Hemochromatosis: A Risk Factor for Breast Cancer? Systematic Review and Meta-Analysis.

Abstract

Objective: Hereditary hemochromatosis and breast cancer are two major public health problems. The HFE gene variants C282Y and H63D, responsible for most cases of hemochromatosis, may contribute to carcinogenesis via iron overload, oxidative stress, and hormonal modulation. The aim of this study was to evaluate the association between HFE variants and breast cancer risk and propose a personalized surveillance strategy.

Materials and methods: A systematic review and a meta-analysis were conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible studies included case-control and cohort studies reporting breast cancer incidence in women with HFE gene C282Y and/or H63D variants. Data were pooled using a random-effects model. Subgroup analyses and meta-regressions explored sources of heterogeneity.

Results: Eight studies comprising 73,981 participants were included, published between 2000 and 2025. Among them, analysis of four revealed a link between hemochromatosis and breast cancer risk. In one study, a link was observed between the HFE C282Y allele and higher lymph node involvement, which may suggest an impact of hemochromatosis on tumor progression. By contrast, three studies did not find any link between the two diseases. Our meta-analysis showed a trend toward increased breast cancer risk in carriers of HFE variants, particularly C282Y homozygotes (odds ratio = 1.36, 95% confidence interval = 0.75-1.98). Substantial heterogeneity was present (I² >50%), but no tested covariates significantly explained this variation. Sensitivity analyses confirmed the robustness of the estimate.

Conclusion: In the absence of randomized trials with mortality endpoints, our findings do not yet justify changes in clinical practice. They nevertheless support prospective studies to assess whether women carrying these pathogenic variants, especially C282Y/C282Y homozygotes, could benefit from adapted breast cancer surveillance, potentially involving more frequent evaluations or advanced imaging to improve early detection.