One of the commonly used treatments for patients diagnosed with BRAF V600 mutation-positive melanoma with unresectable stage III and IV disease includes selective BRAF inhibitor with or without a MEK inhibitor.
A team of researchers from Indiana University School of Medicine set to evaluate if in patients suffering from metastatic melanoma, all metastatic lesions carried the same BRAF mutation status found in the primary tumor. Furthermore, if discordancy exists at what frequency does it occur?
In their study “Discordancy in BRAF mutations among primary and metastatic melanoma lesions: clinical implications for targeted therapy”, published in the Modern Pathology journal, the team preformed BRAF testing in tissue samples (primary skin, skin metastasis, lymph node metastasis, and one metastatic lesion to the larynx) from 177 patients diagnosed with unresectable and/or metastatic melanoma. Of the total cohort of patients, 54% were female and 46% were male, with ages ranging from 23 to 81 years. Importantly, 25 patients had tumor tissue from both primary and metastatic sites available for testing.
DNA was extracted from tumor samples and submitted to a BRAF assay using real time polymerase chain reaction (PCR) amplification that can detect five different somatic mutations in the BRAF gene.
After analyzing BRAF mutations in both primary and metastatic sites from 25 melanoma patients, BRAF mutations were found in 64% of all patients. Moreover, 16% of patients were found to present BRAF mutation discordancy between the primary and metastatic lesions, 8% of which had BRAF V600 mutation-positive primary melanomas with wild-type metastatic lesions and another 8% presented a BRAF V600 wild-type primary melanoma with a V600 mutation-positive metastatic lesion.
Upon testing multiple metastatic sites (six patients), researchers found a much higher discordancy rate of BRAF mutations.
These findings support the fact that patients with BRAF V600 mutation-negative melanoma do not derive any benefit from BRAF inhibitor therapy. Furthermore, previous research has found that, upon treatment with selective BRAF inhibitors, BRAF V600 mutation-negative tumor cells exhibited increased proliferation, reduced cell adherence, and increased mobility, factors that contribute towards the development of tumors.
“Through optimizing the identification of different types of BRAF mutations, those patients with less frequent BRAF mutations may have access to this life-extending class of drugs, who would have otherwise been excluded from selective BRAF or MEK inhibitor therapy. Additionally, development of therapeutic agents with varied spectrums of BRAF (and MAPK pathway) inhibition may lead to more therapeutic options for patients with non-V600E BRAF aberrations”, the authors state in their study.
According to the results found in this study, discrepancies in BRAF mutations could account for the big response variability to BRAF inhibitor therapy found among melanoma patients.