Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer

Abstract

Purpose: To identify biomarkers and gene expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD).

Experimental design: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response.

Results: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-beta (PDGFR-beta) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-beta median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P < 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-beta (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005).

Conclusions: Baseline CD31, PDGFR-beta, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy.

Fig.1

Expression of CD31, PDGFR-β and tumor VEGF-A in representative patient tumor biopsies. There were high levels of CD31 (A) and VEGF-A (C), and PDGFR-β (E) in tumor biopsy sections from a patient with PR compared to low levels of CD31 (B) and tumor VEGF-A (D) in those from a patient with PD or low level of PDGFR-β (F) in the section from a patient with SD. PR, partial response; PD, progressive disease; SD, stable disease.

Fig. 2

The change in CD31 expression after BV treatment alone in patients with IBC and LABC. Shown was the relative change in CD31 expression in the tumor vasculature in 15 patients that paired biopsies were available for analysis. Pt, patient; BV, bevacizumab.