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Cited by 47Colorectal Cancer Treatments and StudiesMonoclonal and Polyclonal Antibodies ResearchLung Cancer Treatments and Mutations

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Fc gamma receptor IIIa polymorphisms in advanced colorectal cancer patients correlated with response to anti-EGFR antibodies and clinical outcome

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Calemma, Rosa, Ottaiano, Alessandro, Trotta, Anna Maria, Nasti, Guglielmo, Romano, Carmela, Napolitano, Maria, Galati, Domenico, Borrelli, Pasquale, Zanotta, Serena, Cassata, Antonino, Castello, Giuseppe, Iaffaioli, Vincenzo Rosario, Scala, Stefania·2012·Journal of Translational Medicine
DOI 10.1186/1479-5876-10-232PMC PMC3551834
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Abstract

Background: Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies. Methods: Seventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS. Results: FcγRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for FcγRIIa polymorphisms. Conclusions: In mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.

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Figure 1 FcγRIIa determined by direct sequencing and FcγRIIIa allotyping by allele-specific PCR. v Upper Panel. FcγRIIa determined by direct sequencing: (a) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131H/H; (b) Sequencing electropherogram obtained from a sample heterozygous for allele FcγRIIa 131H/R; (c) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131R/R. Lower Panel. FcγRIIIa allotyping by allele-specific PCR. 100bp ladder marker, FcγRIIIa genotypes direct sequenced F/F, V/F and V/V control and CTL- negative control were represented. Examples represented respectively F/F (a), V/F (b) and V/V (c) patients.
Figure 1 FcγRIIa determined by direct sequencing and FcγRIIIa allotyping by allele-specific PCR. v Upper Panel. FcγRIIa determined by direct sequencing: (a) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131H/H; (b) Sequencing electropherogram obtained from a sample heterozygous for allele FcγRIIa 131H/R; (c) Sequencing electropherogram obtained from a sample homozygous for allele FcγRIIa 131R/R. Lower Panel. FcγRIIIa allotyping by allele-specific PCR. 100bp ladder marker, FcγRIIIa genotypes direct sequenced F/F, V/F and V/V control and CTL- negative control were represented. Examples represented respectively F/F (a), V/F (b) and V/V (c) patients.CC BY · PubMed Central
Figure 2 Progression-free survival curves according to FcγR polymorphisms on 49 mCR Cpatients. Progression-free survival was defined as time elapsed between treatment initiation and tumor progression (a) FcγRIIa: median PFS was 16.1 months in H/H patients (18 patients, 13 events) vs 18.2 months in H/R patients (27 patients, 23 events) vs 13.3 months in R/R patients (4 patients, 3 events); Log Rank test for three curves: p = 0.61. (b) FcγRIIIa: median PFS was 18.2 months in V/V patients (18 patients, 13 events) vs 17.3 months in V/F patients (26 patients, 25 events) vs 9.4 months in F/F patients (5 patients, 5 events); Log Rank test for three curves: p = 0.04.
Figure 2 Progression-free survival curves according to FcγR polymorphisms on 49 mCR Cpatients. Progression-free survival was defined as time elapsed between treatment initiation and tumor progression (a) FcγRIIa: median PFS was 16.1 months in H/H patients (18 patients, 13 events) vs 18.2 months in H/R patients (27 patients, 23 events) vs 13.3 months in R/R patients (4 patients, 3 events); Log Rank test for three curves: p = 0.61. (b) FcγRIIIa: median PFS was 18.2 months in V/V patients (18 patients, 13 events) vs 17.3 months in V/F patients (26 patients, 25 events) vs 9.4 months in F/F patients (5 patients, 5 events); Log Rank test for three curves: p = 0.04.CC BY · PubMed Central

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Authors
Calemma, R., Ottaiano, A., Trotta, A. M., Nasti, G., Romano, C., Napolitano, M., Galati, D., Borrelli, P., Zanotta, S., Cassata, A., Castello, G., Iaffaioli, V. R., & Scala, S.
Affiliations
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
Corresponding author
Scala, Stefania
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2012-11-21
Volume
10
Issue
1
Pages
232-232
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/1479-5876-10-232
PMC
PMC3551834
OpenAlex
W2121910124
Cited by
47
References
22
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 2 · 2017: 3 · 2016: 9 · 2015: 1 · 2014: 3 · 2013: 2
FWCI
0.95
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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, FCGR2A, single nucleotide polymorphisms, metastatic colorectal cancer, anti-EGFR monoclonal antibody, antibody-dependent cellular cytotoxicity, treatment response, progression-free survival, prognostic factors, KRAS wild-type tumors
MeSH terms
Adult, Aged, Aged, 80 and over, Alleles, Antibodies, Monoclonal, Base Sequence, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Neoplasm Metastasis, Neoplasm Staging, Proto-Oncogene Proteins, Colorectal Neoplasms, Multivariate Analysis, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Receptors, IgG, Disease-Free Survival, ras Proteins, Polymorphism, Single Nucleotide, ErbB Receptors

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