Germline evaluation of mismatch repair (MMR) genes in breast cancer patients missing Lynch syndrome criteria: Clinical behavior, preventive paths and therapeutic implications.

Abstract

e22507 Background: Currently,Breast Cancer (BC) is not considered a mismatch repair (MMR)-deficiency (MMRd)–spectrum tumor. The BC patients carrying constitutional MMR pathogenic variants (PVs) are not eligible for dedicated screening programs and risk-reducing strategies, which are addressed only to the BC individual carriers of specific Homologous Recombination Repair (HRR) variants. The MMRd status, as well as the high levels of microsatellite instability (MSI-H) that occur upon loss of the expression of MMR genes, may have direct therapeutic implications for the patients, who may benefit from the treatment with immune-checkpoint inhibitors (ICIs). Methods: This was an observational, hospital-based, cohort study to investigate the prevalence of germline MMR PVs in BC patients who were appropriate candidates for hereditary breast and/or ovarian cancer (HBOC) predisposition evaluation. BC patients were tested through NGS-based multigene panel testing including MMR-associated genes, according to clinical established criteria. Results: Between January 2016 and December 2024, 6.020 BC patients were referred for genetic counseling and HBOC predisposition evaluation. In the cohort of consecutive 5.595 BC patients tested with multigene panel testing, a subgroup of 26 patients resulted carriers of germline MMR PVs. Interestingly, 6 of 26 MMR-mutated patients (23.1%) had also a personal bilateral BC history. The median age at BC diagnosis was 55 (range 31-82). Mutation prevalence showed that PMS2 was the most mutated MMR gene (10 PVs, 38.5%), followed by MLH1 (6 PVs, 23.1%), EPCAM (5 PVs, 19.2%), MSH2 (3 PVs, 11.5%), and MSH6 (2 PVs, 7.7%). Notably, in the MMR - mutated cohort, 73.1% of BC patients (19/26) reported a family history of HRR-associated tumors (BC, ovarian/prostate and/or pancreatic tumors), predominantly BC (78.9%). Conversely, first or second-degree family members with a colorectal or endometrial cancer diagnosis, that represents the main Lynch Syndrome-associate tumors, were reported only for 3 patients (11.5%). The genetic characteristics and the clinical behavior of BC in MMR-, BRCA - and HRR non- BRCA -carriers were also collected. The variant of uncertain significance (VUS) prevalence was described. Conclusions: Our results suggested that, in women who met hereditary BC testing criteria but missed the established Lynch Syndrome clinical or testing criteria, the use of panel testing including MMR genes could lead to the identification of a subgroup of BC patients who are carriers of MMR constitutional PVs, with potential important preventive and therapeutic implications.