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Published on: September 30, 2016
Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer
Background:
Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment.
Methods:
We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS).
Results:
Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC.
Conclusion:
Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.
Insights
A new gene expression test can identify patients with metastatic colorectal cancer (mCRC) who do not benefit from anti-epidermal growth factor receptor (EGFR) therapy, similar to those with KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Metastatic colorectal cancer (mCRC) with KRAS mutations is unresponsive to anti-EGFR therapy.
- A subset of KRAS wild-type (wt) mCRC also shows unresponsiveness to anti-EGFR agents.
- EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are potential predictive markers but lack clinical implementation.
Purpose of the Study:
- To develop a gene expression-based test to identify KRAS wt mCRC patients likely to benefit from anti-EGFR therapy.
- To evaluate the association of gene expression markers with clinical outcomes in mCRC patients treated with cetuximab.
Main Methods:
- RT-PCR was used to analyze 110 candidate gene expression markers in 144 KRAS wt mCRC primary tumors.
- Gene expression data were correlated with disease control, objective response, and progression-free survival (PFS).
- A four-gene predictive classifier was developed using multivariate analysis and cross-validation.
Main Results:
- Expression of EREG and AREG significantly correlated with all clinical endpoints.
- The developed four-gene classifier identified patients with poor outcomes, comparable to KRAS-mutant mCRC.
- Patients below the classifier threshold showed similar disease control and PFS rates as KRAS-mutant mCRC.
Conclusions:
- Gene expression profiling can identify KRAS wt mCRC patients unlikely to benefit from cetuximab.
- This predictive model warrants further validation in independent studies.
- Gene expression signatures offer a promising approach for personalized anti-EGFR therapy selection in mCRC.
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