title: Cutaneous adverse effects of BRAF inhibitors in metastatic malignant melanoma, a prospective study in 20 patients.
abstract: BACKGROUND
  BRAF inhibitors frequently cause significant cutaneous adverse reactions.
  
  
  OBJECTIVE
  To study the timing, prevalence and response to treatment of skin lesions in patients receiving V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors.
  
  
  METHODS
  We prospectively studied the cutaneous side-effects of patients with a BRAF mutant (V600E, V600K, V600R) metastatic malignant melanoma treated with a BRAF inhibitor. We systematically registered prevalence, timing of onset and response to treatment.
  
  
  RESULTS
  Twenty patients were treated for 2-52 weeks with a BRAF inhibitor. Eleven patients on vemurafenib (58%) developed cutaneous side-effects and 10 patients (42%) had more than one cutaneous adverse event. Verrucous papillomas were observed in eight patients (42%), after 1-12 weeks. We diagnosed four keratoacanthomas in two patients (11%) after 6-10 weeks and two squamous cell carcinomas in two patients (11%) after 10-16 weeks. Seven patients (37%) developed a hyperkeratotic, folliculocentric eruption after 2-8 weeks, resolving quickly under topical steroids. Four patients (21%) presented a facial erythema, two patients (11%) a seborrhoeic dermatitis-like eczema on the scalp. Three patients (16%) developed cystic lesions after 2-11 weeks. Three patients (16%) presented a hand-foot skin reaction after 4-6 weeks, which was successfully treated with topical steroids and keratolytics. Hyperkeratosis of the nipples was seen in one patient (5%). We observed phototoxic reactions after UV exposure in five patients (26%) and alopecia in two patients (11%) after 8-10 weeks. One patient on dabrafenib developed curly hairs (24 weeks), keratotic papules (1 and 36 weeks), a keratoacanthoma (4 weeks) and a hand-foot skin reaction (31 weeks).
  
  
  CONCLUSIONS
  Multiple cutaneous toxicities were observed in patients under BRAF inhibitors, mostly well controlled with adequate treatment. We recommend a multidisciplinary approach with regular assessments of the skin by a dermatologist. This allows early identification and adequate treatment to avoid premature discontinuation of a life-prolonging therapy.
authors.affiliation: Department of Dermatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vanneste
authors.forename: P
authors.initials: P
authors.lastname: Wolter
authors.forename: J J
authors.initials: JJ
authors.lastname: Van den Oord
authors.forename: M
authors.initials: M
authors.lastname: Stas
authors.forename: M
authors.initials: M
authors.lastname: Garmyn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000505:Alopecia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced; D017484:Dermatitis, Phototoxic / Q000209:etiology; D004485:Eczema / Q000139:chemically induced; D004890:Erythema / Q000139:chemically induced; D005148:Facial Dermatoses / Q000139:chemically induced; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D007211:Indoles / Q000009:adverse effects*; D007636:Keratoacanthoma / Q000139:chemically induced; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects; D010212:Papilloma / Q000139:chemically induced; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib