Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology

Virginia Valentini; Valentina Silvestri; Agostino Bucalo; Giulia Conti; Mina Karimi; Linda Di Francesco; Giulia Pomati; Silvia Mezi; Bruna Cerbelli; Maria Gemma Pignataro; Arianna Nicolussi; Anna Coppa; Giulia D'Amati; Giuseppe Giannini; Laura Ottini

doi:10.3389/fonc.2022.1092201

Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology

Front Oncol. 2023 Jan 6:12:1092201. doi: 10.3389/fonc.2022.1092201. eCollection 2022.

Authors

Affiliations

¹ Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
² Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
³ Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome, Rome, Italy.
⁴ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.

Abstract

Introduction: Compared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI).

Methods: In this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples.

Results and discussion: A total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy.

Keywords: clinically actionable genetic variants; copy number variations (CNVs); male breast cancer (MBC); microsatellite instability (MSI); precision oncology; targeted gene panel sequencing; tumor mutational burden (TMB); tumor profiling.

Grants and funding

The study is supported by Associazione Italiana Ricerca Cancro (AIRC, IG-21389) to LO, and by Italian Ministry of Education, Universities and Research – Dipartimenti di Eccellenza – L. 232/2016; Associazione Italiana per la Ricerca sul Cancro (AIRC, IG-24329, Istituto Pasteur-Fondazione Cenci Bolognetti and fondi Ricerca Ateneo La Sapienza to GG.