Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents:: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer
Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents:: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer
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DOI：
10.1016/s1470-2045(08)70206-7
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发表时间：
2008-10-01
期刊：
影响因子：
51.1
通讯作者：
Murray, Samuel
中科院分区：
文献类型：
--
作者：
Linardou, Helena;Dahabreh, Issa J.;Murray, Samuel
研究已经评估了k-RAS癌基因体细胞突变作为非小细胞肺癌（NSCLC）患者对表皮生长因子受体（EGFR）酪氨酸激酶抑制和转移性结直肠癌（mCRC）患者对抗EGFR单克隆抗体重新耐药的机制。本系统综述和荟萃分析的目的是评估k-RAS突变是否代表mCRC和NSCLC抗egfr靶向治疗策略的候选预测性生物标志物。方法我们系统地鉴定了在接受酪氨酸激酶抑制剂（TKI）治疗的非小细胞肺癌患者和接受任何基于抗egfr的方案治疗的mCRC患者中k-RAS突变状态的相关文章。符合条件的研究必须报告完全缓解（CR）和部分缓解（PR），并根据k-RAS突变状态分层。通过使用随机效应模型对敏感性和特异性（主要终点）进行双变量荟萃分析，排除了研究间潜在的异质性。预测无反应的k-RAS突变的阳性和阴性似然比（分别为+LR和-LR）被视为次要终点，并通过使用敏感性和特异性的汇总估计来计算。在252篇检索到的论文中，17篇被认为符合NSCLC荟萃分析（1008例k-RAS突变患者中有165例）。k-RAS突变的存在与TKIs无应答显著相关（敏感性=0.21 [95% CI 0.16-0.281，特异性=0.94 [0.89-0.97];+LR=3.52; -LR=0.84）。在68篇报道基于抗egfr单克隆抗体治疗mCRC的文献中，8项研究（817例k-RAS突变患者中的306例）被认为符合最终分析的条件。k-RAS突变的存在与抗egfr单克隆抗体治疗无应答显著相关（敏感性=0.47[0.43-0.52]；特异性=0.93 [0.83-0.97];+LR=6.82; -LR=0.57）。该分析提供了经验证据，证明k-RAS突变是晚期NSCLC患者对单药EGFR TKIs反应（重新耐药）的高度特异性阴性预测因子；并且类似于抗egfr单克隆抗体在mCRC患者中单独使用或联合化疗。k-RAS突变在确定无反应性方面的低敏感性和相对较高的-LR清楚地表明存在对EGFR抑制剂的其他耐药机制。
Background Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC.Methods We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and -LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity.Findings Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0.21 [95% CI 0.16-0.281, specificity=0.94 [0.89-0.97]; +LR=3.52; -LR=0.84). of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57).Interpretation This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high -LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.