Abstract PS4-01-06: Genomic alterations in young adults compared to average-onset patients with breast cancer

Abstract Introduction: In the United States, breast cancer (BC) is the most common cancer and leading cause of cancer-related death among young women. Yet approximately only 17% of young adult (YA) patients (age 40 years) carry a known cancer susceptibility mutation, and the full spectrum of somatic genomic alterations unique to this population remains poorly defined. YA also face worse outcomes than those with average-onset (≥40 years) BC, even after adjusting for tumor characteristics. How genomic features contribute to these disparities and influence outcomes is not well understood. This study aims to characterize clinical and genomic alterations in YA with BC at our institution. Methods: Patients consented to the Total Cancer Care protocol (as part of the Oncology Research Information Exchange Network) at the Ohio State University, whose tumors underwent RNA sequencing and tumor/germline whole exome DNA sequencing were included for analysis. YA were considered 40 years, and average-onset were considered ≥40 years. We focused on clinical characteristics, as well as mutations, copy number alterations, and mRNA expression changes in genes relevant to BC. Descriptive statistics were used to characterize the frequency and co-occurrence of alterations. The Chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was applied to compare continuous variables between groups. Kaplan-Meier survival analyses and log-rank tests were conducted to explore associations between genomic alterations and overall survival (OS). Results: A total of 825 patients were included in the analysis: 98.2% (n=813) were women, 1.4% (n=12) were men, and 0.4% (n=3) had unreported sex. There were 10% (n=83) of patients aged 40 years, and 90% (n=742) were aged ≥40 years. The median age at diagnosis in the 40 cohort was 36.0 years, compared to 56.3 years in the ≥40 cohort. In both age cohorts, most patients were White: 89.3% (n=75) in the 40 cohort and 90.4% (n=672) in the ≥40 cohort. Black patients comprised 10.7% (n=9) and 7% (n=53) in 40 and ≥ 40 cohorts, respectively (p=0.974). Higher pathologic lymph node (LN) involvement was more common in younger patients: 20.3% (n=17) of 40 cohort had pN2 or pN3 disease versus (vs) 15.3% (n=114) in the ≥40 cohort (p=0.066). The median tumor mutational burden (TMB) was significantly lower in the 40 cohort: 5.5 vs 9.7 in the ≥40 cohort (p = 0.001). Genes significantly enriched in the 40 cohort (compared to ≥40 years) were: NBPF12 22.5% (n=16) vs 10.8% (n=73), p =0.007; CDK17 15.3% (n=11) vs 4.5% (n=30); ZNF280B 11.1% (n=8) vs 3.85% (n=26). Genes enriched in the ≥40 cohort were: CDH1 20.1% (n=136) vs 4.2% (n=3); p = 0.003; PIK3CA 39.1% (n=264) vs 18.1% (n=13), p = 0.0003. Looking at specific PIK3CA alterations, H1047 mutations were significantly more frequent in the ≥40 cohort. Lastly, the probability of OS was significantly worse in patients aged 40 compared to those ≥40 years (p= 0.02). Conclusion: While this analysis corroborates existing evidence that, compared to patients ≥40 years diagnosed with BC, YA patients exhibited higher rates of advanced LN involvement, lower TMB, and significantly worse OS, novel findings included differences in genomic alterations by age. Specifically, differences in the frequency of targetable alterations such as PIK3CA highlight biologically and clinically meaningful differences in BC by age, underscoring the need for age-specific therapeutic strategies and further investigation. Citation Format: N. Lopetegui-Lia, A. Davenport, J. Gill, A. M. Roy, S. Myers, D. Agnese, E. Burke, T. Y. Andraos, D. M. Schimming, S. Hulett, H. LeFebvre, M. Gatti-Mays, D. Stover. Genomic alterations in young adults compared to average-onset patients with breast cancer 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 PS4-01-06.