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Molecular Pathology Abstracts, 8/17

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.

Mismatch repair-deficient tumors and immune checkpoint inhibitors

Immune checkpoint inhibitors have yielded highly effective therapeutic responses in a subset of tumors by eliciting an endogenous adaptive immune response. The determinants that define this subset of tumors are still unclear, but several markers, including PD-L1 expression and mutational burden, have been evaluated in various tumor types. Several recent reports have shown that the number of mutations in mismatch repair (MMR)-deficient cancers are associated with response to PD-1 blockade therapies. The authors undertook a study to expand these findings by prospectively evaluating the efficacy of the PD-1 blockade therapy pembrolizumab in a range of histologically distinct MMR-deficient cancers. Among the types of cancer were colorectal (47 percent), endometrial (17 percent), pancreatic (nine percent), small intestine (six percent), gastroesophageal (six percent), and other solid tumors. During a three-year period, 86 patients with MMR-deficient tumors were enrolled in the study, which also assessed inherited mutations in the MMR genes MSH2, MSH6, PMS2, and MLH1, diagnostic of Lynch syndrome, with 32 (48 percent) of the cases carrying inherited MMR mutations. A subset of 78 patients had disease that could be evaluated radiographically using the Response Evaluation Criteria in Solid Tumors (RECIST) system. Slightly more than half (53 percent) the patients achieved objective radiographic response, with 21 percent achieving complete radiographic response. The average time to any response was 21 weeks, and the average time to complete response was 42 weeks. Eleven patients achieved complete response and were taken off therapy after two years of treatment. Neither median progression-free survival nor median overall survival had been reached since the study was still ongoing. Primary clinical resistance to initial therapy with pembrolizumab was observed in 14 percent of patients. The authors compared the mutational burden for these resistant patients to that for patients with objective responses and did not observe any statistically significant differences between the two groups. Finally, the authors sought to extrapolate the number of MMR-deficient cancers that may benefit from PD-1 blockade therapies by evaluating more than 12,000 cancers representing 32 distinct tumor types for MMR deficiency. They found that more than five percent of a variety of adenocarcinomas, as well as neuroendocrine tumors, nonepithelial ovarian cancers, and uterine sarcomas were MMR deficient. The authors estimated that roughly 40,000 annual stage I to stage III cancers and 20,000 annual stage IV cancers would be MMR deficient and potentially benefit from this class of immune therapy, regardless of tumor type. While the study was limited due to the relatively small number of tumors evaluated, the prospective study design will offer insights into progression-free survival and overall survival, as well as continue to provide insights into the efficacy of PD-1 blockade therapies in a variety of tumor types harboring defects in mismatch repair.

Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade [published online ahead of print June 8, 2017]. Science. doi:10.1126/science.aan6733.

Correspondence: Dr. Luiz A. Diaz Jr. at ldiaz@mskcc.org

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