Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer

Rodriguez, J.; Zárate, Ruth; Bandrés, Eva; Boni, Valentina; Hernández, A; Sola, Jesús Javier; Honorato, Beatriz; Bitarte, Nerea; Garcı́a-Foncillas, Jesús

doi:10.1016/j.ejca.2012.01.007

Cited by 70 publications

(57 citation statements)

References 30 publications

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“…Supporting ADCC as a primary mechanism of cetuximab's activity in patients, NK cell infiltrate within primary colorectal tumors independently predicts prognosis (14). Patients with colorectal and HN carcinomas harboring a high-affinity FcγRIII polymorphism have been shown to respond more favorably to cetuximab both ex vivo with higher cytotoxicity against EGFR-expressing cell lines (15) and clinically with superior disease-free and overall survival (15)(16)(17)(18)(19). Therefore, methods to enhance ADCC, such as stimulating the innate immune response, may clinically translate to improved antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Targeting CD137 enhances the efficacy of cetuximab

Kohrt¹,

Colevas²,

Houot³

et al. 2014

J. Clin. Invest.

146

118

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Section: Introductionmentioning

confidence: 99%

Targeting CD137 enhances the efficacy of cetuximab

Kohrt¹,

Colevas²,

Houot³

et al. 2014

J. Clin. Invest.

146

118

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show abstract

“…However, in advanced stages, EGFR mAb's therapeutic efficacy was reported to depend on Fab-mediated effector functions (35). Importantly, the significant role of Fc-mediated effector mechanisms of therapeutic EGFR mAbs on tumor cell destruction was reinforced by observations that distinct genetic polymorphisms of FcgRIIa (131 H/R) and FcgRIIIa (158 V/F) were associated with higher response rates to cetuximab therapy in mCRC patients (36)(37)(38). Additionally, based on immunohistochemical analyses of immune cell infiltrates in primary tumors of mCRC patients treated with a cetuximab-based chemotherapy, tumors with stronger CD56-positive staining correlated with response to cetuximab treatment and with a significantly longer progression-free survival compared with tumors with no CD56 staining.…”

Section: Discussionmentioning

confidence: 88%

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Derer

Bauer

Lohse

et al. 2012

The Journal of Immunology

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The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by mAbs or tyrosine kinase inhibitors. A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. However, the impact of EGFR expression on the different mechanisms of action (MoAs) triggered by the EGFR mAb has not been defined. In this study, BHK-21 cells were stably transfected to express different EGFR levels, which were quantified by immunofluorescence and immunohistochemistry and compared with EGFR levels of clinical non-small cell lung cancer samples. These cells were used to systematically investigate the impact of target Ag expression levels on Fab- or Fc-mediated MoAs of EGFR mAb. A negative correlation between EGFR levels and potency of Fab-mediated MoA was observed. Interestingly, Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing. This correlation between EGFR expression levels and Fc-mediated MoA was confirmed in an independent panel of human tumor cell lines carrying diverse genetic alterations. Furthermore, RNA interference-induced knockdown experiments reinforced the impact of EGFR expression on tumor cell killing by EGFR mAb. In conclusion, these results suggest that EGFR expression levels may determine distinct patterns of MoAs that contribute to the therapeutic efficacy of EGFR mAb.

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“…By multivariate analysis, FcgRIIa-131H/H was significantly correlated with disease control rate (P ¼ 0.008). These data suggest that the mechanism of cetuximab effectiveness in KRAS-mutated patients is in part immune based (18)(19)(20). However, conflicting evidence has been reported on these issues (21,22).…”

Section: Introductionmentioning

confidence: 76%

Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy

Trotta¹,

Ottaiano

Romano

et al. 2016

Cancer Immunology Research

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Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcg receptors on immune cells. Although SNPs in genes encoding Fcg receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcgR status and cetuximab-mediated ADCC. Patients carrying the FcgRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P ¼ 0.013). Patients carrying FcgRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P ¼ 0.001). Progression-free survival of patients with an FcgRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P ¼ 0.05), whereas no significant difference was observed for overall survival. Twentyeight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcgR polymorphisms and predicted cetuximab responsiveness.

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Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer

Cited by 70 publications

References 30 publications

Targeting CD137 enhances the efficacy of cetuximab

Targeting CD137 enhances the efficacy of cetuximab

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy

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