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Gut. 2015 Jun;64(6):921-8. doi: 10.1136/gutjnl-2014-307234. Epub 2014 Jul 10.

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study.

Author information

1
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
2
Laboratory of Molecular Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
3
Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece.
4
Herlev Hospital, Copenhagen, Denmark.
5
USC Norris Comprehensive Cancer Center and Hospital, California, USA.
6
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
7
Hospital Santa Creu i Sant Pau, Barcelona, Spain.
8
Department of Oncology, University Hospital del Mar -IMIM, Barcelona, Spain.
9
Department of Medical Oncology, University General Hospital of Heraklion and Lab of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Greece.
10
Ospedale Civile di Livorno, Livorno, Italy.
11
Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain.
12
Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
13
Department of Pathology, Herlev University Hospital, Copenhagen, Denmark.
14
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
15
Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
16
B. O. Cyprus Oncology Centre, Nicosia, Cyprus.
17
Università Campus Bio-Medico, Rome, Italy.
18
Hospital Vall d'Hebron, Barcelona, Spain.
19
U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
20
Department of Oncology, Vejle Hospital, Vejle, Denmark.
21
Department of Oncology, Odense University Hospital, Odense, Denmark.
22
Division of Medical Oncology, Department of Experimental and Clinical Medicine, Second University of Naples, Naples, Italy.
23
Cliniques universitaires Saint-Luc, Brussels, Belgium.

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.

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.

KEYWORDS:

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

PMID:
25011934
DOI:
10.1136/gutjnl-2014-307234
[Indexed for MEDLINE]

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