Clinicopathologic features and prognosis of breast cancer in germline <i>ATM</i> and <i>CHEK2</i> carriers: A monocentric retrospective study.

e22625 Background: Germline pathogenic or likely pathogenic variants (PV/LPVs) in moderate-risk genes like ATM and CHEK2 are increasingly recognized as contributors to hereditary breast cancer (BC) risk. Although their prevalence is higher than that of high-risk genes like PALB2 , their clinical implications are less clearly understood. Understanding tumor features, therapeutic responses, and outcomes in ATM and CHEK2 carriers is crucial to guide personalized risk management and improve patient care. Methods: We conducted a retrospective, single-institution study including patients with histologically confirmed diagnosis of invasive BC carrying germline PV/LPVs in either the ATM or CHEK2 gene. Genetic testing was performed, as part of a hereditary cancer risk assessment, between January 2018 and January 2025 at our Unit of Genetic Oncology. Clinicopathological data were collected from medical records. Survival outcomes, including real-world invasive disease-free survival (rwIDFS), progression-free survival (rwPFS), and real-world overall survival (OS), were estimated using Kaplan–Meier analysis. Results: Overall, 92 patients were identified: 34 ATM, 56 CHEK2 carriers, and 2 harbouring PV/LPVs in both ATM and CHEK2 . Median age at first BC diagnosis was 50 years for ATM, 46 for CHEK2 and 29 for dual carriers. 12% of ATM and 29% of CHEK2 had a history of second invasive BC. Notably, 3 patients (3.2%) were diagnosed with BC during pregnancy (one ATM , one CHEK2 and one dual carrier). No special type was the most common histology in both groups (86% for ATM , 82% for CHEK2 ). Hormone receptor-positive/HER2-negative (HR+/HER2-) tumors were the most frequent subtype in both ATM and CHEK2 groups (72% and 70%, respectively), with luminal-A-like phenotype predominating in CHEK2 carriers (41%), whereas ATM -associated tumors more often exhibited a luminal B-like/HER2- phenotype (54%). 69% of ATM patients and 66% of CHEK2 carriers were diagnosed at stages I-II, and all of them underwent genomic testing after diagnosis. In patients with stage I–III HR+/HER2- BC, rwOS and rwIDFS at 10 years were 89% (95% CI 77.2-100) and 75.2% (95% CI 58-97%), respectively, for the ATM group, and 93.8% (95% CI 86-100) and 78.7% (95% CI 66–95%) for the CHEK2 group. In the metastatic HR+/HER2- subgroup treated with CDK4/6 inhibitors and endocrine therapy (n = 10), median rwPFS was 19 months (95% CI, 6-39). Conclusions: In this cohort, ATM carriers were more likely to develop luminal B-like BC, while CHEK2 carriers were more commonly associated with luminal-A-like. Overall, patients had a good prognosis for 10-year rwOS. Larger studies are necessary to confirm these findings and implement tailored clinical strategies.