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.

Trial registration: ClinicalTrials.gov NCT00863655.

Fig 1.

(A) Alteration frequency in BOLERO-2 versus The Cancer Genome Atlas (TCGA) estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer cohort. Genes most frequently altered in the BOLERO-2 next-generation sequencing (NGS) subgroup and corresponding frequency in patients with ER+, HER2− breast cancer samples from TCGA were compared. Genes with alteration frequency > 5% (ie, altered in at least 15 patients) in the BOLERO-2 NGS cohort are shown. (B) Alteration frequency in metastatic versus primary tumors in the BOLERO-2 NGS cohort. Genetic alteration rates of ESR1, MDM2, and DNMT3A were different between metastatic versus primary tumors at statistically significant levels. *P ≤ .05; †P ≤ .005.

Fig 2.

Plots of Kaplan-Meier estimates of progression-free survival (PFS) by treatment arm for patient subgroups in the BOLERO-2 next-generation sequencing population. Subgroups were defined by gene mutation (MT) versus wild-type (WT), amplification (amp), chromosomal instability (CIN) score low or high, or pathway activity. (A) PIK3CA pathway status. (B) PI3K pathway status. (C) Cell-cycle control genes. (D) CIN score in which the 75th percentile was used as the cutoff. EVE, everolimus; HR, hazard ratio; PBO, placebo; TRT, treatment; w/o, without.