Abstract Introduction: Hormone replacement therapy (HRT) is a widely recommended strategy for relieving menopausal symptoms, particularly for healthy women under 60 years of age or within 10 years of menopause. However, HRT has been excessively used in Brazil, including less studied compounds and delivery methods, such as subcutaneous implants of gestrinone. Although HRT provides symptomatic benefits, the increased risk of breast cancer has already been confirmed with certain types of hormone therapy. While numerous risk factors—such as age at menarche, menopause, parity, and obesity—are well established, 5-10% of breast cancer cases are linked to hereditary genetic predisposition. In this context, tools such as CanRisk, when integrated with genetic counseling (GC) and germline testing, enable personalized risk assessment and inform clinical decision-making. Objective: To investigate how the integration of GC and CanRisk (v3.0.0) influences BC risk stratification and modifies screening and prevention recommendations in women using or planning to initiate HRT. Methods: This exploratory, quantitative, retrospective study analyzed electronic medical records of women referred for BC risk assessment at a private oncogenetics service in Brazil between September 2022 and May 2025. The primary reason for referral was to discuss HRT initiation or continuation. Testing indications followed the 2025 NCCN guidelines. Risk management recommendations were based on CanRisk estimates: breast MRI for lifetime BC risk 20%; chemoprevention for 5-year BC risk 1,7% or 10-year BC risk 5%; and risk-reducing surgery for carriers of high-penetrance pathogenic variants (PVs). Results: A total of 144 women were included (mean age: 51 years). Of these, 100 (69,4%) met NCCN criteria for genetic testing, and 95 (94,1%) proceeded with testing. Among the 44 women (30,6%) who did not meet criteria, 40 (90,9%) opted for testing after a shared decision-making process, totaling 135 tested individuals. The integration of CanRisk and GC resulted in a change in clinical management for 29 women (21,5%). Regarding chemoprevention, 117 women (86,7%) were initially eligible, and after genetic testing, 9 (6,7%) lost this indication, while 4 (3,0%) gained it due to findings of PVs in BC susceptibility genes. For MRI surveillance, 15 patients (11,1%) were initially eligible; 5 (3,7%) lost and 8 (5,9%) gained the indication based on revised lifetime risk estimates. A total of 14 pathogenic variant (PV) carriers (10.4%) were identified. Among these, nine women (6.7%) received new surgical recommendations due to high-penetrance PVs: four women with BRCA1 mutations were advised to undergo bilateral risk-reducing mastectomy and bilateral salpingo-oophorectomy; two women with BRCA2 mutations were recommended bilateral mastectomy—one had already undergone oophorectomy, while the other was additionally advised salpingo-oophorectomy. One woman with a PALB2 mutation was advised bilateral mastectomy. Two women with RAD51C and RAD51D mutations were recommended bilateral salpingo-oophorectomy. Notably, one patient was diagnosed with ductal carcinoma in situ after undergoing a risk-reducing mastectomy. Discussion and Conclusion: Integrating CanRisk and GC significantly impacted risk stratification, with the new BC risk estimates resulting in reclassification in over one-fifth of the cohort (21,5%). Importantly, genetic testing should not be universally indicated for all women considering or using HRT; however, this context provides a valuable window of opportunity to identify patients who already meet criteria for genetic counseling and testing but had not yet been referred. This proactive approach supports precise cancer prevention, better clinical safety, and informed, shared decision-making for HRT use Citation Format: J. T. Santos, D. B. Macedo, P. B. Porto, I. B. Rocha, R. S. Guindalini. Genetic Risk Stratification for Breast Cancer in Patients Considering or Undergoing Hormone Replacement Therapy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-12.
Santos et al. (Tue,) studied this question.