Pal, T.

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.

Abstract Background: BRCA2 variants with partially aberrant RNA splicing have been associated with a relatively lower breast cancer risk (reduced penetrance) relative to canonical pathogenic variants. However, the existence of partial loss of function (hypomorphic) missense variants, conferring reduced penetrance, is less certain. Identification and assessment of the clinical relevance of such reduced penetrance pathogenic variants (RPPVs) is needed to provide accurate risk estimates. Methods: Comprehensive functional characterization of hypomorphic missense variants (n=70) in the BRCA2 DNA-binding domain, initially identified through homology-directed DNA repair (HDR) assays, was conducted through multiple independent functional assays, including HDR, CRISPR/Cas9-based endogenous targeting, RAD51 foci formation assay, and Poly(ADP-ribose) polymerase (PARP) inhibitor response assay. Risk estimates were obtained using two large datasets from patients referred for hereditary cancer testing. A ClinGen/ACMG/AMP model was used for clinical classification. Results: The variants consistently demonstrated hypomorphic HDR activity and endogenous survival in HAP1 targeted cells, decreased RAD51 foci formation, and increased sensitivity to PARP inhibitors. These variants were associated with a moderate increase in breast cancer risk, as shown in two independent studies: one using multivariable logistic analysis adjusted for age, ancestry and family history (OR=2.41, 95%CI=1.51-3.85) and another comparing frequencies of variants in breast cancer cases to public reference controls adjusted for ancestry (OR=2.09, 95% CI=1.16-4.08). The mean age of breast cancer diagnosis for carriers of hypomorphic variants was 57 years, which was significantly older than the mean age of diagnosis of 51 years for carriers of protein truncating variants. Functional data were combined with other evidence sources in a ClinGen/ACMG/AMP model to classify 14 variants as “likely pathogenic”. Conclusions: We identified partially functional, hypomorphic missense variants associated with reduced penetrance for breast cancer. Cancer risk management guidelines for this new category of variants should be revisited given that the associated breast cancer risks warrant high risk screening but do not meet the threshold at which risk reducing mastectomy is offered. This study supports a shift in paradigm to considering variant-based risks on a continuum, with implications for risk-appropriate cancer risk management. Citation Format: H. Huang, C. Hu, J. Na, M. Kucera, T. Simmons, E. Mundt, C. C. Young, Z. Heidari, P. C. Lyra, Y. Y. Tan, K. L. Nathanson, T. Pal, R. Karam, T. Pesaran, S. Yadav, S. M. Domchek, A. N. Monteiro, E. Hughes, N. Boddicker, W. Chen, M. E. Richardson, F. J. Couch. Partially functional (hypomorphic) missense variants in BRCA2 are reduced penetrance pathogenic variants [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 PD4-05.