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Molecular Alterations and Everolimus Efficacy in HER2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3

Fabrice, Andre and Hurvitz, Sara and Fasolo, Angelica and Tseng, Ling-Ming and Jerusalem, Guy and Wilks, Sharon and O'Regan, Ruth and Isaacs, Claudine and Toi, Masakazu and Burris, Howard and He, Wei and Riester, Markus and Taran, Tetiana and Chen, David and Slamon, Dennis (2016) Molecular Alterations and Everolimus Efficacy in HER2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3. JCO, 34 (18). pp. 2115-2124. ISSN 1527-7755

Abstract

Purpose: Two recent phase 3 trials, BOLERO-1 and BOLERO-3, evaluated the addition of everolimus to trastuzumab and chemotherapy in HER2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment.

Patients and 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% in 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. PFS benefit of everolimus in patients with these molecular alterations was consistently observed in both the studies. In a pooled analysis, patients with PIK3CA alteration derived greater PFS benefit with everolimus (HR=0.67 [95% CI 0.45-1.00]), compared to patients with wild type PIK3CA (HR=1.1 [95% CI 0.83-1.46]). Similarly, PFS benefit with everolimus was greater in patients with PTEN loss (HR=0.54 [95%CI 0.31-0.96]), compared to patients with normal PTEN (HR=1 [95% CI 0.8-1.26]). Furthermore, patients with hyperactive PI3K pathway also derived greater PFS benefit with everolimus (HR=0.67 [95% CI 0.48-0.93]) whereas patients with normal PI3K pathway activity did not (HR=1.19 [95% CI 0.87-1.62]). The PFS benefit with everolimus in patients with PIK3CA mutations, PTEN loss or hyperactive PI3K pathway was maintained irrespective of hormone receptor (ER/PgR) status.

Conclusions: This exploratory analysis suggests that patients with HER2-positive advanced breast cancer with PIK3CA mutations, PTEN loss and/or hyperactive PI3K pathway derived greater PFS benefit from addition of everolimus to trastuzumab and chemotherapy.

Item Type: Article
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45
URI: https://oak.novartis.com/id/eprint/26917

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