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High microsatellite instability rare, but clinically meaningful in prostate cancer
Microsatellite instability-high or mismatch repair-deficient solid tumors appeared to be uncommon in prostate cancer but clinically important, with the potential for durable responses to immune checkpoint blockade, according to a study published in JAMA Oncology.
“Pembrolizumab (Keytruda, Merck), an antibody targeting the programmed cell death protein receptor, recently earned accelerated approval by the U.S. FDA for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, independent of site of origin,” Wassim Abida, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Detection of MSI, thus, represents the first clinical indication for prospective tumor profiling in patients with prostate cancer. However, the optimal method for determining MSI-H/dMMR status in patients with prostate cancer and the clinical implications of broader screening for this phenotype remain unknown.”
Abida and colleagues sought to determine the frequency of the molecular phenotype in metastatic castration-resistant prostate cancer and outcomes among men in the disease subset who received treatment with anti-PD1/PD-L1 therapy.
In the case series, researchers used a hybridization capture-based, targeted sequencing assay to prospectively analyze 1,551 tumors from 1,346 men with prostate cancer who received treatment at Memorial Sloan Kettering between 2015 and Jan. 31, 2018.
The researchers performed tumor molecular profiling using samples acquired from biopsies or archival tissue and calculated tumor mutation burden and MSIsensor score, a quantitative measure of microsatellite instability.
Samples from 1,033 men (mean age, 65.6 years; standard deviation, 9.3 years) underwent MSI sensor analysis. Results showed 32 men (3.1%) had MSI-H/dMMR prostate cancer, including 23 with MSIsensor scores classified as high, and nine with indeterminate scores with signs of dMMR. Among these men, seven (21.9%) had a pathogenic germline mutation in a Lynch syndrome-related gene.
The researchers analyzed more than one tumor in six men, two of whom showed an acquired MSI-H phenotype that emerged later in their disease development.
Eleven men with the subtype received anti-PD-1/PD-L1 treatment, and six (54.5%) showed a decline of more than 50% in PSA levels, with four attaining more than a 99% decline. Eight patients could be evaluated for radiographic response, and four of these patients achieved objective responses. Five of the six responders continued on treatment for as long as 89 weeks.
In a related editorial, Zachary R. Reichert, MD, PhD, assistant professor of medical oncology and internal medicine at University of Michigan Rogel Cancer Center, and colleagues underscored the importance of these findings and discussed the potential utility of MSI-H/dMMR testing in prostate cancer.
“That biomarkers of anti-PD-1 and anti-PD L1 checkpoint inhibitor response are emerging in prostate and other cancers is clearly a positive advance,” the authors wrote. “These markers may help to stratify those patients who are most likely to respond, spare those patients who are unlikely to respond or merely develop autoimmune toxic effects ... and prevent unnecessary expenditures on these costly agents.” – by Jennifer Byrne
Disclosures: Abida reports consultant roles with Clovis Oncology, Janssen Pharmaceuticals and More Health Inc.; honoraria from Caret Healthcare; research funding from AstraZeneca, Clovis Oncology and Zenith Epigenetics Ltd. and travel funding from Clovis Oncology, GlaxoSmithKline and Sanofi. Please see the study for a list of all other authors’ relevant financial disclosures. Reichert reports no relevant financial disclosures. Please see the editorial for a list of all other editorial authors’ relevant financial disclosures.