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Everolimus in Advanced HER2-Positive Breast Cancer With PIK3CA Mutation, PTEN Loss, or Hyperactive PI3K Pathway



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

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.

Everolimus in HER2-Overexpressing Breast Cancers

  • The benefit of everolimus was observed among patients with HER2-positive metastatic breast cancer who had PIK3CA mutation, PTEN loss, or hyperactive PI3K pathway.
  • Hyperactivity of the PI3K pathway was found in 47% of BOLERO-1 and 41% of BOLERO-3 samples.

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.



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