Vemurafenib Accelerates Secondary Skin Cancer in Some Patients

Although vemurafenib improves outcomes in patients with advanced melanoma that harbors a BRAF gene mutation, the drug also accelerates the development of squamous-cell carcinomas and keratoacanthomas in some patients. Results that show a skin cancer drug that causes secondary skin cancers was unexpected, according to the researchers [N Engl J Med. 2012;366(3):207-215]. Approximately 50% of all late-stage melanomas carry a specific BRAF mutation known as V600E. Vemurafenib, a type 1 BRAF inhibitor, blocks the function of the protein produced by this mutated gene and inhibits cell growth through the mitogen-activated protein kinase (MAPK) pathway. However, well-differentiated squamous-cell carcinomas and keratoacanthomas have developed in approximately 15% to 30% of patients treated with type 1 BRAF inhibitors. For the study, researchers sought to characterize the molecular mechanism behind the development of secondary skin cancers in patients treated with vemurafenib. The researchers performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TPS53) in the lesions from patients treated with vemurafenib. Also, an analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of prevalent RAS mutations was performed. Patients participated in the vemurafenib phase 1 dose-escalation study, the phase 2 study, the phase 3 study, or the drug–drug interaction study. All patients had BRAF V600-mutant resistant metastatic melanoma and received 720 or 960 mg of vemurafenib orally twice daily. Patients gave written consent for DNA sampling of the skin cancer lesions excised during dermatologic examinations while participating in the study. As part of the dermatopathologic review of vemurafenib-treated patients, 21 centrally confirmed samples of cutaneous squamous-cell carcinoma or keratoacanthoma obtained from 11 patients with metastatic melanoma were analyzed. A validation set of 14 samples from 12 vemurafenib-treated patients was subsequently analyzed to confirm the high frequency of RAS mutations. Overall, the mean time to diagnosis of the first cutaneous squamous-cell carcinoma or keratoacanthoma in the combined series was 10 weeks, with the earliest lesion appearing at 3 weeks. The mean age at diagnosis was 60 years. Eighteen of the 23 patients (78%) had a history and clinical signs of chronically sun-damaged skin, and 4 (17%) had a history of cutaneous squamous-cell carcinomas or keratoacanthomas. The results found that among the 21 tumor samples, 13 had RAS mutations (12 in HRAS; 62%; 95% confidence interval [CI], 38-82). In the validation set of 14 samples, 8 had RAS mutations (4 in HRAS; 57%, 95% CI, 29-82). Thus, 60% (21 of 35) of samples had a high rate of RAS mutations. Furthermore, increased proliferation of HRAS Q611-mutant cell lines, the most prevalent mutation, exposed to vemurafenib was associated with MAPK-pathway signaling activation of ERK-mediated transcription.