Number of Breast Cancer Gene Alterations Predicts Everolimus Benefit
CHICAGO―Although no single genetic alteration predicts which patients will benefit from adding everolimus to exemestane in the treatment of advanced hormone receptor–positive, HER2-negative breast cancer, the number of genetic alterations harbored by tumors just might, report authors of a retrospective analysis of genetic data from the phase 3 BOLERO-2 trial presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.
Although the analysis revealed no single, predictive biomarker of everolimus efficacy, everolimus was associated with a greater progression-free survival (PFS) benefit among patients with “minimal genetic alterations in PIK3CA/PTEN/CCND1 or FGFR1/2 genes combined,” reported Gabriel N. Hortobagyi, MD, of the M. D. Anderson Cancer Center in Houston, TX.
Patients with no genetic alterations or only one alteration in PI3K or FGFR pathways or at CCND1 had greater treatment benefits from everolimus, than those whose tumors harbored more than one alteration in these regions (hazard ratio [HR], 0.27; 95% CI: 0.18-0.41), he noted.
Previous analysis of BOLERO-2 outcomes had found that everolimus plus exemestane “more than doubled” progression-free survival (PFS; P<0.0001) while maintaining quality of life, when compared to exemestane alone among postmenopausal women diagnosed with hormone receptor–positive, HER2-negative advanced breast cancer, Dr. Hortobagyi said. The advantage was found in all clinically defined patient subgroups, he noted.
The new analysis was undertaken to assess the role of genetic variations in everolimus outcomes in this setting. All patients enrolled in BOLERO-2 had provided tumor tissue and consent for exploratory analysis of the archived samples.
Using next-generation sequencing (NGS), the coauthors assessed sequence and gene copy number variations in 3,230 exons and 182 oncogenes and tumor suppressor genes, and assessed their statistical associations with PFS outcomes, Dr. Hortobagyi explained. A total of 227 archived samples were successfully analyzed.
“The everolimus benefit was maintained in patients regardless of gene alterations in PIK3CA” or CCND1 amplifications, he reported. Everolimus benefit was “slightly less pronounced” in patients with FGFR1/2 alterations.
The findings suggest that patients with “minimal genetic variations in the PI3K or FGFR pathways, or CCNDI, derive the most benefit from everolimus therapy (HR, 0.27 vs. 0.40 for the full NGS population),” he said.
It is not yet clear if the correlation between alteration number and everolimus benefit was driven by greater general genetic instability in tumors that harbor more alterations, or some interaction between combinations of specific alterations, Dr. Hortobagyi said in response to a question from the audience.
“This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy,” Dr. Hortobagyi said. “These results may help generate new hypotheses for combinations of novel targeted therapies as treatment for hormone receptor–positive/HER2-negative breast cancer.”
However, prospective validation in an independent cohort of patients would first be necessary, he noted.
The analysis was supported by Novartis.