Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From BOLERO-2

Abstract

Purpose To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. Patients and Methods Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated. Results Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues. Conclusion The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.

Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

“…Exploratory analysis from BOLERO-2 suggests that the efficacy of everolimus is largely independent of the most commonly altered genes or genetic pathways in HR-positive, HER2-negative breast cancer. 53 The positive results from BOLERO-2 contrast with those reported for HORIZON and this may, in part, be a reflection of the different patient populations, in particular, of the proportion of patients with secondary resistance.…”

Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology

“…PIK3CA E542K is an activating mutation found on exon 9 of the PIK3CA gene (15). The BOLERO-2 trial which assessed the efficacy of everolimus plus exemestane for Her2-Neu-negative breast cancer showed a greater progression-free survival benefit with everolimus compared with placebo for patients with a PIK3CA exon 9 mutation compared with those with other PIK3CA mutations (16,17). A recent correlative analysis of genetic alterations and everolimus benefit in hormone-positive breast cancer demonstrated more efficacy in individuals with exon-specific mutations in PIK3CA exon 9 compared with exon 20 (17).…”

“…The BOLERO-2 trial which assessed the efficacy of everolimus plus exemestane for Her2-Neu-negative breast cancer showed a greater progression-free survival benefit with everolimus compared with placebo for patients with a PIK3CA exon 9 mutation compared with those with other PIK3CA mutations (16,17). A recent correlative analysis of genetic alterations and everolimus benefit in hormone-positive breast cancer demonstrated more efficacy in individuals with exon-specific mutations in PIK3CA exon 9 compared with exon 20 (17). Preclinically, in MCF7 breast cancer cells harboring the PI3KCA E542K mutation, the combination of everolimus with antiestrogen therapy can inhibit proliferation and trigger apoptotic cell death (18).…”

“…Preclinically, in MCF7 breast cancer cells harboring the PI3KCA E542K mutation, the combination of everolimus with antiestrogen therapy can inhibit proliferation and trigger apoptotic cell death (18). Individuals who had higher chromosomal instability did less well than those who had lower chromosomal instability (17).…”

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

“…This field is particularly challenging, as some available examples clearly show. For example, considering CDK4/6 inhibitors, preclinical data and phase 1 studies suggested that CCND1 amplification or p16 loss was predictive of response, but the phase 2 PALOMA 1 study, which was designed to specifically address these biomarkers, showed equal benefit of palbociclib, regardless of their status in the tumor [95,42] Another example is the biomarker analyses included in the BOLERO 2 trials, failing to show that biomarkers of dysregulated PI3K/Akt/mTOR pathway could predict for the efficacy of everolimus added to exemestane [96]. On the other hand, the intriguing results of the BELLE2 trial showing that PIK3CA mutations in ctDNA predict for the activity of buparlisib suggest that the status of a biomarker should be assessed at the time the disease is treated.…”