The incidence of male breast cancer in Klinefelter Syndrome and its proposed mechanisms.

Introduction: Men with Klinefelter Syndrome (KS) have been previously reported to have an increased risk of Male Breast Cancer (MBC). This systematic review provides the latest information regarding the incidence of MBC in the KS population compared to the standard male population and identifies mechanisms by which MBC may develop in KS.

Material And Methods: Several databases were searched including PubMed/MEDLINE and EMBASE between October 2023 and March 2024. The review was conducted in accordance with the latest Preferred Reporting Items for Systematic Reviews and Meta-analyses-guidelines and was registered in PROSPERO (CRD42024551110). Overall, 332 papers were identified for screening. Standardised incidence ratios (SIRs) were calculated in comparison to national incidence figures. Additionally, a literature review was conducted looking at potential MBC mechanisms in KS.

Results: Across Danish and British cohorts, incidence of MBC in KS was significantly higher than the general population: SIR 18.1 (95 % CI: 13.53 to 24.74), p<0.001. Breast cancer rates in women are still far higher (68.50 per 100,000 woman-years). MBC mechanism in KS may involve decreased micro-RNA (MIR-3648 and MIR3647) expression, increased oestrogen/progesterone receptor expression and exogenous androgen use.

Conclusions: Rates of MBC are significantly raised in KS and a higher clinical suspicion of breast cancer should be considered when assessing men with KS. The true aetiology of MBC in KS, however, requires further research. There is a need for an accurate and up to date study of MBC incidence in KS to define the current risk.