Abstract P1-03-01: Towards Universal Germline Screening for Breast Cancer, Planning for a Sustainable Future: A Single-Center Retrospective Analysis

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Abstract Background: The implementation of germline genetic testing is complex due to emerging therapeutic indications such as adjuvant Olaparib for BRCA-mutated breast cancer (BC). Understanding the clinical-pathological characteristics of individuals meeting testing criteria for genetic testing can provide insights into the factors associated with identifying pathogenic germline variants (PVs) and likely pathogenic germline variants (LPVs). This knowledge can enhance the precision of genetic counseling and testing strategies. In this study, we reviewed our single-center experience of testing selected patients meeting clinical and pathological features, to develop a progressive and more sustainable model on the way towards universal germline screening. Methods: We evaluated 1,060 consecutive individuals with a personal history of breast cancer (BC) who met regional criteria for germline testing at the Hospital Clinic of Barcelona between 2016 and 2022. We excluded individuals diagnosed before 2000 (n=70), those women with DCIS (n=60), and those with missing clinical information (n=18). Clinical-pathological and molecular characteristics between carriers of PV/LPV and non-carriers. Chi-square tests or Student’s t-tests were used to compare the distribution of variables between two groups. Logistic regression analysis was then employed to evaluate the association of each variable with PV/LPV. The significance level for all statistical analyses was set at a two-sided alpha of 0.05. Results: A total of 912 individuals were evaluated. Most cases were women (n=898, 98.5%) with a median age of 49 (range 24-88) and had a family history (n=706, 78.3%). The main reasons for testing were family aggregation (n=357, 39.1%), BC onset ≤40 yrs-old (n=199, 21.8%), and triple-negative breast cancer (TNBC) onset ≤60 yrs-old (n=162, 17.7%). The rate of PV/LPV was 14.9% (n=136), and 151 individuals (16.6%) had variants of unknown significance (VUS). Overall, 776 (85.1%) had no PV/LPV identified. A higher number of PV/LPVs were identified in the BRCA2 gene (n = 41, 30.1%), followed by BRCA1 (n=31, 22.8%), CHEK2 (n=17, 12.5%), ATM (n=15, 11.0%), PALB2 (n=13, 9.6%), BRIP1 (n=5, 3.7%), TP53 (n=5, 3.7%), BARD1 (n=2, 1.5%), MSH2 (n=2, 1.5%), PTEN (n=2, 1.5%), BAP1 (n=1, 0.7%), CDKN2A (n=1, 0.7%), and RAD51C (n=1, 0.7%). Notably, 2 individuals with a PV in BRCA2 had another PV (i.e., MSH6 and CDK2NA), and 2 individuals with a PV in PALB2 had another PV (i.e., both in CHEK2). Most VUS (n=151) were identified in ATM (n=38, 25.2%), BRCA2 (n=23, 15.2%), PALB2 (n=15, 9.9%), MSH6 (n=12, 7.9%), and BRCA1 (n=10, 6.6%). The BC subtype distribution was 62.4% (n=563) HR+/HER2-, 15.0% (n=141) HER2+, and 22.0% (n=198) TNBC. The clinical-pathological variables significantly associated in univariate analyses with the identification of PV/LPV were sex, age, personal history of other cancer types, advanced TNM stage, TNBC, and bilateral BC. In a multivariable analysis, all the previously mentioned variables remained significantly associated with the identification of PV/LPV. The highest odds ratios (OR) were found for the following 2-group variables: male (OR=4.8), stage IV versus stage I (OR=3.1), bilateral BC (OR=2.7), other personal histories of cancer (OR=2.2), and TNBC (OR=1.7). Age was considered a continuous variable, and for every 10-year increase, the odds of detecting a PV/LPV decreased by approximately 34%. Conclusions: Based on established historical testing criteria, specific clinicopathological features were significantly and independently associated with the detection of clinically significant variants. As we move towards universal germline screening for breast cancer, well-established information continues to help prioritize individuals who will benefit most from early detection of breast cancer susceptibility. Citation Format: Adela Rodriguez Hernandez Barbara Adamo, Fara Brasó-Maristany, Benedetta Conte, Olga Martínez-Sáez, Miriam Potrony, Lorena Moreno, Elia Grau, Esther Sanfeliu, Raquel Gómez, Isabel García, Beatrice Fatrini, Elia Segui, Maria Vidal, Montserrat Muñoz, Teresa Ramón y Cajal, Francesc Balaguer, Aleix Prat, Barbara Adamo. Towards Universal Germline Screening for Breast Cancer, Planning for a Sustainable Future: A Single-Center Retrospective Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-03-01.

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