title: VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.
abstract: BACKGROUND
  No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone.
  
  
  METHODS
  Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (-2578A/C, -634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan-Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant.
  
  
  RESULTS
  Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the -2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the -634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the -634CC genotype had a median PFS of 2.2 months whereas patients with the genotype -634CG/GG had a median PFS of 6.25 months (P=0.0042).
  
  
  CONCLUSIONS
  The -634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Orlandi
authors.forename: A
authors.initials: A
authors.lastname: Fontana
authors.forename: A
authors.initials: A
authors.lastname: Fioravanti
authors.forename: T
authors.initials: T
authors.lastname: Di Desidero
authors.forename: L
authors.initials: L
authors.lastname: Galli
authors.forename: L
authors.initials: L
authors.lastname: Derosa
authors.forename: B
authors.initials: B
authors.lastname: Canu
authors.forename: R
authors.initials: R
authors.lastname: Marconcini
authors.forename: E
authors.initials: E
authors.lastname: Biasco
authors.forename: A
authors.initials: A
authors.lastname: Solini
authors.forename: G
authors.initials: G
authors.lastname: Francia
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.forename: G
authors.initials: G
authors.lastname: Bocci
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059250:Administration, Metronomic; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D018931:Antineoplastic Agents, Hormonal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone; D003520:Cyclophosphamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D000068579:Celecoxib