DNA Mismatch Repair Proteins May Predict ICI Response in Cutaneous Melanoma

Patients with cutaneous melanoma who have reduced DNA mismatch repair (MMR) proteins may respond better to immune checkpoint inhibitors (ICIs), according to a new study, although the investigators say their findings need to be replicated in larger studies before MMR could be shown to have prognostic value.

The report was published in Journal of Cancer Research and Clinical Oncology.

ICIs such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) have become important first-line therapies for patients with advanced cutaneous melanoma, the investigators of this study said about half of patients do not respond and there is not yet a good method of determining which patients are most likely to respond.

In search of biomarkers that might predict ICI response in these patients, the authors decided to look at MMR protein expression. MMR deficiency can be identified through the presence of microsatellite instability (MSI). High MSI resulting from reduced MMR expression has been shown to have prognostic value in several other malignancies, including colorectal, endometrial, and prostate cancers, the authors said. Patients with high MSI tend to have better responses to ICIs.

The investigators wanted to know whether MMR might also be related to treatment response in patients with cutaneous melanoma. They recruited 50 patients with metastatic cutaneous melanoma who had been treated with ICIs and performed an immunohistochemistry analysis on the patients’ tumor tissues. They searched for 4 MMR proteins: MLH1, MSH2, MSH6, and PMS2. Patients with less than 80% nuclear expression of the MMR proteins were considered to have reduced MMR expression. Eight patients (16%) were found to have reduced MMR under that definition.

Overall, 24 patients achieved best overall responses, and each of the 8 patients with reduced MMR responded to ICI therapy. In a univariate analysis, 2 parameters—baseline neutrophil to lymphocyte ratio and reduced intratumoral MMR protein expression—were found to be positively associated with best overall response. However, in a multivariate analysis, the association between response and reduced MMR protein expression did not reach statistical significance. The authors said this was likely due to the small number of patients included in their investigation.

They said their research also lended insight into questions surrounding the definition of MMR deficiency. Earlier studies have suggested that if MMR deficiency were defined as the complete loss of nuclear expression of MMR proteins in tumor cells, then it would be rare. This new study affirms that characterization, as none of the patients in the new analysis met that criterion. However, defining MMR deficiency as a decrease in single MMR proteins resulted in a significant minority meeting the criterion, and those patients uniformly responded to ICI therapy, suggesting the biomarker and definition used in the study were meaningful.

As for the reasons these patients appear to do better with ICI therapy in various malignancies, the authors said the answer is not yet clear, but it may be due to an increased number of frameshift mutations in tumors resulting in the presentation of neoantigens. The cause-effect relationship will need to be the subject of future research. In the meantime, the investigators said there appears to be sufficient evidence to support further investigation of MMR protein expression as a biomarker.

“In conclusion, reduced MMR protein expression is not uncommon in [cutaneous melanoma] and might be a predictor for improved response to treatment with ICIs,” they wrote. “However, the present data have to be substantiated in larger trials.”

Reference

Gambichler T, Finis C, Abu Rached N, et al. Expression of DNA mismatch repair proteins in melanoma patients treated with immune checkpoint inhibitors. J Cancer Res Clin Oncol. Published online April 13, 2022. doi:10.1007/s00432-022-04002-4