Abstract PS3-05-03: Clinicopathologic and Molecular Characteristics of Middle-Eastern Breast Cancer Patients with Pathogenic or Likely Pathogenic ATM Variants: A Comprehensive Cohort Analysis

Abstract Background: ATM gene alterations have increasingly been recognized for their role in breast cancer susceptibility and therapeutic implications. However, the phenotypic and molecular features of ATM-mutant breast cancers remain under-characterized in Middle Eastern populations. This study provides a comprehensive analysis of breast cancer patients harboring pathogenic or likely pathogenic (P/LP) ATM variants treated in Jordan, with emphasis on clinicopathologic features, genetic context, and therapeutic outcomes. While ATM mutations confer a moderate lifetime breast cancer risk (25%), their impact on treatment decisions remains under investigation. Methods: We retrospectively reviewed data on 52 female patients with breast cancer and confirmed pathogenic or likely pathogenic ATM mutations. Parameters analyzed included age at diagnosis, family history, histopathology, stage, hormone receptor status, Ki-67 proliferation index, and genetic testing eligibility based on NCCN/ASCO guidelines. Co-occurring variants in other genes and variant types (missense, nonsense, frameshift, splice site) were compiled. Results: The median (range) age at diagnosis was 48 (27-79) years, with 32 (61.5%) diagnosed before age 50. Invasive ductal carcinoma (IDC) was the predominant histologic subtype (n = 41, 78.8%), followed by invasive lobular carcinoma (ILC). Hormone receptor (HR) positivity was high: ER-positive (92.3%), PR-positive (90.4%), and HER2-negative in most cases (n=36, 70.6%). High-grade tumors (GIII) comprised 39.2% of the cohort. The majority of ATM variants were deletions (frameshift, 46.2%), followed by nonsense (17.3%), missense (15.4%), and splice site alterations (11.5%). Common hotspots included c.2284_2285del and c.5755C>T. Co-occurrence with other susceptibility genes was notable; 6 (11.5%) had additional pathogenic variants in other genes: 3 with BRCA2, 1 with RAD50, 1 with MUTYH, and 1 with a second distinct ATM mutation. Furthermore, 16 of the 52 patients (30.8%) harbored additional variants of uncertain significance (VUS). Despite a high prevalence of early-stage disease 39 (75.0%), lymph node involvement was observed in 27 (51.9%) cases. Neoadjuvant chemotherapy was utilized in 16 (32.7%) patients with a modest rate of pathologic complete response (12.2%). Notably, 5 (9.6%) of patients did not meet testing criteria per conventional guidelines, suggesting gaps in current eligibility frameworks, particularly for patients under universal genetic testing. Conclusions: ATM-mutant breast cancers in this Jordanian cohort exhibited a predominance of HR-positive, high-grade tumors with frequent lymph node involvement. The diversity in variant types and co-existing mutations underlines the clinical complexity of these cases. A proportion of patients would have been missed by existing genetic testing guidelines, emphasizing the utility of universal testing in this setting. These findings advocate for broader germline screening in Middle Eastern populations to inform precision oncology strategies. Citation Format: H. Abdel-Razeq, L. El Saket, H. Bani Hani, S. Abdel-Razeq, F. Tamimi, B. Sharaf, Y. Talab, A. Al-Atary, M. El-Atrash, T. Al-Batsh, M. Horani, O. Othman, Y. Al-Masri, O. El Khatib, M. Abunasser. Clinicopathologic and Molecular Characteristics of Middle-Eastern Breast Cancer Patients with Pathogenic or Likely Pathogenic ATM Variants: A Comprehensive Cohort Analysis [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 PS3-05-03.