William J. Gradishar, MD reviewing Andre F et al. J Clin Oncol 2016 Apr 18.

Those with PI3KCA mutations and PTEN loss were less likely to experience disease progression.

Two prior industry-sponsored, randomized, phase III trials, BOLERO-1 (Lancet Oncol 2015; 16:816) and BOLERO-3 (Lancet Oncol 2014; 15:580), explored whether the mTOR inhibitor everolimus would provide clinical benefit to patients with advanced breast cancer. In BOLERO-1, adding everolimus to trastuzumab and paclitaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive disease did not improve progression-free survival (PFS). In the BOLERO-3 trial, adding everolimus to trastuzumab and vinorelbine significantly improved PFS in HER2-positive patients who developed disease progression after treatment with trastuzumab and paclitaxel.

Given that the mechanism of action of everolimus is on the PI3K/AKT/mTOR pathway — which is frequently altered in patients with HER2-positive disease — industry-supported investigators conducted exploratory biomarker analyses of data from the two BOLERO trials to determine if a specific abnormality could identify patients most likely to benefit from everolimus. Biomarker data obtained from next-generation sequencing, immunohistochemistry, and Sanger sequencing were available for 549 patients (approximately 42% of participants in both trials); 76% of samples were from the primary tumor, and 24% were from a metastatic site.

PI3KCA mutations and PTEN loss were seen in a fraction of tumors (30% and 16%, respectively, in BOLERO-1; 32% and 12% in BOLERO-3). When data from both trials were combined, patients with tumors having a PI3KCA mutation were less likely to experience disease progression with everolimus (hazard ratio, 0.67), as were those with PTEN loss (HR, 0.54). Tumors with wild-type PI3KCA, normal PTEN, or normal activity of the PI3K pathway gained no benefit from everolimus.

Citation(s):

Andre F et al. 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. J Clin Oncol 2016 Apr 18; [e-pub].

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