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

Fabrice André, Sara Hurvitz, Angelica Fasolo, Ling Ming Tseng, Guy Jerusalem, Sharon Wilks, Ruth O'Regan, Claudine Isaacs, Masakazu Toi, Howard Burris, Wei He, Douglas Robinson, Markus Riester, Tetiana Taran, David Chen, Dennis Slamon

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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.

Original languageEnglish
Pages (from-to)2115-2124
Number of pages10
JournalJournal of Clinical Oncology
Volume34
Issue number18
DOIs
Publication statusPublished - Jun 20 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    André, F., Hurvitz, S., Fasolo, A., Tseng, L. M., Jerusalem, G., Wilks, S., O'Regan, R., Isaacs, C., Toi, M., Burris, H., He, W., Robinson, D., Riester, M., Taran, T., Chen, D., & Slamon, D. (2016). 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. Journal of Clinical Oncology, 34(18), 2115-2124. https://doi.org/10.1200/JCO.2015.63.9161