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; p<0.0002). 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.
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