Tracking of Second Primary Melanomas in Vemurafenib-Treated Patients

Abstract

Author Contributions: Dr Chen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: A study of 19 lesions from 10 patients

“…All of our tested cases expressed pERK and, in accord with prior studies, this finding supports the hypothesis of paradoxical activation of the MAPK pathway by BRAF inhibitor therapy in BRAF wild-type melanocytic lesions. 10,15,16 Similar to our findings, Dalle et al 15 and Goppner et al 16 reported pERK expression in melanomas developed in the setting of BRAF inhibitor therapy. A recent case report of marked resolution of vemurafenib-induced cutaneous lesions upon changing to dual BRAF/MEK combined therapy would be also compatible with these findings.…”

“…[9][10][11]15,17 Based on our study and previous reports that these lesions are predominantly BRAF wild-type and express pERK but not pAKT, we hypothesized that these melanocytic lesions would have distinct histopathologic and immunohistochemical features as a result of paradoxical MAPK pathway activation. In the largest series of 36 melanocytic lesions excised during vemurafenib therapy by Perier-Muzet et al, 17 histopathologic details were not reported.…”

“…Several studies including ours have demonstrated that the atypical melanocytic lesions associated with BRAF inhibitor therapy invariably lack BRAFV600E mutation. 7,9,10,15,16 The changes observed in melanocytic lesions during BRAF inhibitor treatment may be explained by the previously characterized amplification of MAPK activity in the setting of BRAF inhibition of BRAF wild-type tumors. 23,24 In vitro experimental findings demonstrated paradoxical activation of the MAPK pathway in wild-type BRAF cells via CRAF activation under treatment with BRAF inhibition.…”

“…6 In addition to these toxicities, investigators have reported changes in existing melanocytic nevi and development of new primary melanomas and atypical nevi in the setting of therapeutic BRAF inhibition. [7][8][9][10][11][12][13][14][15][16][17][18] Studies have classified excised lesions as common nevi, dysplastic nevi, and melanoma but have not examined these lesions for distinctive histologic features. [9][10][11]17 Although BRAF inhibition has been reported to produce side effects through the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in both keratinocytic and melanocytic lesions, 1 the profile of immune response in these lesions has not been previously investigated to our knowledge.…”

Distribution of Subsequent Primary Invasive Melanomas Following a First Primary Invasive or In Situ Melanoma in Queensland, Australia, 1982-2010

“…15,16 Dalle et al 17 and Haenssle et al 18 have stressed the importance of repeated skin examination, including sequential dermoscopy, for the early detection of subsequent primary melanomas in patients who receive these treatments. Also of interest was our finding that the risk of a subsequent primary invasive melanoma following a first primary in situ melanoma was more than 4 times higher than that in the general population, and only slightly lower than the relative risk following a first primary invasive melanoma.…”