Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF Inhibition Journal Article


Authors: Zimmer, L.; Hillen, U.; Livingstone, E.; Lacouture, M. E.; Busam, K.; Carvajal, R. D.; Egberts, F.; Hauschild, A.; Kashani-Sabet, M.; Goldinger, S. M.; Dummer, R.; Long, G. V.; McArthur, G.; Scherag, A.; Sucker, A.; Schadendorf, D.
Article Title: Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF Inhibition
Abstract: Purpose: Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. Patients and Methods: In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment. Results: Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. Conclusion: Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted. © 2012 by American Society of Clinical Oncology.
Keywords: immunohistochemistry; signal transduction; mitogen activated protein kinase; protein kinase b; adult; clinical article; protein expression; aged; middle aged; young adult; gene mutation; advanced cancer; clinical trials as topic; melanoma; enzyme inhibition; skin neoplasms; somatomedin c receptor; protein kinase inhibitors; enzyme phosphorylation; melanocytic nevus; cell growth processes; tumor growth; cyclin d1; b raf kinase; proto-oncogene proteins b-raf; skin carcinogenesis; platelet derived growth factor beta receptor; b raf kinase inhibitor; oncogene n ras
Journal Title: Journal of Clinical Oncology
Volume: 30
Issue: 19
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2012-07-01
Start Page: 2375
End Page: 2383
Language: English
DOI: 10.1200/jco.2011.41.1660
PROVIDER: scopus
PUBMED: 22614973
PMCID: PMC3646308
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 1 August 2012" - "CODEN: JCOND" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Mario E Lacouture
    276 Lacouture
  2. Richard D Carvajal
    133 Carvajal
  3. Klaus J Busam
    540 Busam