Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.
Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.
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获得的BRAF抑制剂耐药性：耐药机制的光谱和频率，临床行为和表型关联的多中心荟萃分析。
DOI：
10.1016/j.ejca.2015.08.022
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Schadendorf D
中科院分区：
文献类型：
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作者：
Johnson DB;Menzies AM;Zimmer L;Eroglu Z;Ye F;Zhao S;Rizos H;Sucker A;Scolyer RA;Gutzmer R;Gogas H;Kefford RF;Thompson JF;Becker JC;Berking C;Egberts F;Loquai C;Goldinger SM;Pupo GM;Hugo W;Kong X;Garraway LA;Sosman JA;Ribas A;Lo RS;Long GV;Schadendorf D
BRAF 抑制剂获得性耐药 (BRAFi) 是一种几乎普遍的现象，由大量遗传和非遗传改变引起。在这项研究中，我们评估了与特定耐药机制相关的谱系、发病、进展模式以及随后的临床结果。我们收集了 100 名患者的临床和遗传数据，以及在 BRAFi 治疗进展时获得的 132 个组织样本，这些样本来自先前发表的 3 项大型 BRAFi 耐药研究。这些样本接受了全外显子组测序和/或基于 PCR 的基因检测。在 132 个样本中，58% 的样本发现了假定的耐药机制，包括 NRAS 或 KRAS 突变 (20%)、BRAF 剪接变异 (16%)、BRAFV600E/K 扩增 (13%)、MEK1/2 突变 (7%) 和非 MAPK 通路改变 (11%)。在肿瘤和患者中观察到明显的异质性； 19 名进行 >1 次进展活检的患者中，有 18 名 (95%) 的样本之间存在明显/未知的耐药驱动因素。 NRAS 突变与维莫非尼使用 (p=0.045) 和颅内转移 (p=0.036) 相关，MEK1/2 突变与肝进展相关 (p=0.011)。不同耐药机制的无进展生存期和总生存期相似。疾病进展后的中位生存期为 6.9 个月，对随后的 BRAF 和 MEK 抑制的反应并不常见（15 例中的 2 例；13%）。进展后结果与特定的获得性 BRAFi 耐药机制无关。这是第一项系统地描述 BRAF 突变黑色素瘤患者特定获得性 BRAFi 耐药机制的临床意义的研究，也是编制耐药情况的最大研究。尽管患者体内的耐药机制存在明显的异质性，但 NRAS 突变与维莫非尼的使用和颅内疾病的参与相关。
Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole exome sequencing and/or PCR-based genetic testing. Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with >1 progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p=0.045) and intracranial metastases (p=0.036), and MEK1/2 mutations correlated with hepatic progression (p=0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi resistance mechanisms. This is the first study to systematically characterize the clinical implications of particular acquired BRAFi resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.