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Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology
Virginia Valentini1, Valentina Silvestri1, Agostino Bucalo1
1Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
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.
Insights
Next Generation Sequencing (NGS) identified targetable molecular alterations in over 70% of male breast cancer (MBC) cases. This comprehensive tumor profiling enables precision therapy selection for MBC patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Male breast cancer (MBC) is rare, with limited specific molecular biomarker data.
- Current therapies for MBC are extrapolated from female breast cancer, despite distinct disease characteristics.
- Lack of MBC-specific biomarkers hinders personalized treatment strategies.
Purpose of the Study:
- To comprehensively profile the molecular landscape of male breast cancer using Next Generation Sequencing (NGS).
- To identify actionable molecular alterations, including somatic variants, copy number variations (CNVs), tumor mutational burden (TMB), and microsatellite instability (MSI) in MBC.
- To assess the potential of NGS for guiding precision/targeted therapy in male breast cancer patients.
Main Methods:
- Analyzed 15 male breast cancer samples using NGS multigene panel sequencing (TruSight Oncology 500, Illumina).
- Characterized somatic variants, CNVs, TMB, and MSI in tumor DNA.
- Targeted 523 cancer-relevant genes across 1.94 Mb of the genome.
Main Results:
- Detected 40 pathogenic variants in 24 genes; all MBC cases had at least one.
- PIK3CA mutations were most frequent (40.0%), with targetable alterations found in 70% of cases.
- Identified frequent copy number gains (86.7%), notably MYC amplification (53.3%), and detected high TMB/MSI in 13% of cases each.
Conclusions:
- NGS multigene panel sequencing provides a robust molecular tumor profile for male breast cancer.
- The high prevalence of targetable alterations supports the use of NGS for selecting MBC patients for precision therapies.
- This approach can bridge the gap in understanding MBC's unique molecular characteristics and improve treatment outcomes.
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