Morphological and genomic characteristics of breast cancers occurring in individuals with Lynch Syndrome.

Purpose Lynch syndrome (LS) is defined by germline pathogenic mutations involving DNA Mismatch Repair (MMR) genes and linked with the development of MMR-deficient (MMRd) colon and endometrial cancers. Whether breast cancers (BC) developing in context of LS are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphological and genomic characteristics of BCs occurring in LS individuals. Experimental design A retrospective analysis of 20,110 cancer patients who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6 or PMS2 who developed BCs. The histological characteristics and immunohistochemical (IHC) assessment of BCs for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with MSK-IMPACT ({greater than or equal to}468 key cancer genes). MSI status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA. Results 272 LS individuals were identified, 13 (5%) of whom had primary BCs. The majority of BCs (92%) were hormone receptor positive tumors. Five (42%) of 12 BCs displayed loss of MMR proteins by IHC. Four (36%) of 11 BCs subjected to tumor-normal sequencing showed dominant microsatellite instability mutational signatures, high tumor mutational burden and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd BC received anti-PD1 therapy and achieved a robust and durable response. Conclusions A subset of BCs developing in LS individuals are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.