丝裂原活化蛋白激酶（MAPK）信号通路基因变异对一线FOLFIRI方案联合贝伐单抗治疗的转移性结直肠癌患者预后的影响：来自FIRE-3和TRIBE试验的数据
Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: data from FIRE-3 and TRIBE trials.
作者信息
Berger M D, Stintzing S, Heinemann V, Yang D, Cao S, Sunakawa Y, Ning Y, Matsusaka S, Okazaki S, Miyamoto Y, Suenaga M, Schirripa M, Soni S, Zhang W, Falcone A, Loupakis F, Lenz H-J
机构信息
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Department of Medical Oncology and Comprehensive Cancer Center, University of Munich (LMU), Munich, Germany.
出版信息
Ann Oncol. 2017 Nov 1;28(11):2780-2785. doi: 10.1093/annonc/mdx412.
BACKGROUND
The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev).
PATIENTS AND METHODS
A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed.
RESULTS
AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005).
CONCLUSION
MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.
背景
丝裂原活化蛋白激酶相互作用激酶1（MKNK1）定位于RAS/RAF/ERK和MAP3K1/MKK/p38信号通路的下游。通过磷酸化作用，MKNK1调节真核生物翻译起始因子4E的功能，该因子是翻译控制中的关键因子，其表达在转移性结直肠癌患者（mCRC）中常常上调。临床前数据表明，MKNK1通过上调血管生成因子来增加血管生成。因此，我们推测MKNK1基因的变异可预测一线FOLFIRI和贝伐单抗（bev）治疗的mCRC患者的预后。
患者与方法
本研究纳入了随机III期FIRE-3和TRIBE试验中567例KRAS野生型mCRC患者，这些患者接受一线FOLFIRI/bev（发现和验证队列）或FOLFIRI和西妥昔单抗（cet）（对照组）治疗。分析了MAPK信号通路中的5个单核苷酸多态性。
结果
在发现队列（FIRE-3）中，接受FOLFIRI/bev治疗的MKNK1 rs8602单核苷酸多态性的AA基因型携带者的无进展生存期（PFS）短于携带任何C的患者（7.9个月对10.3个月，风险比（HR）1.73，P = 0.038）。在多变量分析的验证队列（TRIBE）中可以确认这种关联（PFS 9.0个月对11.0个月，HR 3.04，P = 0.029）。此外，验证队列中的AA携带者总体缓解率降低（25%对66%，P = 0.049）。相反，接受FOLFIRI/cet的对照组中的AA基因型携带者未显示出较短的PFS。通过合并两个FOLFIRI/bev队列，AA携带者中较差的预后在单变量（HR 1.74，P = 0.015）和多变量分析（HR 1.76，P = 0.022）中变得更加显著（PFS 9.0个月对10.5个月）。因此，与携带任何C的患者相比，AA携带者的总体缓解率也较低（36%对65%，P = 0.005）。
结论
MKNK1多态性rs8602可能作为一线接受FOLFIRI/bev治疗的KRAS野生型mCRC患者的预测标志物。此外，MKNK1可能是药物开发的一个有前景的靶点。
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