Abstract P2-03-16: Prevalence of PIK3CA/AKT1/PTEN and other genomic alterations in primary and recurrent tumor tissue: exploratory analysis from the Phase 3 CAPItello-291 clinical trial

Abstract Background: Based on the positive results from the CAPItello-291 trial, capivasertib plus fulvestrant is a treatment option for adult patients with HR+/HER2− locally advanced or metastatic breast cancer who have progressed on an endocrine-based regimen and whose tumors harbor one or more alterations in PIK3CA, AKT1, or PTEN. In CAPItello-291, participants were requested to provide a formalin-fixed, paraffin-embedded tumor sample from the most recently collected tumor tissue for next-generation sequencing (NGS) testing at the stage of either primary or recurrent disease. Overall, 48% of samples with a valid NGS test result had a PIK3CA/AKT1/PTEN alteration. In this exploratory analysis, we assessed the prevalence of PIK3CA/AKT1/PTEN alterations in tissue samples from primary versus recurrent disease and explored the broader molecular profiles between cohorts. Methods: A retrospective review of molecular profiles of non-matched primary and recurrent breast cancer samples from CAPItello-291 was performed to assess the prevalence of PIK3CA/AKT1/PTEN alterations in tissue from the primary tumor versus recurrent disease. Based on the tissue requisition forms, samples were classified as primary if the type of tissue provided was reported as ‘primary’ and had breast/lymph node as the anatomic site, while samples were classified as ‘recurrent’ if the tissue provided was reported as ‘recurrence’ and the anatomic site was not breast. Analysis for pathogenic/likely pathogenic genes with alteration prevalence of ≥2% captured by FoundationOne®CDx was carried out by primary/recurrent and PIK3CA/AKT1/PTEN-altered/non-altered status. Statistical analyses were performed using chi-square or Fisher exact test. All analyses were exploratory. Results: A total of 381/594 (64.1%) of the analyzed samples were defined as primary, 156/594 (26.3%) were defined as recurrent, and 57/594 (9.6%) were defined as unknown/not valid and excluded from further analysis. Prevalence of PIK3CA/AKT1/PTEN alterations was similar in primary and recurrent cohorts, overall (50.7% primary vs 46.2% recurrent, p=0.39) and by gene (PIK3CA: 36.2% primary vs 30.8% recurrent, p=0.27; AKT1: 5.5% primary vs 6.4% recurrent, p=0.84; PTEN: 5.7% primary vs 6.4% recurrent, p=0.94). Compared with primary samples, recurrent samples were enriched for alterations in ESR1 (5% vs 17%, p≤0.001), BRCA2 (5% vs 11%, p=0.02), GATA3 (17% vs 24%, p=0.04), CDKN2A (2% vs 6%, p=0.04), and SMAD4 (1% vs 4%, p=0.04). Notably, ESR1 mutations were enriched at recurrence in both the PIK3CA/AKT1/PTEN-altered and non-altered cohorts, whereas GATA3 alterations were enriched in the PIK3CA/AKT1/PTEN non-altered cohort and CDKN2A alterations in the PIK3CA/AKT1/PTEN-altered cohort at recurrence. When comparing the overall PIK3CA/AKT1/PTEN-altered versus the non-altered cohorts, the altered cohort had more alterations in CDH1, MAP3K1, TBX3, CBFB, and BCL6, whereas the non-altered cohort had more alterations in genes associated with cell cycle, such as GATA3, CCND1, and MYC. Conclusions: Overall, the prevalence of PIK3CA/AKT1/PTEN alterations was comparable between non-matched tumor tissue samples collected at primary or recurrent disease used for NGS testing in CAPItello-291, in line with their role as oncogenic drivers in HR+/HER2− breast cancer. Consistent with the literature, recurrent tissues were enriched for ESR1, BRCA2, GATA3, CDKN2A, and SMAD4 alterations, indicating a potential role for these gene alterations in driving disease recurrence. The PIK3CA/AKT1/PTEN-altered cohort was enriched for CDH1 mutations while the non-altered cohort was enriched for alterations in cell cycle-related genes previously associated with endocrine and cyclin-dependent kinase 4/6 inhibitor resistance. Citation Format: Javier Cortés, Hope S. Rugo, Mafalda Oliveira, Sacha J. Howell, Florence Dalenc, Henry L. Gomez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Meena Okera, Yeon Hee Park, Joo-Hyuk Sohn, Masakazu Toi, Eriko Tokunaga, Lyudmila Zhukova, Agostina Nardone, Elza C. de Bruin, Robert McEwen, Marta Fulford, Nicholas C. Turner. Prevalence of PIK3CA/AKT1/PTEN and other genomic alterations in primary and recurrent tumor tissue: exploratory analysis from the Phase 3 CAPItello-291 clinical trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-16.