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

The effects of gender-affirming testosterone therapy (TT) on breast cancer (BC) risk in the general trans masculine population and among BRCA1/2mut carriers are unclear. We found that TT reduced the size but not the number of terminal duct lobular units, increased stromal expression of estrogen receptor (ER), progesterone receptor, and Ki67, and had an immunosuppressive effect. We leveraged preclinical models to assess TT’s effect on BC incidence and biology. Consistent with the human data, TT reduced mouse mammary gland branching and the number of terminal end buds. TT decreased Pik3ca-related ER+ BC incidence by 81% compared to female controls (adj RR 0.19, 95% CI 0.08-0.45), but had no effect on Brca1-related triple negative BC incidence. Our findings clarify that TT modifies the risk for PIK3CA-related ER+ BC but not BRCA1-associated triple-negative BC, emphasizing the ongoing need for surveillance and individualized care in this population.