Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma
Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma
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DOI：
10.1111/j.1365-2133.2012.11155.x
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发表时间：
2012-11-01
影响因子：
10.3
通讯作者：
Fernandez-Penas, P.
中科院分区：
文献类型：
--
作者：
Anforth, R. M.;Blumetti, T. C. M. P.;Fernandez-Penas, P.
背景
突变型BRAF抑制剂正在成为携带相关致癌突变的转移性黑色素瘤患者的标准治疗方法。皮肤反应频繁且显著。我们对在突变型BRAF抑制剂达拉非尼（GSK2118436）I/II期临床试验中单个机构招募的所有患者进行了系统的前瞻性皮肤病学评估。
目的
确定BRAF抑制剂达拉非尼的皮肤表现；制定诊断标准以规范疣状角化鳞状增生性病变的诊断；并使医学界认识到对服用达拉非尼的患者进行皮肤病学评估的重要性。
方法
对参与I/II期试验（n = 43）的患者进行监测，观察新皮肤病变的发展。对每个新病变进行拍照，记录临床诊断，并在适当情况下进行活检。进行人乳头瘤病毒（HPV）和p16免疫组化分析。
结果
最常观察到的病变是疣状角化鳞状增生性病变（49%）、格鲁夫病（27%）以及足底摩擦部位的反应性角化过度病变（22%）。20%的患者发生了18例鳞状细胞癌（SCC）。大多数SCC在治疗开始后的第6至24周出现在受日光损伤和未受日光损伤的皮肤上。所有SCC均分化良好，5例为角化棘皮瘤型，2例为原位SCC。观察到的其他病变包括脂溢性角化病、表皮囊肿、痤疮样皮疹、脱发和毛发结构改变。在研究的16个组织中，15个HPV呈阴性，与疣状角化病相比，SCC中p16表达更高。
结论
突变型BRAF抑制剂达拉非尼的使用与角质形成细胞增殖有关，在某些情况下会发展出低度恶性的特征。高致癌性HPV感染不太可能是SCC或疣状角化病形成的原因。
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).Objectives 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.