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

Abstract

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.

Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy

“…Similarly, a previous study reported that the presence of nuclear Aurora B was strongly associated with lymph node metastasis in colorectal cancer [16]. In metastatic colorectal cancer, patients with a high expression level of Aurora B lived significantly shorter compared with patients with a low expression level [17]. Taken together, these studies highlight the association of altered aurora kinases and CRC.…”

CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges

“…Because the stromal contribution to colorectal cancers is highly variable, transcript‐based analysis on microdissected tumour cells seems sensible. High CD133 expression levels in pre‐ and post‐treatment (chemoradiotherapy) samples or an increase in CD133 levels correlate with poor prognosis (Supplementary Table ). A predictive value was also reported.…”

Clear Cell Renal Cell Carcinoma as a Model of Pathological Angiogenesis: Which Actors to Target for Treatment?

“…Hypertension was suggested as a marker of BVZ efficacy for colorectal cancer but only one on seven clinical trials correlated increased blood pressure with progression free and overall survival [50][51]. Pharmacogenetic profiling (tumour levels and polymorphisms) has identified CD133, a surface protein used to isolate stem cells, as a predictive marker of progression free and overall survival [52]. Genomic profiling also identified the VEGFR-1 319 C/A single nucleotide polymorphism as a relevant marker, patients with the A allele appearing to have increased response rates (Nordic ACT trial) [53].…”