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

ABSTRACT 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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    • "This is our next plan and will be a long-range research and the results we get will be very valuable for the clinic. Khambata-Ford et al. demonstrated that DUSP4 is one of the top drug resistance markers in metastatic colorectal cancer patients [35]. Lung cancer patients with EGFR mutations respond well to Cetuximab, and it was recently shown that DUSP4 is downregulated in lung cancers with EGFR mutations [27]. "
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    • "Finally, recent studies have shown that high levels of expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with response to anti-EGFR MoAbs in CRC patients [Khambata-Ford et al., 2007; Jacobs et al., 2009]. These data suggest that in CRC the regulation of downstream EGFR signaling pathways depends mainly on AREG and EREG binding to ErbB receptors in KRAS wild-type patients. "
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    • "Oncogenic mutations in the NRAS gene, a homologue of KRAS, also result in resistance to anti-EGFR agents, but are far less frequent (2% -4% of all cases) [21] [22]. The RNA expression of amphiregulin (AREG) and epiregulin (EREG), ligands of the EGF receptor, may also be linked with response to cetuximab in KRAS wildtype patients [23]. These findings were recently confirmed in 144 mCRC patients with KRAS wildtype genotype. "
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