First Genetic Analysis of Metastatic Melanoma: Prognostic Significance of the BRAF Mutation

For the first time, a series of metastatic melanoma (MM) patients have been genetically tested for the constitutively activating BRAF mutation and assessed for its prognostic significance as is routinely done for breast cancer (HER2) and chronic myeloid leukemia (ABL). To date, the American Joint Committee on Cancer staging system for melanoma incorporates two disease characteristics to define melanoma substages: extent of metastatic disease and serum lactate dehydrogenase levels.

It is still difficult to discriminate between aggressive and more indolent metastatic melanoma and standardized molecular characterization would be a step toward better patient classification.

The current study, published this week in the Journal of Clinical Oncology (DOI: 10.1200/JCO.2010.32.4327), sought to explore 1) how the mutated BRAF gene relates to pathology and clinical outcome and 2) the effect of treatment with a selective BRAF inhibitor on the overall survival from the diagnosis of the first distant metastasis.

Out of the197 metastatic melanoma patients from Australia involved in the study, 48% had a mutated BRAF gene, consistent with previous frequencies found among MM patients. 20% of the BRAF mutations were V600K mutations, more common that previously reported, and 74% were V600E BRAF mutations. 

Patients with a mutant BRAF gene were younger than wt BRAF patients and this difference was statistically significance. However, no specific clinical features of metastatic disease correlated with BRAF mutation status, including location of metastases: no difference in sex, family history of melanoma, type of distant metastases, lactate dehydrogenase or Eastern Cooperative Oncology Group (ECOG) performance status (adjusted for age) at first diagnosis of metastatic melanoma, development of brain metastases, or response to first-line chemotherapy was found between the two groups.

Remarkably, the presence of the BRAF mutation in an initial primary melanoma diagnosis had no impact on the time to distant metastasis, although the patient cohort did not allow this connection to be asserted with high confidence and follow-up studies are needed. As Keith Flaherty pointed out in an accompanying editorial to the article, 40% of melanomas that lack a BRAF mutation have an activating NRAS mutation that activates the same signaling pathway as BRAF and there is evidence that this pathway is also activated in melanomas that do not harbor either of these mutations. The implication here is that most primary melanomas have a similar biology and, therefore, do not have dissimilar outcomes. 

Overall, the BRAF mutation was associated with poorer survival in the metastatic setting, unless the patient received treatment with a BRAF inhibitor. In light of primary melanoma patients with either a BRAF wt or mutant gene having the same time to disease progression, this result suggests that the BRAF mutation may provide an essential genetic background for a faster evolution of metastasis.

Eligible BRAF mutant patients in the study were enrolled in BRAF inhibitor trials, either the RG7204 Phase II trial from Roche or the Phase I GlaxoSmithKline (GSK), GSK2118436 trial. Both treatments are undergoing clinical trials in the U.S. for MM. GSK’s GSK2118436 is currently in Phase III and has shown activity in both V600E and V600K MM patients in Phase I and II trials. RG7204 is targeted to patients harboring the V600E BRAF mutation. The high response to BRAF inhibitors presented in this study and others suggests that these drugs deter the aggressive tumor growth seen with mutated BRAF metastatic melanoma. Importantly, results from this study show that patients harboring the V600K BRAF mutation respond to the GSK drug, one case of a V600K mutation patient responding to RG7204 was reported in this study. 

Progress in sub-classifying melanoma is a step toward better treatment and developments of algorithms for aiding physicians to decide on the appropriate treatment. As we move towards a more thorough molecular classification of melanoma, researchers will be able to investigate the other genetic changes along with BRAF mutations that make a melanoma more or less aggressive to influence the course of treatment.  It is still too early to establish BRAF as a prognostic marker, but this study is a step in the right direction. For a cancer that has not had a positive Phase III trial in more than a decade until Bristol Myers Squibb’s ipilimumab and Roche’s RG7204, all of this is potentially good news for melanoma patients.