New Screening Tool for Detecting Melanoma Mutations

Our understanding of the genetic mutations in melanoma is growing, but sometimes the more we learn, the more we realize we have yet to learn.

The emergence over the past 10 years of BRAF-targeted melanoma therapies constitutes a breakthrough, but it is not a panacea. BRAF is a human gene that makes the protein B-Raf, mutations, which can cause explosive growth and spread of tumors. FDA approval of drugs such as vemurafenib have been shown to be effective in rapidly shrinking tumors.

But many more genes contribute to cancer development than was originally thought, and targeting BRAF alone doesn’t definitively stop disease progression. Other mitogen-activated protein kinase (MAPK) pathway proteins such as the neuroblastoma RAS viral (v-ras) oncogene homologs (NRAS) are now the targets of new agents that are tested in a growing number of clinical trials. By combining these agents, BRAF inhibitors’ effectiveness may increase exponentially.

A study in Diagnostic Pathology looked at NRAS ^Q61R, which is a fairly frequent mutation in melanoma. Previous research has shown that NRAS mutations are common mechanisms of resistance during treatment with BRAF inhibitors, and other studies have shown that NRAS mutation in melanoma was also a predictive factor for response to high-dose interleukin 2—indicating that immunotherapy could become the first-line treatment for NRAS-mutated metastatic melanomas, prior to MEK inhibition.

The study authors collected 142 melanoma samples from 79 patients selected from the cases analyzed at the Brest Molecular Genetic Cancer Platform (France) for theranostic purposes or archived specimens from deceased patients. Some patients were included because of their known BRAF and NRAS mutated status. Patients with ongoing anti-BRAF target treatment were not included in the study, because BRAF inhibitors can induce acquired NRAS mutations.

The study showed that combining immunohistochemistry (IHC) analysis targeting NRAS ^Q61R and BRAF ^V600E proteins with molecular analysis was a reliable theranostic* tool to face challenging samples of melanoma. IHC detection of NRAS ^Q61R protein with the novel SP174 antibody detected all (100 %) the NRAS ^Q61R -mutant samples. “As expected,” the study authors note, “for other mutations spots/points, NRAS ^Q61R and BRAF ^V600E antibodies were ineffective. These mutations represented 29/142 (20.4 %) of the samples (17/79 patients, 21.5 %) in this study.

Although the study authors acknowledge that IHC cannot replace molecular analysis, due to a number of limitations listed in the study, they conclude that IHC can be used as a first-line or a concomitant screening tool in the management of samples, especially the more challenging ones. They suggest that a combination of screening techniques that includes IHC analysis alongside molecular analysis may reduce the drawbacks of each.

“As multiple primary melanomas can exist in a same patient, and as those primary malignant lesions can sometimes be totally regressive and unnoticed, precaution is required when selecting the sample to test for molecular status. This is why we recommend a more exhaustive and systematic analysis of multiple-tumor specimens for patient’s care and management rather than a single molecular status,” the study authors conclude.

(*theranostic is defined as: developing more specific, individualized therapies for various diseases, and to combine diagnostic and therapeutic capabilities into a single agent.)