Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2007; 25(22):3230-7. DOI: 10.1200/JCO.2006.10.5437
Source: PubMed


The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.
One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.
Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).
Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

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    • "KRAS protein is a key signaling molecule between extracellular EGFR ligands and signaling in cells. Extensive retrospective studies and phase III trials disclosed that KRAS gene activating mutations are the main negative predictor of mCRC anti-EGFR therapy [8]–[10]. Based on these findings, the FDA changed the guidelines to recommend that cetuximab and panitumumab only be given to CRC patients with wild-type KRAS [11]. "
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    ABSTRACT: Background The survival rate of colorectal cancer (CRC) patients carrying wild-type KRAS is significantly increased by combining anti-EGFR monoclonal antibody (mAb) with standard chemotherapy. However, conflicting data exist in both the wild-type KRAS and mutant KRAS groups, which strongly challenge CRC anti-EGFR treatment. Here we conducted a meta-analysis in an effort to provide more reliable information regarding anti-EGFR treatment in CRC patients. Methods We searched full reports of randomized clinical trials using Medline, the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO). Two investigators independently screened the published literature according to our inclusive and exclusive criteria and the relative data were extracted. We used Review Manager 5.2 software to analyze the data. Results The addition of anti-EGFR mAb to standard chemotherapy significantly improved both progression-free survival (PFS) and median overall survival (mOS) in the wild-type KRAS group; hazard ratios (HRs) for PFS and mOS were 0.70 [95% confidence interval (CI), 0.58–0.84] and 0.83 [95% CI, 0.75–0.91], respectively. In sub-analyses of the wild-type KRAS group, when PCR-based assays are employed, PFS and mOS notably increase: the HRs were 0.74 [95% CI, 0.62–0.88] and 0.87 [95% CI, 0.78–0.96], respectively. In sub-analyses of the mutant KRAS group, neither PCR-based assays nor direct sequencing enhance PFS or mOS. Conclusion Our data suggest that PCR-based assays with high sensitivity and specificity allow accurate identification of patients with wild-type KRAS and thus increase PFS and mOS. Furthermore, such assays liberate patients with mutant KRAS from unnecessary drug side effects, and provide them an opportunity to receive appropriate treatment. Thus, establishing a precise standard reference test will substantially optimize CRC-targeted therapies.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Different EGFR-specific ligands could differently influence the clinical activity of cetuximab: while high mRNA levels of either amphiregulin or epiregulin may predict a better response [21, 116-119], high levels of TGF-α as well as HB-EGF could confer lack of sensitivity [107, 118]. These findings, together with the role of other growth factors mentioned in this review, i.e., HGF, sustain the potential but understudied contribution of tumor-stromal interactions in influencing drug response in mCRCs [104, 120, 121]. "
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    ABSTRACT: Only approximately 10 % of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab (“primary” or “de novo” resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory (“secondary” or “acquired” resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap. By trying to extrapolate a unifying perspective out of many idiosyncratic details, here, we discuss the molecular underpinnings of therapeutic resistance, summarize research efforts aimed to improve patient selection, and present alternative therapeutic strategies that are now under development to increase response and combat relapse.
    Full-text · Article · Jul 2014 · Journal of Molecular Medicine
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    • "FDA-approved EGFR targeted inhibitors include the low-molecular-weight ATP-competitive kinase inhibitors, such as gefitinib and erlotinib, and humanized monoclonal antibodies directed against the extracellular domain, notably cetuximab and panitumumab [13]. Although high-level expression of EGFR ligands and/or increased EGFR gene copy numbers may be predictive markers for antitumor response by cetuximab in colon cancer [14-16], and patients with RAS driven cancers are known not to benefit from cetuximab treatment, a clear molecular explanation of cancer response to cetuximab has remained elusive. "
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    ABSTRACT: Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.
    Full-text · Article · Jun 2014 · Molecular Cancer
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