alexa Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3.
Oncology

Oncology

Journal of Cancer Clinical Trials

Author(s): Andr F, Hurvitz S, Fasolo A, Tseng LM, Jerusalem G,

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Abstract PURPOSE: Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment. METHODS: Archival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing. RESULTS: Biomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30\% and 16\% of BOLERO-1 samples and in 32\% and 12\% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47\% of BOLERO-1 and 41\% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95\% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95\% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95\% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95\% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95\% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95\% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus. CONCLUSION: This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus. © 2016 by American Society of Clinical Oncology. This article was published in J Clin Oncol and referenced in Journal of Cancer Clinical Trials

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