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.
