Abstract PD4-11: Contralateral Breast Cancer Risk in Women with PALB2-Associated Breast Cancer

Abstract Introduction: Women with a germline pathogenic variant (PV) in PALB2 face a lifetime risk of breast cancer, generally exceeding 40%. We have initiated an international clinical follow up study of women with stage 0 to stage 4 breast cancer and a PALB2 PV to evaluate clinical characteristics and to determine optimal treatments. The objective of the current study was to estimate and to identify factors predictive of contralateral breast cancer (CBC) risk. Methods: Clinical data, including diagnostic, treatment, and follow-up data, were collected by medical record review for eligible women with breast cancer and a germline PV in PALB2. PV carriers were followed every two years to collect information about recurrences, new cancers, and vital status. Data was summarized using descriptive statistics. The risk of CBC was estimated by following women from the date of breast cancer diagnosis until the date of: 1) contralateral breast cancer, 2) contralateral mastectomy, 3) death from any cause, or 4) last follow-up. The cumulative incidence of CBC was calculated with the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with contralateral breast cancer risk. Covariates included age at diagnosis, ER status, grade, nodal status, chemotherapy, radiation therapy, tamoxifen, and bilateral salpingo-oophorectomy (time-dependent). Results: Among 888 PALB2 carriers, the mean age at diagnosis of breast cancer was 49.3 years (range 22 to 83 years). Overall, 36 women (4.1%) were diagnosed with synchronous bilateral breast cancer. 73.6% of the breast cancers were ER-positive, and 29% were lymph node-positive. Patients were followed for a mean of 5.6 years (range 0.3 to 22 years) from date of diagnosis. During the follow-up period, 53 patients were diagnosed with a metachronous CBC. The 15-year risk of metachronous CBC was 26.4% overall; 19.5% for those diagnosed younger than 50 years, and 34.8% for those diagnosed at 50 years or older. In a multivariate analysis, ER status was not significantly associated with CBC risk (RR 1.15, 95%CI 0.45-2.93, p=0.77). Bilateral salpingo-oophorectomy (BSO) was associated with a significant reduction in the risk of CBC (RR 0.17, 95%CI 0.04-0.70, p=0.02). In the follow-up period, 47 women were diagnosed with another incident cancer, including seven with pancreatic cancer and three with ovarian cancer Conclusion: The high 15-year risk of contralateral breast cancer suggests that bilateral mastectomy should be considered for primary surgical intervention. Moreover, bilateral salpingo-oophorectomy (BSO) significantly reduces the risk of CBC and should be considered post-treatment. Citation Format: K. Metcalfe, A. Stachowski, F. Couch, M. Marabelli, S. Wong, S. Domchek, A. Aeilts, A. Eisen, R. Kim, T. Ramon y Cajal, R. Fruscio, S. Yadav, C. Hoey, S. Karamali, P. Sun, J. Lubinski, S. Narod, T. Pal. Contralateral Breast Cancer Risk in Women with PALB2-Associated Breast Cancer 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 PD4-11.