title: Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.
  
  
  METHODS
  A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).
  
  
  RESULTS
  The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).
  
  
  CONCLUSIONS
  In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.
authors.affiliation: Division of Medical Oncology, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Los Angeles, California, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohanes
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.forename: Thomas
authors.initials: T
authors.lastname: Winder
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Labonte
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wilson
authors.forename: Leonor
authors.initials: L
authors.lastname: Benhaim
authors.forename: David
authors.initials: D
authors.lastname: Paez
authors.forename: Rita
authors.initials: R
authors.lastname: El-Khoueiry
authors.forename: Gudrun
authors.initials: G
authors.lastname: Absenger
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D018925:Chemokines / Q000235:genetics; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010071:Oxaloacetates; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D018925:Chemokines; D016207:Cytokines; D009944:Organoplatinum Compounds; D010071:Oxaloacetates; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil