Abstract PS2-06-23: Impact of somatic PIK3CA Mutations on clinical outcomes in HER2-Positive Breast Cancer

Abstract Background: The phosphatidylinositol-3-kinase (PI3K) pathway, driven by the PIK3CA gene, is crucial for tumor initiation, growth, proliferation and therapy resistance. PIK3CA mutations (PIK3CAm) occur in ∼35% of all breast cancers (BC), most commonly in estrogen receptor positive (ER+) and HER2-negative BC. In HER2-positive (HER2+) BC, these mutations are found in ∼25-30% of cases. Although PIK3CAm are linked to lower rates of pathological complete response (pCR) in the neoadjuvant setting for HER2+ patients (pts), the prognostic significance of somatic PIK3CAm remains unclear. In the recently presented phase 3 Destiny Breast09 trial, the presence of a PIK3CAm was identified as a marker of early progression in HER2+ metastatic BC (mBC) on first line therapy with trastuzumab/pertuzumab monoclonal antibody therapy. We, therefore, aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2+ BC pts receiving first- and second-line therapy. Methods: We analyzed clinico-genomic data from the BC cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (version 1.2), which includes pts diagnosed between 18-56 years of age who underwent tumor sequencing between 2013 and 2020. We included adult HER2+ BC pts who had received at least one line of therapy. The primary outcomes were overall survival (OS) and progression-free survival (PFS). We used Kaplan-Meier curves to estimate and compare OS and PFS. Univariable and multivariable Cox proportional hazard regressions were used to compare outcomes between patient groups, accounting for line of therapy. Subgroup analysis was performed according to TNM stage and PIK3CA wild type (wt) vs PIK3CAm. Results: We included 212 pts, of which 58 (27.3%) had a documented PIK3CAm. Of the 212, 62 were mBC, of which 15 (26%) had PIK3CAm. The median age at diagnosis was 43. Most patients were White (77%), Non-Hispanic (95%), and initial TNM stage II BC diagnosis (33%). Statistically significant differences between PIK3CAm and PIK3CAwt were observed in use of endocrine therapy (78% vs 62%, p=0.04) as well as the median time to distant metastasis (38 vs 22 months, p= 0.01). The observed median OS for the overall cohort starting from the date of first-line therapy, was 121.8 months. Median OS between pts with PIK3CAm and PIK3CAwt did not significantly differ (121.8 vs. 125.1 months, p=0.42). In the multivariable Cox regression, line of therapy was not significantly associated with an increased risk of death. The observed median PFS for the overall cohort from start of first-line therapy was 14.2 months. These results showed a trend by PIK3CAm status: 20.3 months for PIK3CAwt and 6.9 months for PIK3CAm (p=0.4). Multivariable Cox regression also revealed a higher associated risk of progression for patients with PIK3CAm on their second line of therapy (HR = 2.65, 95% CI 1.02-6.94). These findings were consistent in the subgroup analysis by TNM stage (Stages I-III and Stage IV). Conclusion(s): In this real-world cohort of HER2+ BC patients, PIK3CA mutations were not associated with worse median OS but demonstrated a trend toward shorter median PSF survival in early lines of therapy. Multivariable analysis revealed that patients with PIK3CAm receiving second-line therapy had a statistically significant 2.6-fold increased associated-risk of disease progression. These findings suggest the presence of a PIK3CAm may serve as a negative predictive biomarker for treatment duration in HER2+ disease. Given that approximately 30% of HER2+ BC harbor PIK3CAm, our results support prioritizing clinical investigation of PI3K inhibitors in combination with anti-HER2 therapy in the first-line metastatic setting for HER2+/PIK3CA-mutant BC to optimize treatment sequencing and potentially delay disease progression. Citation Format: N. Stabellini, S. D. de Oliveira, T. Mizukami, A. J. Montero. Impact of somatic PIK3CA Mutations on clinical outcomes in HER2-Positive 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 PS2-06-23.