Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2013 Feb 15;119(4):799-805. doi: 10.1002/cncr.27790. Epub 2012 Sep 12.
The high prevalence of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma v-ras oncogene homolog (NRAS) mutations in melanoma provides a strong rationale to test the clinical efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in this disease. The authors hypothesized that the presence of BRAF or NRAS mutations would correlate with clinical benefit among patients who received treatment with combination regimens that included the MEK inhibitor selumetinib.
BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib). The clinical response rate and the time to progression (TTP) were assessed as a function of BRAF and NRAS mutation status.
Among 18 patients analyzed, 9 patients (50%) harbored a BRAF mutation (8 had a valine-to-glutamic acid substitution at residue 600 [V600E]; 1 had an arginine nonsense mutation at residue 603 [R603]), 4 patients (22%) harbored an NRAS mutation (2 had a glutamine-to-arginine substitution at residue 61 [Q61R], 1 had a glutamine-to-lysine substitution at residue 61 [Q61K], and 1 had a glycine-to-lysine substitution at residue 12 [G12S]), and 5 patient (28%) had the wild type of both genes. These mutations were mutually exclusive. Among the 9 patients who had BRAF mutations, 5 patients (56%) achieved a partial response, and 4 patients (44%) achieved stable disease for at least 6 weeks. No patient with the wild-type BRAF gene achieved a clinical response (P = .01 vs patients with BRAF mutations). The presence of an NRAS mutation did not correlate with the clinical response rate. The presence of a BRAF mutation was correlated significantly with the TTP in a multivariate model (hazard ratio, 0.22; P = .02 vs wild-type BRAF).
Higher response rates and longer TTP were observed with selumetinib-containing regimens in patients who had tumors that harbored a BRAF mutation compared with patients who had wild-type BRAF.
黑色素瘤中 v-raf 鼠肉瘤病毒癌基因同源物 B1（BRAF）和神经母细胞瘤 v-ras 癌基因同源物（NRAS）突变的高发生率为检测丝裂原活化蛋白激酶激酶（MEK）抑制剂在该疾病中的临床疗效提供了强有力的理论依据。作者假设 BRAF 或 NRAS 突变的存在与接受包括 MEK 抑制剂 selumetinib 的联合治疗方案的患者的临床获益相关。
在接受 selumetinib 联合 4 种药物（达卡巴嗪、多西他赛、替西罗莫司或厄洛替尼）治疗的黑色素瘤患者的一项 1 期试验中，回顾性地确定了组织标本中 BRAF 和 NRAS 突变状态。评估了 BRAF 和 NRAS 突变状态与临床反应率和疾病进展时间（TTP）的关系。
在分析的 18 例患者中，9 例（50%）存在 BRAF 突变（8 例为 600 位缬氨酸到谷氨酸取代[V600E]；1 例为 603 位精氨酸无义突变[R603]），4 例（22%）存在 NRAS 突变（2 例为 61 位谷氨酰胺到精氨酸取代[Q61R]，1 例为 61 位谷氨酰胺到赖氨酸取代[Q61K]，1 例为 12 位甘氨酸到赖氨酸取代[G12S]），5 例（28%）患者两种基因均为野生型。这些突变是相互排斥的。在 9 例存在 BRAF 突变的患者中，5 例（56%）获得部分缓解，4 例（44%）至少 6 周疾病稳定。没有野生型 BRAF 基因的患者获得临床反应（P =.01 与 BRAF 突变患者相比）。NRAS 突变的存在与临床反应率无关。在多变量模型中，BRAF 突变的存在与 TTP 显著相关（风险比，0.22；P =.02 与野生型 BRAF 相比）。
与野生型 BRAF 的患者相比，在存在 BRAF 突变的肿瘤患者中，含有 selumetinib 的方案观察到更高的反应率和更长的 TTP。
