AbstractPurpose:The first comprehensive analysis of the detailed clinico-genomic landscape of the breast cancer (BC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC).Methods:We analyzed 1, 045 BC patients treated at three GENIE-participating institutions. Breast cancer patients in the GENIE registry aged 18-56 at sequencing and with tumor(s) sequenced between 2013 and 2018 were randomly chosen for curation using the PRISSMM framework. Sites of distant metastasis were captured from imaging and pathology reports. A previously published cohort of older patients was used as a point of comparison in identifying age-related differences. Overall survival (OS) was estimated for patients with advanced disease.Results:Clinical and genomic features were compared across the four subtypes HR+/ HER2 - (N=660), HR+/HER2+ (N=138), HR-/HER2+ (N= 74), and TNBC (n = 173). The age distribution was similar across subtypes, HR+/HER2+ had the highest percentage of patients ages 18-39 (HR+/HER2-: 28%, HR+/HER2+: 39%, TNBC: 33%, HR-/HER2+ 35%). The most frequently altered genes in the cohort were TP53 (HR+/HER2-: 33%, HR+/HER2+: 58%, TNBC: 95%, HR-/HER2+ 80%), PIK3CA ( HR+/HER2-: 35%, HR+/HER2+: 33%, TNBC: 8%, HR-/HER2+ 15%), and ERBB2 (HR+/HER2-: 3%, HR+/HER2+: 71%, TNBC: 2%, HR-/HER2+ 84%).Analysisof patients with metastatic disease (n=818) revealed robust associations with OS and TP53 (HR = 1.87, SF = 100%), ERBB2 amplification (HR = 0.61, SF = 98%), MYC (HR = 1.09, SF = 52%), FGFR2 (HR=0.89, SF = 49.3%), MAP3K1 (HR = 0.94, SF = 35%), DDR2 (HR = 1.09, SF = 33%) and ESR1 (HR=1.07, SF = 32.7%).In a comparison of older and younger patients with HR+/HER2- subtype, we found that mutations in TP53 (18-39: 35% vs >60: 22%), GATA3 (18-39: 21% vs >60: 10%), and MAP2K4 (18-39: 10% vs >60: 4%) were significantly (q<0.1) more prevalent among younger patients. Conversely, PIK3CA (18-39: 31% v >60: 48%), CDH1 (18-39: 3% v >60: 21%), and MAP3K1 (18-39: 5% v >60: 12%) showed higher alteration rates in seniors. These trends were consistent at pathway level with higher alteration of p53 (18-39: 44% vs >60: 29%) and PI3K (18-39: 46% vs >60: 62%).In patients with any distant metastases, we calculated the metastatic burden, or the number of distant metastases reported in key sites of interest. Patients with a history of adrenalMetastasis had a higher metastatic burden (49/61, 80.3% with at least 4 distinct sites recorded) than those with no adrenal metastasis recorded (326/764, 42.6% with at least 4 distinct sites recorded).Conclusions:The GENIE BPC cohort provides a comprehensive clinico-genomic dataset enriched with younger patients with BC, providing a valuable source to improve our understanding of age-related clinical and genomic characteristics and their impact on real-world patient outcomes.Citation Format:Evan Seffar, Brooke Mastrogiacomo, Alex Paynter, Protiva Rahman, Jesus Fuentes Antras, Sonya A. Reid, Nikolaus Schultz, Michael J. Hassett, Ben Park, Shawn Sweeney, Walid K. Chatila, Pedram Razavi. The GENIE BPC BRCA Cohort: a real-world repository of standardized clinical and genomic data for young patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1118.