title: Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity.
abstract: BACKGROUND
  We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy.
  
  
  METHODS
  Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity.
  
  
  RESULTS
  After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS.
  
  
  CONCLUSIONS
  To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. figgw@helix.nih.gov.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Chau
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: Shawn
authors.initials: S
authors.lastname: Spencer
authors.forename: Melony
authors.initials: M
authors.lastname: Beatson
authors.forename: Jeanny
authors.initials: J
authors.lastname: Aragon-Ching
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D043823:Taxoids; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D000077143:Docetaxel; C081294:satraplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D011241:Prednisone
keywords: ERCC1; Genotyping; Prostate cancer; Satraplatin; XRCC1