Masculinizing Testosterone Therapy Reduces the Incidence of PIK3CA-Mutant/ER⁺ Breast Cancer but Not BRCA1-Associated Triple-Negative Breast Cancer

TT reduces ER+ BC risk but does not eliminate risk, and has a negligible impact on BRCA1 -related triple-negative BC risk. TT does not affect tumor growth once tumors are established but modulates the tumor microenvironment. Our work supports the need for breast cancer screening in TT users. Highlights: TT reduces but does not completely ablate the breast epithelium. TT decreases PIK3CA -related ER+ breast cancer incidence by 81% compared to female control mice (adj RR 0.19, 95% CI 0.08-0.45), but does not affect BRCA1 -related triple negative breast cancer incidence. TT does not affect tumor progression once the tumor is established.Trans masculine breast tumors are mostly ER+ (83.3%), small and node-negative, but are also moderately to poorly differentiated (70.8%).Tailored risk assessment and ongoing surveillance strategies are key for the care of transmasculine individuals who use TT.