Alteration in estrogen receptor status in metachronous contralateral breast cancer among unilateral early breast cancer patients with BRCA 1/2 mutations

Background: BRCA1/2 mutations significantly increase the risk of contralateral breast cancer (CBC). However, their influence on estrogen receptor (ER) status changes between primary breast cancer and metachronous CBC remains unclear. This study investigates ER status alterations in CBC patients with BRCA1/2 mutations to clarify their clinical implications. Methods: In this multicenter retrospective study (2004–2020), patients with unilateral early breast cancer who underwent BRCA1/2 testing and developed metachronous CBC were grouped by BRCA1/2 mutation status. ER status of primary and CBC tumors was compared using Fisher's exact test and logistic regression to assess the relationship between BRCA1/2 mutations and ER alterations. Results: Among 423 CBC patients, those with BRCA1 mutation had a higher likelihood of ER negative primary tumors maintaining ER negative disease in CBC (70.7 %) compared to BRCA1/2 negative patients (odds ratio [OR] 3.8, p < 0.001). Similarly, ER negative primary tumors were more likely to remain ER negative in CBC among BRCA1 or BRCA2 mutation carriers (64.8 %, OR 2.9, p = 0.002). These findings demonstrate a strong association between BRCA1 mutations and development of ER negative CBC in ER negative primary breast cancer. Among patients with primary ER negative breast cancer, those who received adjuvant chemotherapy for both primary and CBCs showed a higher rate of ER negative CBC (OR 4.23, p = 0.001). Conclusion: BRCA1 mutation carriers face a higher risk of developing ER negative metachronous CBC, in ER negative primary tumor. These results support genetic counseling and risk-reducing strategies, including prophylactic mastectomy, for BRCA1 mutation carriers.