Abstract PS3-05-23: Characteristics and Outcomes of Breast Cancers Diagnosed in Patients with Germline Hereditary Mutations - The BC Cancer Hereditary Cancer Program High Risk Clinic Experience

Abstract Background. Individuals with germline hereditary mutations in breast cancer (BCa) predisposition genes are at significantly higher risk of developing BCa during their lifetime compared to the general population. In British Columbia, patients identified as carrying a deleterious mutation are followed by the Hereditary Cancer Program (HCP) High Risk Clinic (HRC) for management of their increased BCa risk. This study evaluates the clinical and pathologic features, and outcomes for BCa diagnosed in hereditary mutation carriers under the HRC. Methods. Patients followed in HRC with a confirmed deleterious hereditary mutation, and at least one BCa diagnosis after HCP enrollment were included in this study. Patient and tumor characteristics, detection method, treatment, and survival outcomes were collected. BCa diagnoses were categorized as prevalent (detected on first screening after HCP enrollment); incident (detected on routine imaging beyond first screening). Prevalent or incident BCa detected within 6 months of a normal screening and outside of the usual screening schedule were characterized as interval cancers. Results. Clinico-Pathologic Characteristics. Between 1997-2023, 166 patients were diagnosed with BCa out of 2011 patients (166/2011, 8.2%) seen in HRC in that period. Median age of BCa diagnosis was 45 (IQR 39-57). The most common deleterious mutations were BRCA1 (44.6%) and BRCA2 (40.4%). Other mutations included CHEK2 (4.2%), PALB2 (4.2%), TP53 (3.6%), ATM (2.4%), and NF1 (0.6%). In our cohort, 39 (23.5%) BCa were classified as prevalent, 127 (76.5%) as incident. Twenty-four cases (14.5%) met the criteria for interval BCa. MRI was the most common detection modality (50.6%), followed by mammography (26.5%), clinical exam (10.8%), and ultrasound (2.4%). Of note, 16 (9.6%) cases were diagnosed at time of prophylactic surgery and were not identified on prior imaging. Among all BCa diagnoses, 37 cases (22.3%) were in-situ disease only, and 129 (77.7%) had invasive disease on final pathology. Within invasive tumors, 66.7% had stage 1, 26.4% stage 2, 6.2% stage 3, and one patient had de-novo stage 4 disease at diagnosis. Incident cancers were more likely to be diagnosed at stage 1 compared to prevalent cancers (71% vs 48%, p=0.015). Invasive BCa subtype distribution was 51.9% hormone receptor positive HER2-negative (HR+HER2-), 32.6% triple negative (TNBC), and 15.5% HER2-positive. Of note, BRCA1 tumors were more likely TNBC (52.2%, p<0.001) and BRCA2 tumors were more likely HR+HER2- (60.3%, p<0.001). Treatment. Most patients (153/166, 92.2%) underwent bilateral mastectomies as the surgical treatment of choice. Among patients with invasive BCa, 79 (47.6%) received chemotherapy either in the neo-adjuvant or adjuvant setting. There was no statistically significant association between incident or prevalent BCa and receipt of chemotherapy. There is a marginally statistically significant association between interval cancer and receipt of chemotherapy (p =0.067). Approximately 20% of all patients received adjuvant radiation therapy, including 26/153 (17%) who had bilateral mastectomies; 114/166 (68.7%) underwent prophylactic risk-reducing bilateral salpingo-oophorectomy. Outcomes. At time of last follow up, there were 8 deaths in our cohort, 5 due to metastatic BCa, and 3 due to ovarian cancer. An additional 10 patients were diagnosed with recurrent BCa and undergoing treatment. Three and 5-year overall survival rates in our cohort were 98% and 95.2%. Conclusions. Patients diagnosed with BCa under the HCP program have excellent outcomes. BRCA mutations are the most common identified alteration, and BRCA1 is enriched for TNBC. Further work is needed to identify clinical and biological features of interval cancers in this population. Citation Format: Z. Mitri, K. Preston, A. Harrison, A. Smith, T. Nghiem, R. Cheifetz. Characteristics and Outcomes of Breast Cancers Diagnosed in Patients with Germline Hereditary Mutations - The BC Cancer Hereditary Cancer Program High Risk Clinic Experience [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 PS3-05-23.