The BRAF mutation believed to drive disease in about half of patients with melanoma was found to occur at a significantly lower frequency in patients with melanoma in Ireland, according to data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
The study, which included two independent cohorts of patients in Europe, revealed that only about 20 percent of a cohort of Irish patients with melanoma harbored a BRAF mutation.
"The clinical approval of a BRAF inhibitor that blocks the function of the mutant BRAF protein is currently one of the most promising approaches to treat metastatic melanoma," said William M. Gallagher, Ph.D., associate professor of cancer biology at the UCD Conway Institute in Dublin, Ireland. "The observation of a reduced BRAF mutation rate in Irish patients directly influences future treatment strategies for these patients."
Gallagher and colleagues investigated cancer-related changes in 33 genes known to be of key importance in cancer development. They evaluated two independent cohorts of patients with melanoma, including 94 patients from Ireland and 60 patients from Belgium.
Researchers found that 21 percent of patients with melanoma from Ireland had a BRAF mutation compared with 52 percent of the Belgian patients.
The currently approved BRAF inhibitor specifically targets the BRAFV600E mutation; therefore, the researchers also analyzed the percentage of patients carrying this specific BRAF mutation. They found that 19 percent of the Irish patients had the BRAFV600E mutation compared with 43 percent of the Belgian patients. They found similar results after analyzing tumor tissue from three additional independent cohorts of patients with melanoma from Ireland. In these three groups of 137 patients, 79 patients and 34 patients, the researchers found the BRAFV600E mutation in 21 percent, 20 percent and 32 percent of patients, respectively.
"Treatment with the clinically approved BRAF inhibitor that blocks the function of the mutant BRAF protein will only be applicable to patients who possess the relevant BRAFV600E mutation," Gallagher said. "As a result, the majority of Irish patients with melanoma will not benefit from this therapy and are currently left without good alternative treatment possibilities."
Although the exact reason for this difference is unknown, Gallagher offered some explanations. First, it is known that BRAF and NRAS mutations are mutually exclusive, and he and his colleagues found a higher rate of NRAS mutations among the Irish patients compared with the patients from Belgium (21 percent versus 13 percent).
In addition, 12 percent of Irish patients had a mutation in the c-MET gene; none of the Belgian patients did. A mutation in c-MET has rarely been found in melanoma before, according to Gallagher.
"This study shows that the molecular biology underlying melanoma can change in different demographic areas," Gallagher said. "Hence, to be able to give patients the best possible treatment, we need to take into account the molecular variations, or genomic landscape, contributing to tumor development and progression between different populations."