Tests to predict who will benefit have emerged for other drugs, among them Eli Lilly's mAb Erbitux and AstraZeneca’s small molecule drug Iressa, which both target the EGFR receptor. Only patients with tumors expressing a mutant form of the molecule respond to Iressa.
Scientists are currently working to identify patients who have responded to Avastin and to characterize those responses on a molecular level. For example, researchers from Genentech, which developed Avastin and is now part of Roche, and the NCI sought to find gene-expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD) among women treated for breast cancer with Avastin as a neoadjuvant followed by Avastin plus chemotherapy.
Twenty patients with inflammatory breast cancer and one with locally advanced breast cancer were treated with one cycle of Avastin followed by six cycles of Avastin plus docetaxel/doxorubicin prior to surgery. Baseline angiogenic tumor markers and gene-expression profiles were measured.
The investigators found that angiogenic markers, 26 GO categories, and five functional molecular pathways were differentially expressed between the responders and nonresponders. Key markers in the angiogenesis process that were associated with response to therapy were VEGF-A, the molecular target of Avastin; PDGFRs, the receptors of VEGF-A; and CD31, an endothelial cell-adhesion molecule whose expression may be modulated by VEGF-A. Patients with higher tumor VEGF-A, CD31, and PDGFR-β expression in the tumor vasculature tended to be more likely to benefit from Avastin treatment plus chemotherapy.
The findings indicate, according to the researchers, that Avastin may be specifically given as a targeted agent, although their data requires confirmation by larger cohorts. In a statement to GEN, Genentech said that it is committed to determining whom may benefit the most from its medicine. The firm said that the majority of its clinical trials include tissue collection for biomarker analysis.
“Research to date has shown that the benefits of Avastin-based treatment are not influenced by common cancer biomarkers. More than 150 potential Avastin biomarkers have been studied, but so far none have been found that consistently and accurately predict which patients may benefit most from Avastin-based treatment.
“Expression profiling methods like those described in the paper by Yang et al. are one of the many approaches we are using in our biomarker research program. Their results are consistent with our prior published research that suggests the expression of certain genes in the angiogenesis pathway should be fully evaluated as potential biomarkers for Avastin-based treatment.”
It is possible that response profiles may be different in different patients and shift over time. The aim of efforts to find consistent biomarkers for patient responsiveness is to improve treatment options and enable informed patient inclusion in clinical trials.