Original article
Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

https://doi.org/10.1016/j.jaad.2012.04.008Get rights and content

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.

Section snippets

Case 1

A 47-year-old Caucasian woman (patient 1, Table I) was diagnosed with stage IV melanoma with lung involvement, and was found to have V600E mutation in BRAF. Vemurafenib 960 mg twice daily was initiated, and 12 weeks after beginning therapy she noticed new scaly papules on the central aspect of her chest (Fig 1, A), upper aspect of her shoulders, back, and face. Several biopsies were performed at these sites. A biopsy from a 2-mm, pink, hyperkeratotic papule on the central aspect of her chest

Discussion

Vemurafenib and dabrafenib commonly induce cutaneous reactions. Each of the 14 patients (13 with metastatic melanoma and one with metastatic thyroid cancer) reported here developed one or more skin side effects after initiation of vemurafenib or dabrafenib treatment, and 13 of the 14 exhibited at least two different types of skin reactions (Table I). Verrucous keratoses were most commonly observed, occurring in 12 of 14 patients. SCCs and acantholytic eruptions each appeared in 8 of the 14

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    Dr Fecher is currently affiliated with the Division of Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis.

    Supported by the Skin Disease Research Center at the University of Pennsylvania.

    Disclosure: Dr Amaravadi is a consultant for and has received honoraria from Genentech. Dr Fecher is an investigator for Roche, Genentech, and GlaxoSmithKline, and has received research funding from those sources. Dr Schuchter is an investigator for Roche and GlaxoSmithKline, and has received grant funding from both sources. Drs Chu, Wanat, Miller, Brose, Seykora, and Rosenbach, Ms McGettigan, and Ms Giles have no conflicts of interest to declare.

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