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Detection of subthreshold microsatellite instability in breast cancer: An ongoing investigation.

1089 Background: Microsatellite instability (MSI) and mismatch repair deficiency (MMRd) can occur sporadically in solid tumors across histologic subtype and predict clinical response to immune checkpoint blockade (ICB). MSIsensor uses next generation sequencing to report the percentage of unstable microsatellites in a given tumor sample as a score. While scores of ≥10 and < 3 have excellent sensitivity/specificity for MSI/MMRd, intermediate scores of 3-10 are of unknown clinical significance, and may include patients with MSI-like genomic signatures who would be overlooked by historical assays. Methods: MSIsensor testing was performed on primary or metastatic tumor specimens from 2,371 patients with breast cancer. Scores of 3-10 were considered MSI-Indeterminate (MSI-I). Concurrent somatic mutations were determined using the MSK-IMPACT assay. Results: Of the 2,371 patients tested, 147 were found to have MSI-I tumors. Ninety-nine (67.3%) were metastatic specimens, and 48 (32.7%) were primary specimens. Of the MSI-I patients, 64 (43.5%) were estrogen receptor positive, 57 (38.8%) were triple negative, and 24 (16.3%) were HER-2 amplified. Somatic TP53 mutations were detected in 109 (74.1%) MSI-I patients, including 54 (94.7%) triple negative patients. Fourteen MSI-I patients were found to have somatic mutations in MMR genes ( MLH1, MSH2, MSH6, PMS2 or EPCAM), but no germline mutations were found. Of the 99 patients with MSI-I metastatic disease, 15 received ICB as part of their clinical care, exhibiting a median progression-free-survival (PFS) of 3 months. Of the 4 patients who demonstrated a PFS of > 6 months on ICB, 2 were found to have somatic mutations in MMR genes. Conclusions: We introduce a subpopulation of breast cancer patients whose tumors exhibit genomic signs of microsatellite instability without meeting the classic criteria for MSI/MMRd as previously defined in colon and endometrial cancers. A subset of these patients may exhibit the properties of MSI/MMRd at the epigenetic and protein-expression levels, and thus potentially benefit from ICB.