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. LIMITATIONS: This study was limited by the small number of cases, all from a single institution. CONCLUSION: 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.
BACKGROUND:Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAFV600E 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. LIMITATIONS: This study was limited by the small number of cases, all from a single institution. CONCLUSION: 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: Jeffrey A Sosman; Kevin B Kim; Lynn Schuchter; Rene Gonzalez; Anna C Pavlick; Jeffrey S Weber; Grant A McArthur; Thomas E Hutson; Stergios J Moschos; Keith T Flaherty; Peter Hersey; Richard Kefford; Donald Lawrence; Igor Puzanov; Karl D Lewis; Ravi K Amaravadi; Bartosz Chmielowski; H Jeffrey Lawrence; Yu Shyr; Fei Ye; Jiang Li; Keith B Nolop; Richard J Lee; Andrew K Joe; Antoni Ribas Journal: N Engl J Med Date: 2012-02-23 Impact factor: 91.245
Authors: Poulikos I Poulikakos; Yogindra Persaud; Manickam Janakiraman; Xiangju Kong; Charles Ng; Gatien Moriceau; Hubing Shi; Mohammad Atefi; Bjoern Titz; May Tal Gabay; Maayan Salton; Kimberly B Dahlman; Madhavi Tadi; Jennifer A Wargo; Keith T Flaherty; Mark C Kelley; Tom Misteli; Paul B Chapman; Jeffrey A Sosman; Thomas G Graeber; Antoni Ribas; Roger S Lo; Neal Rosen; David B Solit Journal: Nature Date: 2011-11-23 Impact factor: 49.962
Authors: Daniel N Cohen; Steven K Lawson; Aaron C Shaver; Liping Du; Harrison P Nguyen; Qin He; Douglas B Johnson; Wilfred A Lumbang; Brent R Moody; James L Prescott; Pranil K Chandra; Alan S Boyd; Jeffrey P Zwerner; Jason B Robbins; Stephen K Tyring; Peter L Rady; James D Chappell; Yu Shyr; Jeffrey R Infante; Jeffrey A Sosman Journal: Clin Cancer Res Date: 2015-02-27 Impact factor: 12.531
Authors: A Boada; C Carrera; S Segura; H Collgros; P Pasquali; D Bodet; S Puig; J Malvehy Journal: Clin Transl Oncol Date: 2018-05-24 Impact factor: 3.405
Authors: Karen E Parrish; Ling Cen; James Murray; David Calligaris; Sani Kizilbash; Rajendar K Mittapalli; Brett L Carlson; Mark A Schroeder; Julieann Sludden; Alan V Boddy; Nathalie Y R Agar; Nicola J Curtin; William F Elmquist; Jann N Sarkaria Journal: Mol Cancer Ther Date: 2015-10-05 Impact factor: 6.261
Authors: Vishwas Parekh; Joseph Sobanko; Christopher J Miller; Giorgos Karakousis; Wei Xu; Richard Letrero; Rosalie Elenitsas; Xiaowei Xu; David E Elder; Ravi Amaravadi; Lynn M Schuchter; Katherine L Nathanson; Melissa A Wilson; Emily Y Chu Journal: J Cutan Pathol Date: 2018-12-27 Impact factor: 1.587
Authors: D M Barrios; G S Phillips; A Freites-Martinez; M Hsu; K Ciccolini; A Skripnik Lucas; M A Marchetti; A M Rossi; E H Lee; L Deng; A Markova; P L Myskowski; M E Lacouture Journal: J Eur Acad Dermatol Venereol Date: 2020-02-05 Impact factor: 6.166