title: Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients.
abstract: OBJECTIVE
  The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer.
  
  
  METHODS
  Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry.
  
  
  RESULTS
  Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67).
  
  
  CONCLUSIONS
  This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab.
authors.affiliation: University of California at Los Angeles, Los Angeles, California, USA. SHurvitz@mednet.ucla.edu
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.forename: David J
authors.initials: DJ
authors.lastname: Betting
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Quinaux
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: John
authors.initials: J
authors.lastname: Mackey
authors.forename: Adrian
authors.initials: A
authors.lastname: Driga
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Robert
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Carla
authors.initials: C
authors.lastname: Falkson
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Valerie
authors.initials: V
authors.lastname: Bee
authors.forename: Omkar
authors.initials: O
authors.lastname: Marathe
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000097:blood / Q000235:genetics*; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D000068878:Trastuzumab