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.
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 metastatic colorectal cancer (mCRC), treated in first-line setting with 5-fluorouracil, oxaliplatin and bevacizumab (BV), 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 real-time (RT) PCR from 54 patients and three germline variants of the CD133 gene by PCR-restriction-fragment length polymorphism 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 messenger RNA levels (VEGFR-1 (P<0.01), -2 and -3, P<0.05). Combined analyses of two polymorphisms showed a significant association with progression-free survival (PFS) (18.5 months vs 9.8 months, P=0.004) in a multivariate analysis as an independent prognostic factor for PFS (adjusted P=0.002). These results suggest that CD133 is a predictive marker for standard first-line BV-based treatment in mCRC.
Division of Medical Oncology, Sharon A. Carpenter Laboratory, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
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A
Pohl
A
A
El-Khoueiry
D
D
Yang
W
W
Zhang
G
G
Lurje
Y
Y
Ning
T
T
Winder
S
S
Hu-Lieskoven
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S
Iqbal
K D
KD
Danenberg
M
M
Kahn
J-L
JL
Teo
J
J
Shriki
J
J
Stebbing
H-J
HJ
Lenz
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D015703:Antigens, CD / Q000235:genetics*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010455:Peptides / Q000235:genetics* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D000071916:AC133 Antigen; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D005472:Fluorouracil