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.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 34 Issue 18 Pg. 2115-24 (06 20 2016) ISSN: 1527-7755 [Electronic] United States
• PMID: 27091708 (Publication Type: Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by American Society of Clinical Oncology.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Everolimus
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (analysis)
• Breast Neoplasms (chemistry, drug therapy)
• Class I Phosphatidylinositol 3-Kinases
• Everolimus (therapeutic use)
• Female
• Humans
• Middle Aged
• Mutation
• PTEN Phosphohydrolase (genetics)
• Phosphatidylinositol 3-Kinases (genetics, physiology)
• Receptor, ErbB-2 (analysis)
• Signal Transduction