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Research Identifies Markers of Response to Treatment With Cetuximab/Irinotecan in Patients With Primary Colorectal Cancer Metastases: Presented at EORTC-NCI-AACR

By Chris Berrie

GENEVA -- October 23, 2008 -- Expression of amphiregulin and epiregulin in messenger ribonucleic acid (mRNA) appears to be significantly higher in patients who respond to the combination of cetuximab (CTX) and irinotecan (IRI) for treatment of colorectal cancer (CRC) metastases.

These markers thus provide an improved prediction outcome for patients with metastatic CRC treated with this drug combination.

Bart Jacobs, PhD, Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium, presented these findings here on October 22 at the 20th International Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR).

Dr. Jacobs conducted the study with Sabine Tejpar, MD, PhD, Department of Human Genetics, Katholieke Universiteit Leuven.

Amphiregulin and epiregulin are ligands of epidermal growth factor receptor (EGFR) that have been implicated, along with K-ras mutation status, in liver metastases from colorectal cancer.

Therefore, Dr. Jacobs and colleagues set out to explore their clinical usefulness of amphiregulin and epiregulin to predict patient response to treatment with CTX/IRI after development of CRC metastases.

They studied the expression of these markers in formalin-fixed, paraffin-embedded (FFPE) tissue specimens from primary CRC tumours obtained from patients with IRI-refractory disease receiving CTX/IRI combination treatment after development of metastatic disease.

Specimens from 206 patients were examined for calibrated normalised relative amphiregulin and epiregulin mRNA expression and for K-ras exon-2 mutations. Complete and partial responses, and stable and progressive disease, were identified using computer-tomography imaging and Response Evaluation Criteria in Solid Tumours classification.

Initial results demonstrated significant correlation between amphiregulin and epiregulin mRNA expression (r = .815, P < .001), which was significantly higher in specimens from patients who responded to treatment (P < .001). K-ras mutations were found in 43% of patients.

When the separate K-ras subgroups were analysed according to the amphiregulin and epiregulin mRNA expression, there were no effects on patient outcome according to the K-ras mutation subgroup.

Conversely, high amphiregulin and epiregulin mRNA expression was significantly associated with increased progression-free survival and overall survival only in patients with K-ras wild-type status (P < .001, for both).

Statistical evaluation was then performed to determine the optimal cut-off from the amphiregulin and epiregulin mRNA expression data. For the subsequent prediction of response, a log-hazard model was constructed with probability of response as a continuous function of amphiregulin and epiregulin mRNA expression.

The consequent model for response prediction provided improved prediction of outcome for patients with metastatic CRC who are treated with CTX/IRI.

"I think these kinds of analyses have a lot of future, although this is only 1 marker, which you could combine with 5 or 6 genes, as there is still room for improvement," Dr Jacobs added.


[Presentation title: Amphiregulin and Epiregulin Expression in Primary Colorectal Tumours Identifies a Subgroup of Patients That Will Respond to EGRF Inhibition. Abstract 92]

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