BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies.
BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies.
复制标题
DOI：
10.2147/ott.s39096
复制
发表时间：
2015
影响因子：
4
通讯作者：
Queirolo P
中科院分区：
文献类型：
--
作者：
Spagnolo F;Ghiorzo P;Orgiano L;Pastorino L;Picasso V;Tornari E;Ottaviano V;Queirolo P
BRAF 抑制剂维莫非尼 (vemurafenib) 和达拉非尼 (dabrafenib) 比化疗提高了总体生存率，并已被批准用于治疗 BRAF 突变的转移性黑色素瘤。最近，在一项 II 期研究中，与达拉非尼单药疗法相比，BRAF 抑制剂达拉非尼与 MEK 抑制剂曲美替尼的组合显示出改善的无进展生存期，并已获得美国食品和药物管理局的批准。然而，即使采用联合治疗，大多数患者也会产生获得性耐药机制，并且由于对治疗的内在耐药性，其中一些患者根本无法实现肿瘤消退。随着BRAF抑制剂的发展，免疫疗法向前迈出了重要一步：抗CTLA-4单克隆抗体ipilimumab被批准用于治疗转移性黑色素瘤；抗PD-1药物在I/II期试验中取得了可喜的结果，III期研究的数据即将准备就绪。无论 BRAF 状态如何，此类药物都有效，这使得治疗方法变得更加复杂，因为 BRAF 抑制剂一线治疗可能不是所有 BRAF 突变患者的最佳选择。本文的目的是回顾目前可用于 BRAF V600 突变的转移性黑色素瘤患者的全身治疗方案，总结 BRAF 抑制剂的耐药机制，并讨论克服它们的可能策略。此外，由于肿瘤标本的分子分析现已成为转移性黑色素瘤患者治疗策略的关键和决定性因素，因此将报告BRAF V600突变分子检测技术的进展。
BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported.