title: Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer.
abstract: BACKGROUND
  Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.
  
  
  METHODS
  Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group.
  
  
  RESULTS
  In the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.
  
  
  CONCLUSIONS
  These data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.
authors.affiliation: U,O, Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori and Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie in Medicina, Università di Pisa, Italy. fotiosloupakis@gmail.com
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Paolo
authors.initials: P
authors.lastname: Frumento
authors.forename: Marta
authors.initials: M
authors.lastname: Schirripa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Catalano
authors.forename: Nadia
authors.initials: N
authors.lastname: Galluccio
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Katia
authors.initials: K
authors.lastname: Bencardino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ricci
authors.forename: Mariangela
authors.initials: M
authors.lastname: Manzoni
authors.forename: Marco
authors.initials: M
authors.lastname: Danova
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000368:Aged; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D042442:Vascular Endothelial Growth Factors / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042442:Vascular Endothelial Growth Factors; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin