title: FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study.
abstract: OBJECTIVE
  We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.
  
  
  METHODS
  To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.
  
  
  RESULTS
  Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.
  
  
  CONCLUSIONS
  No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.
authors.affiliation: Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ravit
authors.initials: R
authors.lastname: Geva
authors.affiliation: Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vecchione
authors.affiliation: Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece.
authors.forename: Konstantinos T
authors.initials: KT
authors.lastname: Kalogeras
authors.affiliation: Herlev Hospital, Copenhagen, Denmark.
authors.forename: Benny Vittrup
authors.initials: BV
authors.lastname: Jensen
authors.affiliation: USC Norris Comprehensive Cancer Center and Hospital, California, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Hospital Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Paez
authors.affiliation: Department of Oncology, University Hospital del Mar -IMIM, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Montagut
authors.affiliation: Department of Medical Oncology, University General Hospital of Heraklion and Lab of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Souglakos
authors.affiliation: Ospedale Civile di Livorno, Livorno, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.affiliation: Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Herlev Hospital, Copenhagen, Denmark.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
authors.affiliation: Department of Pathology, Herlev University Hospital, Copenhagen, Denmark.
authors.forename: Estrid Vilma
authors.initials: EV
authors.lastname: Høgdall
authors.affiliation: USC Norris Comprehensive Cancer Center and Hospital, California, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: USC Norris Comprehensive Cancer Center and Hospital, California, USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: B. O. Cyprus Oncology Centre, Nicosia, Cyprus.
authors.forename: Demetris
authors.initials: D
authors.lastname: Papamichael
authors.affiliation: Università Campus Bio-Medico, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.affiliation: Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: De Schutter
authors.affiliation: Department of Oncology, Vejle Hospital, Vejle, Denmark.
authors.forename: Karen Lise Garm
authors.initials: KL
authors.lastname: Spindler
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Division of Medical Oncology, Department of Experimental and Clinical Medicine, Second University of Naples, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Cliniques universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Hubert
authors.initials: H
authors.lastname: Piessevaux
authors.affiliation: Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D060005:Genotyping Techniques / Q000592:standards; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C445323:FCGR2A protein, human; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Antibody Targeted Therapy; Colorectal Cancer; Genetic Polymorphisms; Immune Response