<i>BRAF</i><sup>V600E</sup>Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy With or Without Trametinib
Authors: Phil McClenahan, Lynlee L. Lin, Jean-Marie Tan, Ross Flewell-Smith, Helmut Schaider, Kasturee Jagirdar, Victoria Atkinson, Duncan Lambie, Tarl W. Prow, Richard A. Sturm, H. Peter Soyer
Journal: JAMA Dermatology (2014)

elanocytes, like many other human cells, express the BRAF gene.However, mutation of BRAF in melanocytes occurs at high frequency in melanocytic proliferations such as nevi (70%-82%) and melanomas (50%-60%). 1,2Mutation of BRAF results in a defect of the mitogen-activated protein kinase (MAPK) pathway causing oncogenic proliferation and avoidance of apoptosis. 3Most frequently, BRAF mutations occur at the V600E position (74%-90%), and the next most common mutation occurs at V600K (16%-29%) 4 ; together, these sites account for 95% of all BRAF mutations.Initial breakthrough treatments were made with vemurafenib, a selective inhibitor of BRAF V600E -mutated kinase.The inhibition of BRAF V600E initially induces tumor growth arrest and partial or complete tumor regression in metastatic melanoma. 5Given the frequency of BRAF V600E mutations in benign nevi, 2 it is also not surprising that changes have been observed in existing melanocytic nevi and that new nevi appear during BRAF V600E inhibitor therapy. 6,7Recently, a study of 42 patients treated with vemurafenib for a mean duration of 6.7 months described a high level of dermoscopic change in preexisting lesions such as color changes, appearance and disappearance of globules, dermoscopic island pigmentation, and increases in size of nevi. 8New primary melanomas have also been reported during the early stages of vemurafenib treatment, arising from new erupting melanocytic proliferations or rapidly changing existing nevi. 9Zimmer et al, 9 Dalle et al, 7 and Perier-Muzet et al 8 report that these new primary melanomas arising during vemurafenib therapy are BRAF wild type.Herein we describe an example of nevus volatility and propose the molecular involvement in a patient undergoing BRAF V600E inhibition therapy and who participated in a nevus surveillance study.All patients in the surveillance study provided written consent, and the study followed the Declaration of Helsinki protocols and was approved by the Princess Alexandra Hospital human research ethics committee.IMPORTANCE Recent advances in targeting BRAF V600E mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma.With increased survival, the importance of other comorbidities increases and requires consideration in long-term management.This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes.OBSERVATIONS A man in his 30s had been monitored with whole-body dermoscopy at roughly 7-month intervals as part of a nevus surveillance study.Fourteen months after his initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with or without trametinib therapy.Continued dermoscopic monitoring for the next 12 months revealed that approximately 50% of the existing acquired melanocytic nevi involuted, while the remaining nevi did not change.Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAF V600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one. CONCLUSIONS AND RELEVANCEOur observations indicate that a previously suggested hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E mutation, while others that grow or remain unchanged are wild type.However larger-scale trials are required to gather conclusive data and create a more complete clinical picture.