Malignant Melanoma Recurrence - How To Avoid It After Targeted Treatment

According to a study published in the New England Journal of Medicine, researchers at The Institute of Cancer Research (ICR) have demonstrated how to prevent new cancers that can occur when malignant melanoma patients are treated with drugs known as BRAF inhibitors.

In the past, doctors have observed that between 15 and 30% of patients who were treated with BRAF inhibitors, including the FDA-approved drug vemurafenib (Zelboraf), developed another type of skin cancer known as cutaneous squamous cell carcinoma, which required surgical removal.

Professor Richard Marais from the ICR, and his worldwide collaborators, assessed squamous cell carcinoma tissue, which had been obtained from 21 malignant melanoma patients who were treated with vemurafenib in a clinical trial. They tested the DNA of the new tumors for the presence of known cancer-causing mutations including KRAS, HRAS, NRAS, TP53 and CDKN2A and discovered that 60% of the samples contained either KRAS or HRAS mutations.

They observed that further testing showed that the BRAF inhibitors do not directly trigger squamous cell carcinomas, but speed up the development of existing cancerous changes to the skin that were not yet showing symptoms. Significantly, they observed in mice that another type of drug, a MEK inhibitor, was able to inhibit the development of these second tumors even when BRAF drugs were present.

Professor Marais, who is co-senior author of the study, explains: "Around half of all patients with malignant melanoma have a mutation in their BRAF gene, and can be treated with BRAF-inhibiting drugs. However, between 15 and 30 per cent of the treated patients develop other skin tumors. By determining the mechanism by which these develop, we have been able to devise a strategy to prevent the second tumors without blocking the beneficial effects of the BRAF drugs. This may allow many more patients to benefit from these important drugs."

Dr Antoni Ribas, a professor of hematology and oncology, who is also a researcher with UCLA's Jonsson Comprehensive Cancer Center, commented: "This is one of the very few times that we understand molecularly why a side effect to cancer treatment is happening. The side effect in this case is caused by how the drug works in a different cellular setting. In one case it inhibits cancer growth, and in another it makes the malignant cells grow."

Cancer Research UK's senior science information manager, Dr Julie Sharp, concludes: "This research reveals a possible new approach to avoid the second cancers that affect some malignant melanoma patients taking BRAF inhibitors. The next stage will be to explore these results in more patients in clinical trials to see if this drug combination could treat the original cancer while preventing new cancers from forming."