Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma.
BACKGROUND
Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma carrying relevant oncogenic mutations. Cutaneous reactions are frequent and significant. We conducted a systematic prospective dermatological review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAF inhibitor dabrafenib (GSK2118436).


OBJECTIVE
To identify the cutaneous manifestations of the BRAF inhibitor dabrafenib; to form diagnostic criteria to standardize the diagnosis of verrucal keratotic squamoproliferative lesions; and to bring awareness to the medical community of the importance of dermatological assessment of patients taking dabrafenib.


METHODS
Patients enrolled in the phase I/II trial (n = 43) were monitored for the development of new skin lesions. Each new lesion was photographed, a clinical diagnosis recorded and, where appropriate, a biopsy taken. Human papillomavirus (HPV) and p16 immunohistochemistry analyses were performed.


RESULTS
The most frequently observed lesions were verrucal keratotic squamoproliferative lesions (49%), Grover's disease (27%) and reactive hyperkeratotic lesions on the soles, at points of friction (22%). Eighteen squamous cell carcinomas (SCCs) occurred in 20% of patients. Most SCCs appeared between weeks 6 and 24 following commencement of therapy on both sun-damaged and nonsun-damaged skin. All SCCs were well differentiated, five were of the keratoacanthoma type, and two were SCC in situ. Other lesions observed included seborrhoeic keratoses, epidermal cysts, acneiform eruptions, hair loss and changes in hair structure. HPV was negative in 15 of the 16 tissues studied and p16 expression was higher in SCCs compared with verrucal keratoses.


CONCLUSIONS
Administration of the mutant BRAF inhibitor dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low-grade malignancy. Highly oncogenic HPV infection is unlikely to be a contributor to the formation of SCCs or verrucal keratoses.
Department of Dermatology, Westmead Hospital, Westmead, NSW 2145, Australia. rachael.anforth@sydney.edu.au
R M
RM
Anforth
T C M P
TC
Blumetti
R F
RF
Kefford
R
R
Sharma
R A
RA
Scolyer
S
S
Kossard
G V
GV
Long
P
P
Fernandez-Peñas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D015603:Keratinocytes / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000009:adverse effects*; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012871:Skin Diseases / Q000139:chemically induced* / Q000175:diagnosis; D012878:Skin Neoplasms / Q000188:drug therapy*; D055815:Young Adult
D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib