KRAS status predicts whether patients with newly diagnosed metastatic colorectal cancer will respond to cetuximab

A multinational team of investigators has discovered that patients whose tumours contain the normal form (wild-type) of the gene KRAS are most likely to benefit from the addition of cetuximab (Erbitux) to chemotherapy as part of first-line treatment of metastatic colorectal cancer, compared to patients who have a mutation in the KRAS gene. Cetuximab is a targeted therapy that blocks the epidermal growth factor receptor (EGFR), common in many types of cancer.

"While our initial study indicated that cetuximab has the potential to become part of the standard treatment for patients with newly diagnosed metastatic colorectal cancer, this study helps us to identify which patients are most likely to benefit from adding the drug to treatment," said Eric Van Cutsem, MD, PhD, professor at the University Hospital Gasthuisberg in Leuven, Belgium, and the study's first author.

"KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient."

KRAS mutations, which are found in 30 to 45 percent of all colorectal tumours, have previously been shown to predict whether patients will benefit from EGFR-inhibiting drugs in the second-line or later setting. The CRYSTAL trial was the first randomized study to compare patients who received chemotherapy alone to those who received chemotherapy plus cetuximab as part of initial therapy.

Researchers presented data last year that showed that adding cetuximab to a chemotherapy regimen known as FOLFIRI resulted in longer progression-free survival than treatment with chemotherapy alone.

The current study is an extension of that trial and sought to determine whether certain subsets of patients benefited more from the addition of cetuximab than others.

Researchers had access to tumour material from 587 of the 1,198 patients in the original trial, and used these samples to determine each patient tumour's KRAS status. KRAS mutations were detected in 35.6 percent of patients' tumours. Investigators found that among patients with normal KRAS, 59.3 percent responded to treatment with chemotherapy and cetuximab (their tumours shrank by more than half), compared to 43.2 percent who responded to chemotherapy alone. Among patients with mutated KRAS in their tumours, there was no difference in response rates between those who received chemotherapy alone and those who received chemotherapy and cetuximab.

In the overall study including all patients, the addition of cetuximab to FOLFIRI resulted in a 15 percent decreased risk for progression. When KRAS was evaluated, the normal KRAS gene group was shown to have a 32 percent decreased risk for progression from the addition of cetuximab. Patients with a mutant KRAS gene in their tumour did not have additional benefit from adding cetuximab to chemotherapy.