Men with germline mutations in BRCA1 and, mainly, BRCA2 genes are at increased risk of developing breast cancer (BC). Both BRCA1 and BRCA2 genes are involved in DNA repair. Recent evidence indicates a relevant role of other DNA repair genes, such as PALB2, in male BC (MBC) predisposition.
Tumors with mutations in DNA repair genes have been associated with increased genomic instability, such as tumor mutational burden (TMB) and microsatellite instability (MSI), and seem to be more immunogenic than tumors without these genetic defects.
In the previous project, we obtained promising results showing that TMB may be a predictive biomarker in male breast tumors.
In the present project, we plan on further investigating the somatic mutational landscape in MBC cases previously tested for germline mutations in DNA repair genes, to validate our previous results and also to expand the research on MSI, not yet evaluated in MBC, in order to identify clinically relevant molecular biomarkers.
Breast tumors from MBC patients screened for germline mutations in DNA repair genes, including BRCA1, BRCA2 and PALB2, will be analyzed by targeted panel NGS approach. Evaluation of TMB and MSI status and the integration with germline alterations, clinical-pathologic features and outcome will be performed.
This study will provide insights into the molecular classification of MBCs associated to germline mutations in DNA repair genes in terms of predictive biomarkers, thus allowing the identification of men who could benefit from a more individualized approach to treatment. Overall, the analysis of the somatic landscape in MBC may provide further insights into the comprehension and characterization of the predictors for immune response and add new data to the increasing evidence on their impact in BC.
A better understanding of genetics, genomics and tumor profiles of MBC and the collaborative multidisciplinary approach behind this project will impact on the development of individualized medicine for MBC.
To date, clinical management of MBC has been considered similar to female BC management, however, increasing evidence indicates that BC in men and women may behave differently. Thus, there is an urgent need to obtain further evidence on the genetics and biology of this rare disease and how to best treat and support MBC patients.
Our study will facilitate the development of gender-specific clinical management guidelines in order to offer more targeted screening and surveillance programs for MBC patients and eventually for the delivery of precision medicine approaches.
A comprehensive investigation of the somatic mutational landscape of MBCs characterized for germline mutations in DNA repair genes, could provide opportunities for the delivery of precision medicine approaches facilitating the identification of subgroups of patients that may benefit from agents targeting specific pathway defects and/or immunotherapy. Specifically, the integration between germline mutations in DNA repair genes, TMB and MSI status, and clinical-pathologic information data will allow to select MBC patients and to expand the candidate pool for a more individualized therapeutic approach.