Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy.
BACKGROUND
BRAF inhibitors (BRAFi) cause paradoxical activation of the MAPK pathway in keratinocytes resulting in cutaneous squamous cell carcinoma (cuSCC).


OBJECTIVE
We sought to examine the clinical factors involved in BRAFi-induced cuSCC development.


METHODS
We studied 134 patients with BRAF-mutant metastatic melanoma treated with a BRAFi at Westmead Hospital, Sydney, Australia. Details of cuSCC development and associations with melanoma clinicopathologic features and treatment outcome were examined.


RESULTS
In all, 32 (24%) patients developed 110 cuSCC after commencing treatment. In all, 61 (55%) cuSCC developed within the first 3 months. Age was the only independent risk factor for cuSCC development. After 3 months of therapy 4% of patients younger than 40 years developed cuSCC compared with 33% who were older than 60 years, and the hazard ratio of developing a cuSCC increased by 1.7 (95% confidence interval 1.3-2.3) per decade (P < .001). BRAFi cuSCC occurred more often in sun-protected areas (42%) compared with sporadic cuSCC (21%) (P < .001). cuSCC was not associated with progression-free survival.


CONCLUSIONS
The study was from a single center and patients were also at risk of sporadic cuSCC.


CONCLUSIONS
Most BRAFi-induced cuSCC develop within 3 months of BRAFi therapy. The only independent risk factor is increasing age. cuSCC may present in anatomical locations with low ultraviolet exposure such that thorough dermatologic assessment is required.
Department of Dermatology, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
Rachael
R
Anforth
Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia.
Alexander
A
Menzies
Research and Education Network, Westmead Hospital, Westmead, Australia.
Karen
K
Byth
Department of Dermatology, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
Giuliana
G
Carlos
Department of Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Westmead, Australia.
Shaun
S
Chou
Department of Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Faculty of Medicine, University of Western Sydney, Sydney, Australia.
Raghwa
R
Sharma
Sydney Medical School, University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
Richard A
RA
Scolyer
Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia.
Richard
R
Kefford
Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia.
Georgina V
GV
Long
Department of Dermatology, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: pablo.fernandezpenas@sydney.edu.au.
Pablo
P
Fernandez-Peñas
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000401:mortality; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D007211:Indoles / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012307:Risk Factors; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000401:mortality; D013449:Sulfonamides / Q000009:adverse effects; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
BRAF inhibitors; cutaneous squamous cell carcinoma; dabrafenib; melanoma; vemurafenib