Research reveals a differential clinical response to pembrolizumab in uterine cancer patients

NewsGuard 100/100 Score

New research from Yale Cancer Center reveals for the first time ever a differential clinical response to pembrolizumab in Lynch-like (mutated) vs methylated microsatellite instability-high (MSI-H) uterine cancer patients, increasing our understanding about the proportion of patients that derive benefit from immune checkpoint blockade.

The findings were published today in the journal Cancer Discovery.

Defects in DNA mismatch repair (MMR) genes are common in tumors and are usually caused by an inherited defect in the function of one of the MMR genes. The main characteristic of these tumors is that they are associated with genome-wide instability and the progressive accumulation of mutations, especially in regions of simple repetitive DNA sequences known as microsatellites, resulting in microsatellite instability (MSI) high (MSI-H) tumors. Cancers deficient in MMR gene function (dMMR) are prevalent in many solid tumors and account for up to 30% of all uterine tumors, 20% of gastric cancer, and 15% of colorectal cancer, among others.

Due to the high number of mutations, MSI-H tumors are considered highly immunogenic and accordingly, are very responsive (~50% response rate in terms of complete or partial response) to immunotherapy treatment in the form of immune checkpoint blockade antibodies such as pembrolizumab. However, the question remained as to why only 50% of patients with MSI-H/dMMR characteristics responded, and not 100%."

Dr. Eric Song, Resident in Immunobiology and Study's Co-Author

A phase 2 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 (MMRd) endometrial cancer and it was found that responses to pembrolizumab in Lynch-like (mutated) patients were stronger and significantly more lasting than those experienced by methylated MSI-H uterine cancer patients.

"These results highlighted for the first time the heterogeneity and prognostic significance of Lynch-like versus sporadic/methylated MSI-H endometrial cancer patients in term of overall response, progression free survival, and overall survival when treated with pembrolizumab," said Dr. Alessandro Santin, professor of obstetrics, gynecology, and reproductive sciences and senior author of the study. He is also co-chief for the section of gynecologic oncology.

"Endometrial cancer is the most common gynecologic cancer affecting women in developed countries, partly because of increasing obesity and our aging population," said first author Ryan Chow, MD/PhD student at Yale. "We believe that a fruitful area for future research will be to investigate the underlying mechanisms driving the two distinct modes of anti-tumor 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."

The 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.

Additional Yale authors include Tai Michaels, Stefania Bellone, Tobias MP Hartwich, Elena Bonazzoli, and Akiko Iwasaki.

Journal reference:

Chow, R.D., et al. (2022) Distinct mechanisms of mismatch repair deficiency delineate two modes of response to PD-1 immunotherapy in endometrial carcinoma. Cancer Discovery.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Linking lifestyle to longevity: How diet and hypertension sway risks for heart disease and cancer