Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer

Background: Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme. Methods: Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA. Results: Samples for biomarker analysis were available from 24-54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF(121). No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated. Conclusion: Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.