EVEROLIMUS HELPFUL FOR HER2+ BREAST CANCER

In an analysis of the phase III BOLERO trials reported in the Journal of Clinical Oncology, André et al found that the addition of everolimus (Afinitor) to trastuzumab (Herceptin) and chemotherapy was associated with a progression-free survival benefit in advanced HER2-positive breast cancer with a PIK3CA alteration, PTEN loss, or a hyperactive PI3K pathway.

In BOLERO-1, addition of everolimus to trastuzumab and paclitaxel in first-line treatment of HER2-positive advanced breast cancer did not significantly prolong progression-free survival. In BOLERO-3, everolimus in combination with trastuzumab and vinorelbine significantly prolonged progression-free survival in patients progressing on prior trastuzumab and a taxane.

Study Details

The current analysis includes 549 patents from BOLERO-1 (n = 302) and BOLERO-3 (n = 247; about 43% of the entire populations) with available biomarker data. PIK3CA-activating mutations and PTEN loss were found in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway hyperactivity (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) was found in 47% of BOLERO-1 and 41% of BOLERO-3 samples.

Everolimus Benefit

In each trial, progression-free survival benefit with everolimus was consistently observed in subgroups defined by PI3K pathway status. Analysis of pooled data indicated that everolimus was associated with improved progression-free survival among patients with PIK3CA mutations (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.45–1.00), PTEN loss (HR = 0.54, 95% CI = 0.31–0.96), and hyperactive PI3K pathway (HR = 0.67, 95% CI = 0.48–0.93). In contrast, everolimus was not associated with benefit among patients with wild-type PIK3CA (HR = 1.10, 95% CI = 0.83–1.46), normal PTEN (HR = 1.00, 95% CI = 0.80–1.26), or normal PI3K pathway activity (HR = 1.19, 95% CI = 0.87–1.62).

The investigators concluded: “This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2–positive advanced breast cancer having tumors with PIK3CAmutations, PTEN loss, or hyperactive PI3K pathway could derive [progression-free survival] benefit from everolimus.”

The study was supported by Novartis Pharmaceuticals Corporation.

Fabrice André, MD, of the Institut Gustave-Roussy, Université Paris Sud, is the corresponding author of the Journal of Clinical Oncology article.