Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Fabrice, Andre, Hurvitz, Sara, Fasolo, Angelica, Tseng, Ling-Ming, Jerusalem, Guy, Wilks, Sharon, O'Regan, Ruth, Isaacs, Claudine, Toi, Masakazu, Burris, Howard, He, Wei, Riester, Markus, Taran, Tetiana, 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

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.