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 [progression-free survival] benefit from everolimus.

— Fabrice André, MD, and colleagues

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In an analysis of the phase III BOLERO-1 and -3 trials reported in the Journal of Clinical Oncology, Fabrice André, MD, of Institut Gustav-Roussy, Paris, France, and colleagues 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 PIK3CA alteration, PTEN loss, or hyperactive PI3K pathway.¹

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

Study Details

The current analysis included 549 patients from BOLERO-1 (n = 302) and -3 (n = 247) with available biomarker data, representing 42% to 43% of the entire study populations, respectively. Overall, 76% of samples were from primary tumors, and 24% were from metastases. The BOLERO-3 group had a higher proportion of samples from Asian patients (42% vs 25%).

PIK3CA-activating mutations and PTEN loss were found in 30% and 16% of BOLERO-1 samples, respectively, 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.

Outcome by Marker in Subgroups

According to PIK3CA status, median progression-free survival with everolimus vs placebo was 12.0 vs 7.6 months (hazard ratio [HR] = 0.70, P = .25) in BOLERO-1 and 6.9 vs 5.7 months (HR = 0.65, P = .11) in BOLERO-3 among patients with PIK3CA mutation and 18.5 vs 17.1 months (HR = 1.13, P = .59) and 6.8 vs 6.6 months (HR = 1.08, P = .68), respectively, in the wild-type subgroups.

Corresponding figures for PTEN status were 23.5 vs 16.8 months (HR = 0.56, P = .14) in BOLERO-1 and 9.5 vs 5.5 months (HR = 0.52, P = .13) in BOLERO-3 in the PTEN loss subgroups and 16.1 vs 13.8 months (HR = 1.02, P = .93) and 6.8 vs 6.7 months (HR = 1.00, P = .98), respectively, in the PTEN normal subgroups.

Corresponding figures for PI3K pathway status were 13.9 vs 10.9 months (HR = 0.72, P = .18) in BOLERO-1 and 8.1 vs 5.6 months (HR = 0.62, P = .04) in BOLERO-3 in the hyperactive pathway subgroups and 18.2 vs 17.1 (HR = 1.18, P = .51) and 6.8 vs 7.0 months (HR = 1.19, P = .40), respectively, in the normal pathway subgroups.

Analysis of Pooled Data

Meta-analysis of pooled data showed a progression-free survival benefit with everolimus vs placebo among patients with PIK3CA mutation (HR = 0.67, P = .05), PTEN loss (HR = 0.54, P = .04), and hyperactive PI3K pathway (HR = 0.67, P = .02). No benefit was seen among patients with wild-type PIK3CA (HR = 1.10, P = .5), normal PTEN (HR = 1.00, P = .97), or normal PI3K pathway activity (HR = 1.19, P = .28).

The investigators concluded: “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 [progression-free survival] benefit from everolimus.” ■

Disclosure: The study was supported by Novartis. For full disclosures of the study authors, visit www.jco.ascopubs.org.

Reference

1. André F, Hurvitz S, Fasolo A, 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 34:2115-2124, 2016.