suggesting a possible difference in tumor-immune interaction. Rates of microsatellite instability (MSI)-high is low in prostate cancer overall, with a paucity of data in African-American prostate cancers specifically. The authors sought to indirectly evaluate potential response to immune checkpoint inhibition by measuring MSI using next-generation sequencing assays, Tempus xT (648-gene sequencing panel + whole-transcriptome RNAseq) and/or Tempus xF (105-gene targeted panel), on tissue or liquid compartment, respectively. 

Their retrospective study was of 100 patients with prostate cancer, including 53 African American men, evaluated for the frequency of MSI and correlated with clinical response data to pembrolizumab treatment. Among the cohort were subjects with locally-advanced, biochemically recurrent, or metastatic disease at the Ben Taub Hospital (BTH) in Houston. The authors observed MSI-high in 4% (4/100 subjects) and 3% (662/2090) within a de-identified nationwide cohort of metastatic PC from Tempus. The African American population at BTH and in the large Tempus cohort displayed similar frequency of MSI (3.7%, 2/53; 3.6%, 8/225, respectively). In keeping with other reports evaluating the reliably of genomic assessments from the circulating (blood) compartment, concordance was 100% between the two assays among MSI-high cases.

Beyond demonstrating similar frequencies of MSI-high between African American and non-African American patients with prostate cancer, the authors highlight the potential clinical value of a reliable method for determining high microsatellite instability. Of the four African American patients with MSI-high status, two received immune checkpoint inhibition with an anti-PD1 agent, pembrolizumab, and each had a robust response, including prostate-specific antigen (PSA) responses below the limits of detection, complete radiographic resolution of lymphadenopathy, and an absence of progression of visceral disease (via PCWG3 criteria). Additionally, longitudinal assessment of ctDNA demonstrated the absence of evidence of prostate cancer (Figure).

Notably, the second case study presented by Dr. Tamer Khasab was in a patient with platinum-resistant, poorly-differentiated carcinoma of prostatic origin, highlighting response in MSI-high patients with aggressive variant prostate cancer – a space with a clear unmet clinical need.

longitudinal assessment of ctDNA demonstrated absence of evidence of prostate cancer

While it remains incompletely understood why African American men experience higher rates and worse outcomes than non-African American men with prostate cancer, Khashab et al. demonstrate similar rates of MSI-high in prostate cancer, both from a cohort from their “safety net” hospital in Houston and more broadly from de-identified data from Tempus. These data do not support MSI-high explaining higher immune activity in African American prostate cancers. However, they do support the use of MSI-high in therapy decision-making in African American men with metastatic prostate cancer.

Presented by: Tamer Khashab, MD, Fellow, Department of Medicine, Division of Hematology and Oncology, Harris Health/Ben Taub Hospital and Baylor College of Medicine, Houston, Texas

Written by: Jones Nauseef, MD, Ph.D., Fellow, Division of Hematology and Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York, Twitter: @DrJonesNauseef during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021

Reference:

1. Sartor, Oliver, Andrew J. Armstrong, Chiledum Ahaghotu, David G. McLeod, Matthew R. Cooperberg, David F. Penson, Philip W. Kantoff, et al. "Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry." Prostate cancer and prostatic diseases 23, no. 3 (2020): 517-526.