Abstract PS4-03-03: Age-driven genomic differences in breast cancer: relevance for PI3K-pathway

Abstract Background The rising incidence of Breast cancer (BC) in young women requires further genomic characterization, as only a fraction carry a germline mutation. Given the growing interest in therapies targeting the phosphoinositide 3-kinase/AKT (PI3K/AKT), mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) pathways, central to BC pathogenesis, we evaluated whether PI3K/AKT/mTOR pathway alterations and gene expression differed by age at BC diagnosis. Methods: In this analysis of patients’ tumor/germline whole exome DNA and RNA sequencing data from the Ohio State University Total Cancer Care registry, 71 profiled patients were young adults (YA) aged 40 years, and 675 were non-YA aged ≥40 years. Descriptive statistics characterized the frequency and co-occurrence of BC-specific alterations and mRNA expression profiles by age groups. Results The prevalence of these BC-relevant mutations are reported in Table 1 Table: Prevalence of BC-relevant mutations by age cohort Mutation Age Group % of Patients with Mutation Fisher's Exact Test p-value (40 vs ≥ 40) PIK3CA 40 16.9% (12/71) 0.0002 ≥ 40 39% (263/675) AKT1 40 5.6% (4/71) 0.220 ≥40 10.8% (73/675) mTOR 40 16.9% (12/71) 0.450 ≥40 21.5% (145/675) PTEN 40 12.7% (9/71) 0.550 ≥40 10.5% (71/675) . PIK3CA mutation occurred more frequently in non-YA patients (16.9% YA versus (vs) 39% non-YA; p0.0002). The frequency of driver mutations were similar between cohorts (73% in YA vs 82% in non-YA). Most hotspot mutations were enriched in non-YA group, particularly H1047R (15.11% n=102 non-YA vs 4.23%, n=3 YA; p= 0.01). Others include: E545K (6.52%, n=44 vs 2.82%, n=2, p=0.302), E542K (4.59%, n=31 vs 1.41%, n=1; p=0.352); H1047L (1.93%, n=13 vs none, p=0.625) and N345K (1.78%, n=12 vs 1.41% n=1; p=1.00). There were no age-based differences in AKT1 mutation (5.6% YA vs 10.8% non-YA patients; p=0.220). Hotspot alterations E17K, E17G, and L52R were numerically enriched, albeit nonsignificant, in non-YA. There were no significant differences in the presence of mTOR by age (16.9% YA and 21.5% non-YA; p=0.450). Most alterations in both groups were variants of unknown significance (17/17 in YA, 157/159 in non-YA). YA and non-YA cohorts had similar frequency of PTEN mutations (12.7% YA vs 10.5% non-YA; p=0.550). The proportion of PTEN driver mutations also did not differ (82% YA and 93% non-YA). Conclusion PIK3CA mutations were more prevalent among non-YAs highlighting potential age-associated oncogenic drivers. Although AKT1, mTOR, and PTEN gene mutations did not differ between age groups, in general, oncogenic/hotspot mutations occurred more frequently in patients ≥40 years. As management of BC evolves to incorporate PI3K/AKT/mTOR inhibitors, age-specific somatic alterations may uncover therapeutic vulnerabilities and inform customized treatment. 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. Age-driven genomic differences in breast cancer: relevance for PI3K-pathway 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 PS4-03-03.