Testosterone therapy (TT) is administered to enhance masculinization in transgender individuals. The long term effect of exogenous testosterone on breast tissues remains unclear. Our study evaluated the modulation of breast morphology by TT in transgender individuals with special attention to duration of TT. We reviewed 447 breast surgical specimens from gender affirming chest-contouring surgery, and compared histopathological findings including degree of lobular atrophy, and atypical and non-atypical proliferations between subjects who did ( n =367) and did not ( n =79) receive TT. TT for one patient was unknown. TT for >12 months was associated with seven histopathological features. Longer duration of TT was significantly associated with higher degrees of lobular atrophy ( p <0.001). This relationship remained significant after accounting for age at surgery, ethnicity, body mass index, and pre-surgical oophorectomy (adjusted p <0.001). Four types of lesions were more likely to be absent in breast tissues exposed to longer durations of TT: cysts (median=16.2 months; p <0.01; adjusted p =0.01), fibroadenoma (median=14.8 months; p =0.02; adjusted p =0.07), pseudoangiomatous stromal hyperplasia (median=17.0 months; p <0.001; adjusted p <0.001), and papillomas (median=14.7 months; p =0.04; adjusted p =0.20). Columnar cell change and mild inflammation were also less likely to occur in subjects receiving TT ( p <0.05), but were not linked to the duration of TT. Atypia and ductal carcinoma in situ (DCIS) were detected in 11 subjects (2.5%) all of whom received TT ranging from 10.1 to 64.1 months. The incidental findings of high-risk lesions and carcinoma as well as the risk of cancer in residual breast tissue after chest-contouring surgery warrant the consideration of culturally sensitive routine breast cancer screening protocols for transgender men and masculine-centered gender non-conforming individuals. Long-term follow-up studies and molecular investigations are needed to understand the breast cancer risk of transgender individuals who receive TT.

Background: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk. Methods: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case–control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes. Results: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index (P &lt; 0.05). No measure was correlated with body size at ages 5–10 years, age at menarche, age at first birth, or breastfeeding history (P &gt; 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk. Conclusions: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer. Impact: TDLU involution may not impact breast cancer risk as previously thought.

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