title: FcγRIIa and FcγRIIIa polymorphisms and cetuximab benefit in the microscopic disease.
abstract: OBJECTIVE
  FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX±cetuximab in high-risk, locally advanced rectal cancer.
  
  
  METHODS
  FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.
  
  
  RESULTS
  Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX=54, CAPOX-C=51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcγRIIa-131R (HR, 0.38; P=0.058) and FcγRIIIa-158F alleles (HR, 0.21; P=0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P=0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P=0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P=0.017) and remained significant after adjusting for prognostic variables (P=0.003).
  
  
  CONCLUSIONS
  This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. david.cunningham@rmh.nhs.uk.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Sanna
authors.initials: S
authors.lastname: Hulkki Wilson
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
authors.affiliation: Akademiska Sjukhuset Uppsala, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Institute of Health Research Hospital Clinic of Valencia, University of Valencia, Valencia, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Roselló Keränen
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Gina
authors.initials: G
authors.lastname: Brown
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Tait
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Ruwaida
authors.initials: R
authors.lastname: Begum
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Thomas
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Oates
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005838:Genotype; D006801:Humans; D011379:Prognosis; D017452:Receptors, IgG / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab