title: Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.
abstract: BACKGROUND
  Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy.
  
  
  OBJECTIVE
  We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib.
  
  
  METHODS
  We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients.
  
  
  RESULTS
  Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort.
  
  
  CONCLUSIONS
  This study was limited by the small number of cases, all from a single institution.
  
  
  CONCLUSIONS
  Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.
authors.affiliation: Department of Dermatology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. emily.chu@uphs.upenn.edu
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chu
authors.forename: Karolyn A
authors.initials: KA
authors.lastname: Wanat
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Fecher
authors.forename: Marcia S
authors.initials: MS
authors.lastname: Brose
authors.forename: Suzanne
authors.initials: S
authors.lastname: McGettigan
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Giles
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
authors.forename: Misha
authors.initials: M
authors.lastname: Rosenbach
mesh_terms: D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D007636:Keratoacanthoma / Q000139:chemically induced*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000188:drug therapy*; D013449:Sulfonamides / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf