Rationale for evaluating breast cancers of Lynch syndrome patients for mismatch repair gene expression

Lynch Syndrome (LS) patients harbor germline mutations in one of several mismatch repair (MMR) genes and are predisposed to the development of colon and endometrial cancers and multiple other cancers types as well. Tumors related to LS are characterized by deficient protein expression of one or more MMR genes (dMMR) and/or demonstrate high microsatellite instability (MSI-H) (Win et al. in Breast Cancer Res 15(2):R27, 2013). The National Comprehensive Cancer Network (NCCN) Guideline states that there have been “suggestions” of increased risk of breast cancer in diagnosed LS patients, but does not endorse “increased screening above-average-risk breast cancer screening recommendations” for patients with LS (Provenzale et al. in J Natl Compr Cancer Netw 14(8):1010–1030, 2019).

This report describes a molecularly diagnosed LS patient who developed a dMMR breast cancer.

Sporadic dMMR breast cancers are extremely rare (Davies et al. in Cancer Res 77:4755–4762, 2017). It seems reasonable to conclude that identifying a dMMR breast cancer in a patient with known LS strongly suggests that her LS is breast cancer-predisposing. LS patients with dMMR breast cancers might therefore be considered for above-average breast cancer screening for the development of additional breast cancers. Also, the FDA recently granted approval of checkpoint inhibitor therapy for all metastatic dMMR solid malignancies (Lemery et al. in N Engl J Med 377:1409–1412, 2017). MMR expression assays in metastatic breast cancers of LS patients would represent a more focused approach to identifying patients with breast cancers who are potentially eligible for checkpoint inhibitor therapy than would be universal MMR testing of all metastatic breast cancers.