Assessment of breast and prostate cancer risk in trans and gender diverse individuals receiving gender-affirming hormone therapy.

Introduction: Gender-affirming hormone therapy (GAHT)-most commonly involving estradiol combined with either cyproterone or spironolactone-plays a central role in gender affirmation. However, its expanding use has raised concerns regarding potential health implications, particularly in relation to breast and prostate cancer. This study examines the association between GAHT and the incidence of these cancers in individuals with gender incongruence. Methods: We conducted a retrospective analysis using clinical data from TriNetX, a federated health research network. Individuals diagnosed with gender incongruence (ICD-10-CM: F64) were divided into two groups: the GAHT group, who received estradiol with or without cyproterone or spironolactone, and the non-GAHT group, who received none of these agents. Propensity score matching was performed based on age and sex (as recorded in electronic health records) to balance the groups. Data on confounding lifestyle risk factors such as smoking and alcohol use were not available. Breast and prostate cancer incidence was then compared using risk differences (RD) and risk ratios (RRs). Results: After matching, 18,332 trans individuals (mean age: 30.0 ± 12.5 years) were included in the breast cancer analysis. Breast cancer was diagnosed in 1.0% of the GAHT group and 0.3% of the non-GAHT group, corresponding to an RD of 0.7% (95% CI: 0.6-0.9%) and an RR of 3.57 (95% CI: 2.64-4.84). For prostate cancer, a separate matched cohort of approximately 22,338 individuals was analyzed. Incidence was 0.13% in the GAHT group and 0.06% in the non-GAHT group, with an RD of 0.06% (95% CI: 0.01-0.12%) and an RR of 2.00 (95% CI: 1.05-3.80); however, this difference did not reach statistical significance. Conclusions: While the absolute incidence rates of both breast and prostate cancer were very low in this cohort, we observed modestly higher rates among trans individuals receiving GAHT compared to those who did not. However, in the absence of data on key confounders such as smoking and alcohol use, these associations should be interpreted with caution, as residual confounding cannot be excluded. The results highlight the need for ongoing cancer surveillance, individualized risk-table assessment, and the development of inclusive clinical guidelines to ensure safe and equitable care for gender-diverse populations.