Abstract PS4-11-11: Germline Mutation Landscape in DCIS: Impact of Age and Family History in a Middle Eastern Cohort

Abstract Background: Ductal carcinoma in situ (DCIS) represents a heterogeneous pre-invasive breast cancer entity, with genetic predisposition playing a potential role in disease development. This study aims to evaluate the frequency and spectrum of pathogenic germline variants among Jordanian patients with DCIS who underwent genetic testing. Methods: A retrospective review was conducted on clinical and genetic data on patients diagnosed with DCIS. Variables included age at diagnosis, hormonal receptor status (ER/PR/HER2), family history of cancer, and results of germline genetic testing. Variant classification was harmonized according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Eligible patients, as per the National Comprehensive Cancer Network (NCCN) guidelines, underwent germline genetic testing (GGT) using an NGS-based multi-gene panel. Rates of GGT was stratified against known variables including age, family history and hormonal status. Results: Between July 2006 and September 2024, a total of 622 patients with DCIS were treated and followed at our institution. Germline genetic testing was performed on 271 (43.6%) patients. Except for one, all were female and median age (range) was 47 (20-90) years. Twenty patients (7.4%) were identified as harboring pathogenic or likely pathogenic (P/LP) variants. The most frequently mutated gene was BRCA2, detected in 9 (45.0%) patients, followed by CHEK2 (3 patients including one likely pathogenic), BRCA1 (2 patients), TP53 (2 patients), ATM (2 patients), and single cases involving NF1 and PALB2. Additionally, 4 (1.5%) patients carried variants classified as "Increased Risk Allele"; all were in the APC gene and were considered separately. A significant proportion of patients (n=94, 34.7%) had variants of uncertain significance (VUS), reflecting the challenges of interpretation in underrepresented populations. Patients with P/LP variants tended to be diagnosed about 5 years earlier (mean age: 43.7 years) compared to 48.9 years for those without. The prevalence was notably higher in patients aged ≤50 years (n=16, 9.5%) compared to those over 50 (n=4, 3.9%), though the difference did not reach statistical significance (p = 0.078). While there’s a clear numerical difference in rates among 229 patients with family history of cancer (n=18, 7.9%) versus (n=2, 4.8%) in 42 patients without, it didn't reach statistical significance (p = 0.52), too. Hormone receptors (HR) positivity was high in both groups and did not significantly distinguish carriers from non-carriers. Conclusions: In this Arab DCIS cohort, the observed 7.4% prevalence of pathogenic germline variants supports routine genetic testing, particularly in patients with a family history or early-onset disease. However, the rate was significantly lower than the 11% we previously reported in over 6000 patients with invasive breast cancer. The predominance of BRCA2 mutation suggests a possible founder effect or population-specific enrichment, warranting further genomic studies. High rates of VUS further emphasize the need for regional variant annotation efforts. These findings advocate for integrating germline testing into the diagnostic workup of DCIS in similar populations to inform surveillance, risk-reduction strategies, and familial counseling. Citation Format: S. Abdel-Razeq, L. El Saket, F. Tamimi, H. Bani Hani, B. Sharaf, A. Al-Atary, M. El-Atrash, M. Horani, T. Al-Batsh, O. El Khatib, Y. Talab, Y. Al-Masri, M. Abunasser, H. Abdel-Razeq. Germline Mutation Landscape in DCIS: Impact of Age and Family History in a Middle Eastern Cohort 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 PS4-11-11.