University Hospital Essen, Hufelandstr. 55, Essen, Germany.
J Clin Oncol. 2012 Jul 1;30(19):2375-83. doi: 10.1200/JCO.2011.41.1660. Epub 2012 May 21.
Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules.
In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment.
Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent.
Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.
在转移性黑色素瘤患者中，使用 I 类 RAF 抑制剂选择性抑制突变 BRAF 已产生显著的临床疗效。然而，也有证据表明 RAF 抑制剂可能通过刺激 RAF 野生型细胞中的 MAPK 信号通路而诱导癌变或促进肿瘤进展。我们分析了在 I 类 RAF 抑制剂治疗下出现的黑色素细胞病变，以评估其良恶性、特定的基因突变或信号转导分子的表达。
共分析了 2010 年至 2011 年期间在 7 个国际黑色素瘤中心进行的临床试验中，19 例接受选择性 BRAF 抑制剂治疗 BRAF 突变转移性黑色素瘤的患者的 22 处皮肤黑色素细胞病变，这些病变要么在治疗过程中出现，要么在形态上发生了明显变化。分析了 BRAF 和 NRAS 基因的突变，并与 21 例无 BRAF 抑制剂治疗史的患者的 22 个常见痣进行免疫组织化学评估，以比较各种信号转导分子的表达。
在 27 周的选择性 BRAF 阻断治疗后，11 例患者中确认了 12 例新发现的原发性黑色素瘤。此外，还发现了 10 个痣，其中 9 个是发育不良的。所有黑色素细胞病变均为 BRAF 野生型。研究发现，与痣相比，新发生的原发性黑色素瘤中 cyclin D1 和 pAKT 的表达增加（P =.01 和 P =.03）。常见痣中没有 NRAS 突变，但 BRAF 突变很常见。
接受选择性 BRAF 抑制剂治疗的患者中恶性黑色素瘤的发生频率可能会增加，这支持 BRAF 治疗诱导生长和肿瘤发生的机制。对接受 I 类 RAF 抑制剂治疗的患者的黑色素细胞病变进行密切监测似乎是必要的。
