title: RASopathic skin eruptions during vemurafenib therapy.
abstract: OBJECTIVE
  Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.
  
  
  METHODS
  Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.
  
  
  RESULTS
  Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).
  
  
  CONCLUSIONS
  Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Jeannine D
authors.initials: JD
authors.lastname: Rinderknecht
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.forename: Sima
authors.initials: S
authors.lastname: Rozati
authors.forename: Jivko
authors.initials: J
authors.lastname: Kamarashev
authors.forename: Katrin
authors.initials: K
authors.lastname: Kerl
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Benedetta
authors.initials: B
authors.lastname: Belloni
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006197:Hair / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D009262:Nails / Q000187:drug effects; D012871:Skin Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects*; D013997:Time Factors; D000077484:Vemurafenib; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D018631:ras Proteins