Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year.

With links to diet, exercise and other predisposing factors, mutations remain a key trigger to many tumours.

Using data from a previous phase III NCIC-CTG CO.17 clinical trial, researchers from the Princess Margaret Cancer Centre in Toronto have uncovered than only a specific mutation type is susceptible to adjuvant cetuximab.

Results are available in Clinical Cancer Research.

In the initial trial, 572 patients with metastatic colorectal cancer were enrolled evaluating the addition of cetuximab to best supportive care for patients with metastatic colorectal cancer.

However, among patients with metastatic colorectal cancer harboring normal forms of the KRAS gene, only those who had two copies of a specific version of the FCGR2A gene (FCGR2A H/H) had a statistically significant increase in median overall survival when cetuximab (Erbitux) treatment was added to best supportive care.

Previously published results from the trial reported that adding cetuximab to best supportive care increased median overall survival, and that the benefits of cetuximab were restricted to patients with KRAS-wildtype disease.

“Even so, almost half of the patients with metastatic colorectal cancer receiving cetuximab do not derive much benefit from this treatment”, Geoffrey Liu, MD, the Alan B. Brown Chair in Molecular Genomics at the Princess Margaret Cancer Centre in Toronto explained.” We wanted to find new biomarkers that could improve the way we personalize cetuximab treatment”

In this follow-up study, Liu and his colleagues in the Canadian Cancer Trials Group and the Australasian Gastro-Intestinal Trials Group analyzed archived tumour and normal tissue samples from patients enrolled in the original trial

The researchers were able to identify the FCGR2A genotype of 286 patients, 148 of whom had KRAS-wildtype tumours.

Median overall survival among FCGR2A H/H patients with metastatic colorectal cancer harbouring normal forms of the KRAS gene (KRAS-wildtype) was 5.5 months longer for those who received cetuximab in addition to best supportive care (10.35 months versus 4.83 months).

This was a statistically significant increase in median overall survival. Among patients with KRAS-wildtype disease who had one copy of the specific variant (FCGR2A H/R) or no copies (FCGR2A R/R), the increases in median overall survival were not statistically significant, at 3.9 and 1.7 months, respectively.

“We found that patients with the FCGR2A H/H genotype benefited most from cetuximab, those with the FCGR2A H/R genotype had marginal benefit, and those with the FCGR2A R/R genotype had no real benefit,” said Liu. “If our findings are validated in prospective trials, they suggest that the 25 percent of people who carry the FCGR2A R/R genotype should be treated with therapies other than cetuximab so that they do not experience the potential harmful toxicities of an anticancer agent that will be very unlikely to benefit them.”

According to Liu, the major limitations of the study are the retrospective nature of the analyses and the need for confirmation of the results in multiple studies before they can be used to guide clinical decision making.

He added that a study to validate the findings, called CO.20, which is spearheaded by the Canadian Cancer Trials Group and the Australasian Gastro-Intestinal Trials Group, is already underway.

Source: Clinical Cancer Research