title: Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab.
abstract: OBJECTIVE
  The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included.
  
  
  METHODS
  To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.
  
  
  RESULTS
  Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05-1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95-1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082-1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).
  
  
  CONCLUSIONS
  This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America. fotiosloupakis@gmail.com
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohanes
authors.forename: Marta
authors.initials: M
authors.lastname: Schirripa
authors.forename: Leonor
authors.initials: L
authors.lastname: Benhaim
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.forename: Carlotta
authors.initials: C
authors.lastname: Antoniotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Aprile
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Sara
authors.initials: S
authors.lastname: Lucchesi
authors.forename: Monica
authors.initials: M
authors.lastname: Ronzoni
authors.forename: Ferdinando
authors.initials: F
authors.lastname: De Vita
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000008:administration & dosage; D015870:Gene Expression; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin