Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma
Authors: Aaron R. Mangold, Alan Bryce, Aleksandar Sekulic
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Targeted inhibition of activated v-raf murine sarcoma viral oncogene homolog B (BRAF), a driver in a substantial proportion of melanomas, leads to rapid and dramatic clinical responses and improved survival in patients with metastatic melanomas (84% vs 64% 6-month survival).1Chapman P.B. Hauschild A. Robert C. Hannen J.B. Ascierto P. Larkin J. et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6215) Google Scholar However, this remarkable efficacy, exemplified by vemurafenib, the first Food and Drug Administration–approved targeted BRAF inhibitor, is accompanied by specific toxicities. The most prominent side effect of vemurafenib both in preapproval clinical trials and postmarketing surveillance is the development of keratoacanthoma-like squamous cell carcinomas, induced by paradoxical activation of mitogen-activated protein kinase pathway in cells harboring retrovirus-associated sequence (RAS) mutations, such as keratinocytes on sun-damaged skin.1Chapman P.B. Hauschild A. Robert C. Hannen J.B. Ascierto P. Larkin J. et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6215) Google Scholar, 2Su F. Viros A. Milagre C. Trunzer K. Bollag G. Spleiss O. et al.RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.N Engl J Med. 2012; 366: 207-215Crossref PubMed Scopus (884) Google Scholar Other side effects possibly also representing "RASopathic" effects of vemurafenib include: keratosis pilaris, acanthopapillomas, plantar hyperkeratosis, ultraviolet A–dependent photosensitivity, maculopapular exanthema, pruritus, folliculitis, burning feet, alopecia, curly hair, nail changes, and melanomas.3Rinderknecht J.D. Goldinger S.M. Rozati S. Kamarashev J. Kerl K. French L.E. et al.RASopathic skin eruptions during vemurafenib therapy.PLoS One. 2013; 8: e58721Crossref PubMed Scopus (70) Google Scholar To our knowledge, we describe the first case of vemurafenib-induced gingival hyperplasia. A 29-year-old woman with a history of metastatic melanoma presented to our clinic in 2011 after having developed many subcutaneous metastases with sequential therapy with radiation followed by paclitaxel and carboplatin. Biopsy specimen and polymerase chain reaction analysis of one of the nodules showed a BRAF V600E mutation and the patient subsequently started vemurafenib. After 2 months of therapy, the patient began to develop keratoacanthomas, acanthopapillomas, xerosis, and gastrointestinal distress. None of the side effects were dose-limiting and the patient continued on vemurafenib. After 3 months of therapy, the patient noted severe gum hyperplasia with bleeding, swelling, and pain (Fig 1, A). Multiple cultures were unremarkable and the hyperplasia was refractory to topical steroids, antifungals, and antibacterials. Because of disease progression, vemurafenib was stopped in favor of ipilimumab. Within 1 month of discontinuing vemurafenib, all of the drug-specific side effects, including the gingival hyperplasia, resolved (Fig 1, B). Unfortunately, because of accelerated disease our patient died shortly after starting ipilimumab. Our patient represents the first described case of vemurafenib-induced gingival hyperplasia. The refractory nature of the hyperplasia while on vemurafenib and quick resolution with drug cessation implicate vemurafenib treatment as a causative event. Rinderknecht et al3Rinderknecht J.D. Goldinger S.M. Rozati S. Kamarashev J. Kerl K. French L.E. et al.RASopathic skin eruptions during vemurafenib therapy.PLoS One. 2013; 8: e58721Crossref PubMed Scopus (70) Google Scholar argue that activation of germline mutations likely lead to unique toxicities. We can use the germline RASopathies as guidance for possible side effects of RAS/mitogen-activated protein kinase activation. Interestingly, son of sevenless homolog 1 mutations result in the activation of the RAS/mitogen-activated protein kinase pathway and are seen in Noonan syndrome 4 (Online Mendelian Inheritance in Man: 610733) and hereditary gingival fibromatosis 1 (Online Mendelian Inheritance in Man: 135300).4Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: {610733}. Available from: URL:http://omim.org/. Accessed April 9, 2012.Google Scholar, 5Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: {135300}. Available from: URL:http://omim.org/. Accessed September 29, 2011.Google Scholar Noonan syndrome 4 is characterized by congenital anomalies and ectodermal changes: curly hair, keratosis pilaris, and hyperkeratosis skin.4Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: {610733}. Available from: URL:http://omim.org/. Accessed April 9, 2012.Google Scholar Hereditary gingival fibromatosis 1 is characterized by mild hypertrichosis, gingival fibromatosis, and fibro-osseous dysplasia.5Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: {135300}. Available from: URL:http://omim.org/. Accessed September 29, 2011.Google Scholar Therefore, it seems both biologically plausible and clinically supported that our patient's gingival hyperplasia may represent yet another RASopathic side effect of vemurafenib therapy. This and other documented side effects of vemurafenib further illustrate the importance of recognizing and better understanding the toxicities of targeted agents for improved and more effective patient treatment.