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Impact of FcγRIIa-FcγRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan
Abstract
Purpose: The antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecan-refractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (FcγRs) expressed by immune cells. ADCC is influenced by FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of FcγR polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan. Patients and Methods: Tumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for FcγRIIa and FcγRIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS). Results: KRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P = .021) and shorter PFS (3.0 v 5.3 months; P = .021). Patients with FcγRIIa-131H/H and/or FcγIIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P = .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and FcγR combined status were independent risk factors for PFS. Conclusion: Combined FcγRIIa/FcγRIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed.
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“Currently, it is believed that microenvironment remodelling can reduce the cytotoxicity of anti-EGFR mAbs by impairing antibody-dependent cellular cytotoxicity (ADCC) and secreting growth factors [19, 20].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [20]
In the citing paper
“Antibody-dependent cellular cytotoxicity (ADCC) mediated through Fc receptors (FcγRs) on immune cells is one of the proposed antitumour mechanisms of anti-EGFR mAbs [20].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [20]
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Metadata
- Authors
- Bibeau, F., Lopez-Crapez, E., Di Fiore, F., Thezenas, S., Ychou, M., Blanchard, F., Lamy, A., Penault-Llorca, F., Frébourg, T., Michel, P., Sabourin, J.-C., & Boissière-Michot, F.
- Affiliations
- Inserm (FR)
- From the Departments of Pathology, Biology, Biostatistics, and Oncology, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, Montpellier; Digestive Oncology Unit, Department of Gastroenterology, Rouen University Hospital; Inserm U614, Faculty of Medicine; Department of Pathology, Rouen University Hospital; and the Department of Pathology, Centre Jean Perrin, Clermont-Ferrand, France.
- Venue
- Journal of Clinical Oncology
- Published
- 2009-03-01
- Volume
- 27
- Issue
- 7
- Pages
- 1122-1129
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2122618533
- Cited by
- 521
- References
- 44
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 12 · 2023: 19 · 2022: 16 · 2021: 17 · 2020: 24 · 2019: 16 · 2018: 26 · 2017: 24 · 2016: 32 · 2015: 40 · 2014: 41 · 2013: 46 · 2012: 53
- FWCI
- 31.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- FcγRIIIa, Fc receptor polymorphism, KRAS mutation, cetuximab, irinotecan, metastatic colorectal cancer, antibody-dependent cellular cytotoxicity, progression-free survival, prognostic factors, irinotecan-refractory disease, epidermal growth factor receptor
- MeSH terms
- Cetuximab, Irinotecan, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Female, Humans, Male, Middle Aged, Mutation, Polymorphism, Genetic, Proto-Oncogene Proteins, Retrospective Studies, Colorectal Neoplasms, Multivariate Analysis, Proportional Hazards Models, Survival Analysis, Proto-Oncogene Proteins p21(ras), Receptors, IgG, Disease-Free Survival, ras Proteins, Drug Resistance, Neoplasm, Antibodies, Monoclonal, Humanized
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