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Genetic variations influence everolimus benefit in advanced breast cancer
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Women with hormone receptor-positive, HER-2–negative advanced breast cancer who had minimal genetic variations in PI3K, FGFR or CCND1 derived the most benefit from everolimus therapy, according to study results presented at the Breast Cancer Symposium.
The phase 3 BOLERO-2 study showed the addition of the mTOR inhibitor everolimus (Afinitor, Zortress; Novartis) to exemestane more than doubled PFS in postmenopausal women with HR-positive, HER-2–negative advanced breast cancer compared with exemestane alone.
In the current investigation, researchers used next-generation sequencing to analyze 182 cancer-related genes in 227 patients whose baseline characteristics and clinical outcomes were comparable to the trial population.
Of those patients, 157 had been treated with everolimus plus exemestane, and 70 had undergone treatment exemestane alone.
Univariate and multivariate Cox models helped researchers determine associations between genetic variations and PFS.
Hope S. Rugo
“The treatment benefit of everolimus plus exemestane over exemestane [alone] was maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways,” Hope S. Rugo, MD, director of the breast oncology clinical trials program at the University of California, San Francisco, and colleagues wrote.
After adjustments for covariates, sequencing analyses showed individuals with zero or one genetic alterations in the PI3K and FGFRpathways or in CCND1derived a greater treatment benefit from everolimus (HR=0.27; 95% CI, 0.18-0.41) than the overall population included in the next-generation sequencing analysis (HR=.40).
“These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR-positive, HER-2–negative breast cancer will be further investigated,” Rugo and colleagues wrote.
Disclosure:The researchers report research funding, honoraria and other remuneration from, as well as consultant/advisory roles with, Amgen, AstraZeneca, Bayer, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Sanofi and other pharmaceutical companies.
For more information:
Rugo HS. Abstract #142. Presented at: Breast Cancer Symposium; Sept. 7-9, 2013; San Francisco.