Peters Solange, Bouchaab Hasna, Zimmerman Stefan, Bucher Maya, Gaide Olivier, Letovanec Igor, Homicsko Krisztian, Michielin Olivier
Departments of aOncology bDermatology cPathology, CHUV, Lausanne dService of Hemato-Oncology, Department of Internal Medicine, Hospital of Fribourg, Fribourg, Switzerland.
Melanoma Res. 2014 Oct;24(5):496-500. doi: 10.1097/CMR.0000000000000055.
BRAF inhibitory therapy is the mainstream treatment for BRAF mutant advanced melanoma. However vemurafenib, a type I mutant BRAF V600 inhibitor, induces an array of proliferative skin disorders from keratosis pilaris-like and keratoacanthoma-like lesions to locally aggressive cutaneous squamous cell carcinoma (cuSCC). Dual BRAF/MEK inhibition is known to lower the incidence of such manifestations, but it is not known whether it can counteract established lesions. Here we show, for the first time, a dramatic response and a restitution ad integro upon dual inhibition of a widespread proliferative affection induced by BRAF monotherapy. A 75-year-old woman was diagnosed with a BRAF V600E mutated metastatic melanoma. Following dacarbazine (DTIC) and ipilimumab, the patient was started on 960 mg twice daily vemurafenib (Zelboraf), which resulted in complete response, but the patient also developed grade IV skin toxicity. Despite dose-reduction to 720 mg twice daily the side effects persisted. We hypothesized that a switch to double inhibition of the mitogen-activated protein kinase pathway with dabrafenib and trametinib could lead to improvement of the skin lesions, while preserving tumor control. The patient was closely followed for changes in skin lesions. We witnessed a rapid regression followed by complete disappearance of all side effects of vemurafenib except for grade I fatigue. The biopsied skin lesions show regression of established keratoacanthoma-like lesions with signs of apoptosis. Switching from the current standard of care vemurafenib therapy to the double BRAF/MEK inhibition in BRAF mutant melanoma patients results in rapid disappearance of established proliferative skin disorders.
BRAF抑制疗法是BRAF突变晚期黑色素瘤的主流治疗方法。然而，维莫非尼（一种I型BRAF V600突变抑制剂）会引发一系列增生性皮肤疾病，从毛发角化病样和角化棘皮瘤样病变到局部侵袭性皮肤鳞状细胞癌（cuSCC）。已知双重BRAF/MEK抑制可降低此类表现的发生率，但尚不清楚它是否能对抗已形成的病变。在此，我们首次展示了对BRAF单药治疗引起的广泛增生性病变进行双重抑制后出现的显著反应和完全恢复。一名75岁女性被诊断为BRAF V600E突变的转移性黑色素瘤。在接受达卡巴嗪（DTIC）和伊匹单抗治疗后，患者开始每日两次服用960 mg维莫非尼（佐博伏），这导致了完全缓解，但患者也出现了IV级皮肤毒性。尽管剂量减至每日两次720 mg，副作用仍持续存在。我们推测，改用达拉非尼和曲美替尼双重抑制丝裂原活化蛋白激酶途径可能会改善皮肤病变，同时保持对肿瘤的控制。密切观察患者皮肤病变的变化。我们目睹了维莫非尼所有副作用的迅速消退，除了I级疲劳外，所有副作用均完全消失。活检的皮肤病变显示已形成的角化棘皮瘤样病变消退，并伴有凋亡迹象。在BRAF突变的黑色素瘤患者中，从当前的标准治疗维莫非尼疗法改为双重BRAF/MEK抑制可导致已形成的增生性皮肤疾病迅速消失。
