Abstract PS2-08-12: Age-associated divergence in breast cancer: clinical, molecular, and genomic insights from a large real-world cohort

Introduction: Breast cancer (BC) in younger individuals is often clinically aggressive and biologically distinct. However, comprehensive real-world evidence comparing molecular underpinnings in very early-onset BC (age <35 years) vs. BC in older age groups (ages 36-50 years and age >50 years) remains limited. Here, we evaluate clinicopathologic features and molecular characteristics between BC diagnosed in younger (<35 years) and older (>35 years) age groups, with a focus on subtype distribution, ctDNA dynamics, relapse patterns, and genomic alterations. Methods: This retrospective analysis included patients diagnosed with early-stage BC who underwent tumor-informed circulating tumor DNA (ctDNA) testing (Signatera™, Natera, Inc.) in a real-world clinical setting (2019-2024). Genomic alterations were derived from whole-exome sequencing of tumor tissue as part of their ctDNA testing. Histology, molecular subtype, lymph node (LN) status, recurrence events, ctDNA detection over time, and relapse patterns were compared. Results: The cohort included 10,122 patients stratified by age <35 years (N=334), ages 36-50 years (N=2,501), and age >50 years (N=7,287). Distribution across age groups based on histology, subtype, and nodal status revealed that the age <35 years group exhibited a higher prevalence of aggressive subtypes (triple negative breast cancer [TNBC]: 22.4%, and hormone receptor [HR]−/human epidermal growth factor receptor 2 [HER2]+: 6.7%), predominantly ductal histology (77.6%), and the highest rate of lymph node involvement (44.1%); ages 36-50 years showed intermediate distributions across all features; while age >50 years were enriched for HR+/HER2− tumors (35.7%), had a higher frequency of lobular histology (12.4%), and demonstrated the lowest rate of nodal involvement (38%, p=0.016). Genomic profiling revealed greater prevalence of PIK3CA mutations in the age >50 years group (31%, p <0.0001) and enrichment in TP53 mutations in the age <35 years group (notably in HR−/HER2+: 51%, p=0.12 and TNBC: 53%, p<0.01). Furthermore, the age >50 years group demonstrated the highest prevalence of elevated TMB/MSI-High (53.3%), while the age <35 and age 36-50 years groups exhibited higher rates of TMB/MSS-low tumors (60.6% and 56.3%, respectively) compared to patients with age >50 years (46.6%, p<0.001). With respect to ctDNA detection, we observed the highest cumulative ctDNA positivity (29%) in the age <35 age group, particularly in those with HR-/HER2+ disease (46.2%, p=0.09). Consistent with this finding, patients with HR-/HER2+ BC in the age <35 group exhibited the highest relapse rates (46.7%, p<0.0001) with a high risk of multi-site relapse (13.3%). Notably, patients in the HR+/HER2- age <35 group exhibited a shorter median time to relapse (48 days, p=0.02) compared to other subtypes. Conclusions: Our data confirm that very early-onset breast cancer represents a biologically and clinically distinct entity characterized by more aggressive subtypes, shorter time to ctDNA positivity, higher metastatic burden at time of relapse, and differential patterns of genomic alterations. These findings highlight the need for intensified surveillance and tailored therapeutic strategies in younger BC patients, with a potential role for ctDNA monitoring. Citation Format: J. Foldi, S. Satta, B. Taylor, P. Dutta, S. Oesterreich, A. Lee, E. Kalashnikova, A. Rodriguez, M. Liu, M. Balic, A. Partridge. Age-associated divergence in breast cancer: clinical, molecular, and genomic insights from a large real-world 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 PS2-08-12.