Researchers discovered a differential clinical response to pembrolizumab in patients with Lynch-like (mutated) vs methylated microsatellite instability–high endometrial cancer, outlining characteristics of patients who may derive benefit from immune checkpoint blockade antibodies, according to new findings published by Chow et al in Cancer Discovery.
Functional defects in DNA mismatch repair genes are common in tumors and are usually inherited. The main characteristic of these tumors is that they are associated with genome-wide instability and the progressive accumulation of mutations, especially in microsatellite regions, resulting in microsatellite instability–high tumors. Cancers deficient in mismatch repair gene function account for up to 30% of all uterine cancers, 20% of gastric cancers, and 15% of colorectal cancers.
“Due to the high number of mutations, [microsatellite instability–high] tumors are considered highly immunogenic, and accordingly, are very responsive ([with a] 50% response rate in terms of complete or partial response) to immunotherapy treatment in the form of immune checkpoint blockade antibodies such as pembrolizumab,” said study coauthor Eric Song, MD, PhD, a resident at the Yale University School of Medicine. “However, the question remained as to why only 50% of patients with [microsatellite instability–high/mismatch repair–deficient gene] characteristics responded, and not 100%.”
A phase II clinical trial of the PD-1 inhibitor pembrolizumab provided a partial answer to this question. The study was conducted in 24 patients with mismatch repair–deficient endometrial cancer, and it was found that responses to pembrolizumab in patients with Lynch-like (mutated) endometrial cancer were stronger and significantly more lasting than those experienced by patients with methylated microsatellite instability–high endometrial cancer.
“These results highlighted for the first time the heterogeneity and prognostic significance of [patients with] Lynch-like [vs]… methylated microsatellite instability–high endometrial cancer in terms of overall response, progression-free survival, and overall survival when treated with pembrolizumab,” said senior study author Alessandro Santin, MD, Professor of Obstetrics, Gynecology, and Reproductive Sciences and Co-Chief of Gynecologic Oncology at the Yale University School of Medicine.
“Endometrial cancer is the most common gynecologic cancer affecting [patients] in developed countries, partly because of increasing obesity and our aging population,” said first study author Ryan Chow, an MD/PhD student at the Yale University School of Medicine. “We believe that a fruitful area for future research will be to investigate the underlying mechanisms driving the two distinct modes of antitumor immunity in patients. This data could reveal whether the distinguishing features of the circulating immune response we identified here are similarly observed in tumor-infiltrating immune cells.”
Disclosure: The research in this study was funded in part by grants from the National Institutes of Health, Gilead Sciences, Merck & Co. Inc., and the Stand Up To Cancer Foundation. For full disclosures of the study authors, visit aacrjournals.org.
