Bevacizumab and Paclitaxel in Advanced, Hormone Receptor-Positive Breast Cancer: Multifactor Dimensionality Reduction Methodology to Identify Best Overall Survival.

BACKGROUND: The treatment of advanced hormone receptor-positive (HR+) breast cancer has seen relevant changes in last years. However, bevacizumab remains an option when combined with paclitaxel, but no certified pharmacogenetic profiles are now usable for the prediction of its response in breast cancer patients. This study aimed to explore the pharmacogenetic interactions among single nucleotide polymorphisms (SNPs) of genes involved in the angiogenic process and their impact on progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+) metastatic breast cancer subjects administered with bevacizumab plus paclitaxel, or with paclitaxel alone (clinicaltrial.gov identifier NCT01935102).

METHODS: Germline DNA extracted from blood samples was analyzed using real-time polymerase chain reaction to investigate SNPs. The multifactor dimensionality reduction (MDR) analysis was employed to assess interactions between these genetic variants. A total of 168 eligible patients were analyzed. Among these, 106 patients received both paclitaxel and bevacizumab, while 62 received paclitaxel alone.

RESULTS: In the combination therapy group, MDR analysis identified two pharmacogenetic interaction profiles involving specific genotypes of vascular endothelial growth factor-A(VEGF-A) rs833061 and vascular endothelial growth factor receptor-2 (VEGFR-2) rs1870377. Patients with a favorable genetic profile had a median PFS (mPFS) of 22.9 months, compared to 8.7 months in those with an unfavorable profile (p = 0.001). Cox proportional hazards analysis displayed an adjusted hazard ratio of 0.443 (95% CI: 0.284-0.691; p < 0.0001). The median OS (mOS) was 50.2 months for the favorable profile vs. 23.5 months for the unfavorable (p = 0.003), with an adjusted hazard ratio (HR) of 0.404 (95% CI: 0.249-0.657; p < 0.0001). In the 62 subjects administered with just paclitaxel, no significant differences in PFS (p = 0.820) or OS (p = 0.143) were observed between favorable and unfavorable genetic profiles.

CONCLUSIONS: The MDR analysis of VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes can detect a subgroup of bevacizumab-administered+ metastatic breast cancer patients with improved PFS and OS.