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Abstract BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest. METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT]) and efficacy (progression-free and overall survival [PFS/OS]) in different biomarker and clinical subgroups. Confounder adjustment was conducted for age, Eastern Cooperative Oncology Group Performance Status, body mass index, treatment, disease type, and number of metastases (all at baseline). “Study” was included as a random effect in the IPD meta-analysis model to account for variability between studies. A landmark analysis was conducted on fast and non-fast progressors (cutoff of >137 days [i.e., after six chemotherapy cycles]) from CLEOPATRA and PUFFIN only, since they include the current standard-of-care regimens (PHD), by using Day 137 as the landmark time with separate Cox proportional hazards models. RESULTS: PIK3CA mutation data were available for 1905/2146 patients (89%; ~80% from primary tissue); mutation prevalence was 27% (n = 521). PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms is shown in the table. OS data were consistent. CONCLUSIONS: PIK3CA mutations were associated with a worse prognosis across subgroups of interest, including in fast and non-fast progressors, in the two PHD-containing studies as compared with the overall ITT population. Table: PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms Citation Format: Sandra Swain, Javier Cortés, Binghe Xu, Chiara Lambertini, Laurent Essioux, Adam Knott, Eleonora Restuccia, Katrin Madjar, Sanne Lysbet De Haas. Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-07.