Breast cancer (BC) in men is a rare and less investigated disease compared with BC in women. Germline mutations in BRCA1 and, mainly, BRCA2 genes are associated with increased risk of developing male BC (MBC). A relevant role of PALB2 gene in MBC predisposition has recently emerged. Overall, all these genes are primarily involved in DNA repair processes.
Pathogenic variants in DNA repair genes have been associated with increased tumor mutational burden (TMB) and, in turn, tumors with defects in these genes are hypothesized to be more immunogenic than tumors without these genetic defects.
Currently, preclinical and clinical studies are investigating whether the immunogenic microenvironment seen in BC patients could be leveraged with checkpoint blockade. However, the degree of anti-tumor response has been observed to vary widely and molecular features contributing to this variability remain yet unknown.
In this research project, we plan to investigate TMB status in MBCs previously tested for germline mutations in genes that are functionally linked to the DNA repair in order to provide a better understanding of mechanisms underlying different immunophenotype, with relevant clinical implications.
Breast tumors from MBC patients screened for germline mutations in DNA repair genes, will be analyzed by targeted panel NGS approach. Evaluation of TMB status and the integration with germline alterations and clinical-pathologic features 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 TMB and immunophenotype, thus allowing the identification of men who could benefit from a more individualized approach to treatment.
Overall, the analysis of the molecular profiles of MBC associated to TMB status may provide further insights into the comprehension and characterization of the BC somatic landscape and add new data to the increasing evidence on the impact of TMB in BC.
A fundamental goal of cancer precision medicine is to incorporate individualized factors into clinical decision making.
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.
To the best of our knowledge, a comprehensive genome analysis associated to TMB status has not yet been performed in MBC cases.
A comprehensive investigation of the molecular profiles of MBCs characterized for germline mutations in DNA repair genes, as proposed in our study, could provide opportunities for the identification of subgroups of patients that may benefit from agents targeting specific pathway defects, as for example PARP inhibitors for DNA repair deficiency, and eventually facilitating the delivery of precision medicine approaches.
In particular, the integration between germline mutations in DNA repair genes, TMB status, and clinical-pathologic information will allow to provide information on the characterization of actionable strategies for MBC patients that may eventually lead to a more individualized approach to immune checkpoint inhibitor therapy.
Overall, this study will facilitate the development of gender-specific clinical management guidelines in order to offer more targeted screening, surveillance and therapeutical approaches for MBC patients.
Furthermore, as MBC may represent an ideal "model" to improve knowledge of the genetics and biology of BC, since it is not affected by confounding factors commonly observed in female BC, the findings of this study may be of relevance in the clinical management of BC patients of both sexes.