Male breast cancer is rare, accounting for less than 1% of all breast cancers and roughly 0.5% of cancers diagnosed in men, which has left the disease chronically understudied. Now, a multicenter retrospective study from two Brazilian institutions, A.C. Camargo Cancer Center and the University of Campinas, has assembled one of the largest clinicopathological and multigene germline datasets in an admixed, non-Caucasian, Latin American male breast cancer population. The findings, published in Breast Cancer Research and Treatment, describe a disease that is overwhelmingly hormone receptor-driven, frequently caught at advanced stages, and underpinned by inherited cancer predisposition variants in a strikingly high proportion of the men tested.
The researchers identified 106 adult men with histologically confirmed invasive or in situ breast carcinoma diagnosed between January 2000 and June 2022. The median age at diagnosis was 58.5 years, with ages spanning 33 to 84. Two-thirds of the men were treated at A.C. Camargo and one-third at UNICAMP, and about 35% of the diagnoses occurred before 2010. A family history of cancer was reported by 64% of patients, including breast cancer in 32% of cases, although no cases of male breast cancer were reported among relatives. Thirteen patients, or 12.3%, developed a second primary malignancy, most commonly prostate cancer, which accounted for 12 of those 13 cases.
The tumor profile matched the classical description of male breast cancer. Invasive ductal carcinoma dominated the histological landscape at 88% of cases, while ductal carcinoma in situ and invasive lobular carcinoma were rare, at 1.9% and 1.0% respectively. Most tumors were histological grade 2 or 3, and 93% were hormone receptor-positive, consistent with a predominantly luminal phenotype. HER2-positive tumors lacking hormone receptors were almost nonexistent at 0.9%, and triple-negative breast cancer accounted for just 3.9% of cases. At diagnosis, 89% of patients had localized or locally advanced disease, while 9.4% already presented with metastatic disease, predominantly involving bone.
Treatment patterns largely mirrored those used in female breast cancer, an approach the authors note is mostly extrapolated rather than validated in men. Every patient with non-metastatic disease, including those with ductal carcinoma in situ, underwent surgery, with total mastectomy the most frequent procedure at 85.8% of cases and axillary lymph node dissection performed in 63.2%. Among men with localized disease, 66% received chemotherapy, split between the adjuvant setting at 54% and neoadjuvant at 12%. The most common regimens were doxorubicin plus cyclophosphamide followed by weekly paclitaxel at 23.6% and doxorubicin plus cyclophosphamide alone at 18.9%. Adjuvant radiotherapy reached 48% of patients, and endocrine therapy with tamoxifen was used in 70% of cases.
The germline analysis forms the study’s scientific core. Testing was possible for 55 patients, or 52% of the cohort, using DNA from biobanks in 15 cases, saliva samples in 38, and prior clinical testing in 2. The remaining 51 men could not be tested because no biological material was available rather than because of any systematic clinical criterion, a limitation the authors acknowledge reduces but does not eliminate selection bias. Using custom multigene panels covering high- and moderate-penetrance cancer susceptibility genes, sequenced on an Illumina NextSeq platform and classified under ACMG/AMP guidelines, the team found pathogenic or likely pathogenic variants in 12 patients, or 21.8% of those tested.
BRCA2 was by far the most frequently affected gene, harboring pathogenic variants in 11% of tested men, followed by CHEK2 at 5.5%, MUTYH at 3.6%, and RAD51C at 1.8%. This distribution confirms that hereditary predisposition in male breast cancer extends well beyond BRCA2, even though BRCA2 remains the dominant contributor. The non-BRCA yield alone, four of 55 tested patients or 7.3%, is described by the authors as clinically meaningful at the individual-patient level, given the actionability of CHEK2 and RAD51C findings for cascade testing in relatives. Notably, variants of uncertain significance were detected in 25 patients, or 45.5% of those tested, a rate the authors attribute largely to the underrepresentation of admixed Latin American and Brazilian populations in the reference databases used for variant classification, such as ClinVar.
Perhaps the most consequential finding is what the data did not show. The presence of a pathogenic variant was not associated with differences in age, family history, histological grade, staging, molecular subtype, or overall survival. Family history of breast cancer was reported by 21% of carriers versus 5.7% of non-carriers, a difference that did not reach statistical significance with p equal to 0.16. The authors caution that the small absolute number of carriers, just 12, limits statistical power, so the absence of association should be read as inconclusive rather than as evidence of no effect. Still, the pattern reinforces what prior male breast cancer studies have suggested: family history alone is an imperfect predictor of germline risk, which strengthens the case for testing all men regardless of relatives’ cancer histories.
Survival analysis over a median follow-up of 64.5 months recorded 20 deaths among the 106 patients. Median overall survival was not reached, and the estimated 5-year overall survival rate was 80.6%, comparable to figures from large population-based datasets including SEER analyses. In univariate analysis, poorer survival was associated with histological grade 3, larger tumor size, lymph node involvement, metastases at diagnosis, and having received neoadjuvant or adjuvant chemotherapy. In multivariate Cox regression, three factors remained independently associated with mortality: histological grade 3 with a hazard ratio of 7.6, lymph node involvement with a hazard ratio of 6.4, and neoadjuvant or adjuvant chemotherapy with a hazard ratio of 8.7. The authors interpret the chemotherapy association as indication bias, since the treatment is preferentially given to patients with more aggressive and advanced disease, making it a marker of disease severity rather than a prognostic factor in its own right.
The clinical implications are direct. Current guidelines already recommend genetic counseling and germline testing for all men diagnosed with breast cancer regardless of family history, and these data support that position. For carriers, the identification of BRCA2 and RAD51C variants has therapeutic relevance, particularly regarding eligibility for PARP inhibitors in advanced disease, although prospective data in men remain limited. The authors also highlight the counseling implications of MUTYH findings, noting that while the gene is classically tied to autosomal recessive colorectal polyposis risk, monoallelic variants have been reported to confer a modest and potentially clinically relevant increase in breast cancer risk, with relevance for colorectal cancer surveillance in carriers and their relatives. In resource-limited settings, prioritizing BRCA2 testing may be pragmatic, with multigene panels considered when feasible.
More than 40% of patients in this cohort presented with stage III or IV disease at diagnosis, a figure the authors link to delayed diagnosis driven by absent screening programs, low clinical suspicion, and the stigma surrounding the disease in men. The study’s limitations include its retrospective design, testing of only a portion of the cohort, and the small number of variant carriers, which the authors say means results for some subgroups should be treated as hypothesis-generating rather than conclusive. Even so, the combination of frequent hormone receptor-positive disease, late-stage presentation, and a one-in-five carrier rate among tested men makes a clear case: male breast cancer is a biologically distinct entity with specific genetic implications, and every man diagnosed with it deserves a conversation about genetic counseling and multigene testing.
Subject of Research: Clinicopathological features and germline pathogenic variant prevalence in male breast cancer
Article Title: Male breast cancer: clinicopathological features and prevalence of germline pathogenic variants
Article References: Cerqueira, P. V. B. D., Campos, F. A. B., Caputo, S. M., Rouleau, E., Mantovani, H. K., da Silva, L. R., Cicilini, A. L., Sanches, S. M., Makdissi, F., da Costa, A. A. B. A., De Brot, M., Osório, C., Vasconcelos, V. C., de Lima, V. C., Casali da rocha, J. C., Carraro, D., Torrezan, G., & Santana dos Santos, E. (2026). Male breast cancer: clinicopathological features and prevalence of germline pathogenic variants. Breast Cancer Research and Treatment, 220(1), Article 26. https://doi.org/10.1007/s10549-026-08062-9
Image Credits: AI Generated
DOI: 10.1007/s10549-026-08062-9
Keywords: male breast cancer, germline variants, BRCA2, CHEK2, MUTYH, RAD51C, genetic testing, multigene panel, hormone receptor-positive, overall survival, PARP inhibitors, variants of uncertain significance
News Source: Nathaniel Bowman. (November 6, 2026). One in five men with breast cancer carries inherited cancer gene variants. Scienmag.
