Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression–free survival (PFS) in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy

摘要

Recent studies suggest CD133, a surface protein widely used for isolation of colon cancer stem cells, to be associated with tumor angiogenesis and recurrence. We hypothesized that gene expression levels and germline variations in CD133 will predict clinical outcome in patients with mCRC, treated in first-line setting with 5-FU, oxaliplatin and bevacizumab and we investigated whether there is a correlation with gene expression levels of CD133, vascular endothelial growth factor (VEGF) and its receptors.We evaluated intra-tumoral gene expression levels by quantitative RT-PCR from 54 patients and 3 germline variants of the CD133 gene by PCR-RFLP from 91 patients with genomic DNA. High gene expression levels of CD133 (>7.76) conferred a significantly greater tumor response (RR=86%) than patients with low expression levels (≤7.76, RR=38%, adjusted p=0.003), independent of VEGF or its receptor gene expression levels. Gene expression levels of CD133 were significantly associated with VEGF and its receptors mRNA levels (VEGFR-1 (p<.01), -2, and -3, p<0.05). Combined analyses of two polymorphisms showed a significant association with PFS (18.5 months vs 9.8 months, p=0.004), in multivariate analysis as an independent prognostic factor for PFS (adjusted p=0.002). These results suggest CD133 is a predictive marker for standard first-line bevacizumab-based treatment in mCRC.