title: Association studies of Fcγ receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831.
abstract: Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab, and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal, with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T polymorphisms in 1,325 patients from the N9831 clinical trial. Patients in arm A (N = 419) received chemotherapy only. Patients in arms B (N = 469) and C (N = 437) were treated with chemotherapy and trastuzumab (sequentially in arm B and concurrently in arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high-affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (P < 0.001), compared with the T carriers who did not (P = 0.81). The interaction between FCGR2B genotype and treatment was statistically significant (P = 0.03). Our analysis did not reveal an association between FcγR high-affinity genotypes and outcomes. However, it seems that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit.
authors.affiliation: Mayo Clinic, Jacksonville, Florida.
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.affiliation: Stanford University, Stanford, California.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Olson
authors.affiliation: Stanford University, Stanford, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tenner
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.affiliation: Columbia University, New York, New York. perez.edith@mayo.edu kknutson@vgtifl.org rc645@cumc.columbia.edu.
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
authors.affiliation: Mayo Clinic, Rochester, Minnesota. Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida. perez.edith@mayo.edu kknutson@vgtifl.org rc645@cumc.columbia.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.affiliation: Mayo Clinic, Jacksonville, Florida. perez.edith@mayo.edu kknutson@vgtifl.org rc645@cumc.columbia.edu.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics*; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C499173:FCGR2B protein, human; C508053:ERBB2 protein, human