To date, the characterization of tumor microenvironment and immunological properties of tumors has proven to be essential for immunotherapy strategies, a cutting-edge cancer treatment.
Recently, unique immunophenotype in breast cancer cases with germline mutations in BRCA1/2 genes has been suggested.
BRCA1/2 belong to the homologous recombination (HR) pathway and, mainly BRCA2, play a central role in male breast cancer (MBC) predisposition.
Increasing evidence also indicate a relevant role of other HR genes in MBC susceptibility.
Our preliminary data on MBC transcriptome indicated differentially expressed genes in MBCs with and without mutations in HR genes. In particular, pathway-based analyses showed different transcriptomic profiles for genes involved in translational initiation, cell cycle, DNA damage and repair pathways, suggesting that germline mutations in HR may define molecular subgroups of MBCs with peculiar biological features.
This proposal is aimed at deeply characterize HR-related MBCs analyzing immunological features and MBC immunophenotype by using transcriptomic data. In particular, tumor purity and the presence of infiltrating stromal/immune cells in tumor tissues, the fraction of immune cell types, and parameters of response to immunotherapy (T cell-inflamed and cytolytic activity) signature will be evaluated.
The study will be performed on a well-characterized series of MBC cases, including MBCs with or without mutations in HR genes.
Overall, transcriptomic profile may provide key insights into the characterization of tumor microenvironment specifically regarding immune-gene expression, allowing for an improved understanding of immune-genetic properties of MBCs, in particular in cases with mutation in BRCA1/2 and other HR genes, with relevant clinical implications.
Analysis of the transcriptomic profile in MBC with or without mutation in HR genes may provide key insights into the characterization of tumor microenvironment specifically regarding immune-gene expression and will shed light on immune-genetic properties of MBC tumors, particularly HR-related MBCs.
In particular, the characterization of the immunological features of MBC will allow for the identification of men who could benefit from a more individualized approach to treatment, especially regarding sensitivity to immunotherapy (possible response to immunotherapy)
To date no gender-speci¿c guidelines for the treatment of BC exist, and clinical management of MBC has been largely extrapolated from studies on female BC. While thought traditionally to be similar to ER/PR positive post-menopausal female BC, emerging evidence suggests that MBC may be different, with unique molecular subtypes. The identification of specific MBC features is essential for developing an appropriate and specific clinical approach.
In this regard, RNA-based measure of immune gene expression could add significant information on specific immune signatures among different subtypes of BCs, particularly HR-related MBCs.
Due to the rarity of MBC, studies with a multicenter setting including sufficiently large numbers of samples are essential for robust data with possible clinical utility.
Taking advantage of our large and well-characterized series of MBCs and based on our preliminary results on trascriptome profiles in MBCs with or without mutation in HR genes, we plan on going further inside into the characterization of transcriptome landscape of MBCs, focusing on immune-gene-expression analysis, in order to identify specific immune-genetic properties by mutation status and/or molecular subtype. Overall, this characterization could eventually improve our understanding of mechanisms underlying BC development and progression and may offer targets for clinical management of BC patients, particularly for carriers of mutation in HR genes.