Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade

Abstract

: More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers.

Implications for practice: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade.

Keywords: Colonic neoplasms; Colorectal neoplasms; DNA mismatch repair; Hereditary nonpolyposis; Immunotherapy; Microsatellite instability.

Figure 1.

Test schemas for mismatch repair deficiency with IHC staining (A) and MSI with PCR (B) per NCI guidelines. Abbreviations: dMMR, deficient mismatch repair; IHC, immunohistochemical; MSI, microsatellite instability; NCI, National Cancer Institute; PCR, polymerase chain reaction.

Figure 2.

MSI-H frequency. (A): Colon, small bowel, endometrial, gastric ovarian, gallbladder, prostate, glioma, and breast cancer based on MSI-H frequency rates in populations reported in the literature. (B): Colon cancer MSI-H frequency by stage. Abbreviations: MSI-H, high-frequency microsatellite instability.

Figure 3.

Total somatic mutations per tumor identified by comparison exome sequencing of tumor and matched normal DNA according to tumor type [181]. Abbreviations: dMMR, deficient mismatch repair; pMMR, proficient mismatch repair.

Figure 4.

Responses to anti-PD-1 therapy in tumors with dMMR. (A): Single patient response after 20 weeks of anti-PD-1 therapy with complete response of retroperitoneal lymphadenopathy. (B): CEA response to checkpoint inhibition in the same patient with durable response over time. (C): Radiographic response to pembrolizumab as represented by the largest percentage change of SLD based on RECIST. Each bar represents one patient. Abbreviations: CEA, carcinoembryonic antigen; CRC, colorectal cancer; dMMR, deficient mismatch repair; MMR, mismatch repair; anti-PD-1, antibodies to programmed cell death protein 1; RECIST, Response Evaluation Criteria in Solid Tumors; SLD, sum of longest diameters. Figure 4B adapted from [1].

Figure 5.

Schematic of anti-PD-1-responsive tumors. Abbreviations: MSI-H, high-frequency microsatellite instability; NSCLC, non-small-cell lung cancer.