Mutations impair response to EGFR-targeted therapies in metastatic colorectal cancer

21 Apr 2009

New research shows that in patients with metastatic colorectal cancer, certain gene mutations may be associated with resistance to cetuximab and panitumumab – two monoclonal antibodies that target the epidermal growth factor receptor (EGFR). 

Findings from previous studies have shown that the KRAS gene is a major predictive biomarker of resistance to EGFR-targeted therapies in these patients; however gene mutations only account for about 40 to 50 per cent of those who are resistant.

"This study evaluates, for the first time, the relative contribution of all these molecular alterations. We performed a comprehensive analysis of KRAS, BRAF, PIK3CA gene mutations and loss of PTEN expression in patients with metastatic colorectal cancer treated with cetuximab and panitumumab," said Federica Di Nicolantonio, Pharm.D.,
Ph.D., research fellow in the Laboratory of Molecular Genetics at The Institute for Cancer Research and Treatment of the University of Turin Medical School, Turin, Italy. 

“While KRAS and BRAF mutations never occur at the same time within the same sample, PTEN and/or PIK3CA genetic alterations can present concomitantly with either KRAS or BRAF mutations,” she added. 

Di Nicolantonio and colleagues conducted univariate and multivariate analysis of these four biomarkers. They retrospectively reviewed gene mutations in tumour samples of 132 patients with metastatic colorectal cancer. Patients were treated with EGFR-targeted monoclonal antibody regimens. 

A significant fraction (23/55) of patients with no molecular alterations received some clinical benefit from the treatment, compared to 5 per cent (3/56) among patients with one alteration and 0 per cent (0/24) for patients with at least two alterations. Notably, none of the responders displayed PIK3CA or BRAF mutations. 

"If you consider alterations in all four genes, then more than 70 per cent of colorectal cancer patients unlikely to respond to EGFR-targeted therapies can be identified," Di Nicolantonio said. "This work has major potential clinical implications. Once prospectively validated, our results could immediately turn into molecular tests to be used in clinical practice."