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Original article
FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study
  1. Ravit Geva1,
  2. Loredana Vecchione2,
  3. Konstantinos T Kalogeras3,
  4. Benny Vittrup Jensen4,
  5. Heinz-Josef Lenz5,
  6. Takayuki Yoshino6,
  7. David Paez7,
  8. Clara Montagut8,
  9. John Souglakos9,
  10. Federico Cappuzzo10,
  11. Andrés Cervantes11,
  12. Milo Frattini12,
  13. George Fountzilas3,
  14. Julia S Johansen4,
  15. Estrid Vilma Høgdall13,
  16. Wu Zhang5,
  17. Dongyun Yang5,
  18. Kentaro Yamazaki14,
  19. Tomohiro Nishina15,
  20. Demetris Papamichael16,
  21. Bruno Vincenzi17,
  22. Teresa Macarulla18,
  23. Fotios Loupakis19,
  24. Jef De Schutter2,
  25. Karen Lise Garm Spindler20,
  26. Per Pfeiffer21,
  27. Fortunato Ciardiello22,
  28. Hubert Piessevaux23,
  29. Sabine Tejpar2
  1. 1Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  2. 2Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium
  3. 3Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece
  4. 4Herlev Hospital, Copenhagen, Denmark
  5. 5USC Norris Comprehensive Cancer Center and Hospital, California, USA
  6. 6Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
  7. 7Hospital Santa Creu i Sant Pau, Barcelona, Spain
  8. 8Department of Oncology, University Hospital del Mar -IMIM, Barcelona, Spain
  9. 9Department of Medical Oncology, University General Hospital of Heraklion and Lab of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Greece
  10. 10Ospedale Civile di Livorno, Livorno, Italy
  11. 11Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain
  12. 12Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland
  13. 13Department of Pathology, Herlev University Hospital, Copenhagen, Denmark
  14. 14Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
  15. 15Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
  16. 16B. O. Cyprus Oncology Centre, Nicosia, Cyprus
  17. 17Università Campus Bio-Medico, Rome, Italy
  18. 18Hospital Vall d'Hebron, Barcelona, Spain
  19. 19U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy
  20. 20Department of Oncology, Vejle Hospital, Vejle, Denmark
  21. 21Department of Oncology, Odense University Hospital, Odense, Denmark
  22. 22Division of Medical Oncology, Department of Experimental and Clinical Medicine, Second University of Naples, Naples, Italy
  23. 23Cliniques universitaires Saint-Luc, Brussels, Belgium
  1. Correspondence to Professor Sabine Tejpar, Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Herestraat 49, Leuven B—3000, Belgium; sabine.tejpar{at}


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.

Design 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.

  • Antibody Targeted Therapy
  • Colorectal Cancer
  • Genetic Polymorphisms
  • Immune Response

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