Linardou Helena, Dahabreh Issa J, Kanaloupiti Dimitra, Siannis Fotios, Bafaloukos Dimitrios, Kosmidis Paris, Papadimitriou Christos A, Murray Samuel
1st Department of Medical Oncology, Metropolitan Hospital, Athens, Greece.
Lancet Oncol. 2008 Oct;9(10):962-72. doi: 10.1016/S1470-2045(08)70206-7. Epub 2008 Sep 17.
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.
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.
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 0.16-0.28], 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).
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.
k-RAS癌基因的体细胞突变已被评估为非小细胞肺癌（NSCLC）患者对表皮生长因子受体（EGFR）酪氨酸激酶抑制产生原发性耐药的机制，以及转移性结直肠癌（mCRC）患者对抗EGFR单克隆抗体产生耐药的机制。本系统评价和荟萃分析的目的是评估k-RAS突变是否是mCRC和NSCLC中抗EGFR靶向治疗策略的候选预测生物标志物。
我们系统地检索了有关接受酪氨酸激酶抑制剂（TKI）治疗的NSCLC患者以及接受任何基于抗EGFR方案治疗的mCRC患者的k-RAS突变状态的文章。符合条件的研究必须报告按k-RAS突变状态分层的完全缓解（CR）和部分缓解（PR）情况。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来处理潜在的研究间异质性。将k-RAS突变预测无反应的阳性和阴性似然比（分别为+LR和-LR）视为次要终点，并通过合并敏感性和特异性估计值来计算。
在检索到的252篇手稿中，17篇被认为符合NSCLC荟萃分析的条件（1008例k-RAS突变患者中的165例）。k-RAS突变的存在与对TKI无反应显著相关（敏感性=0.21 [95%CI 0.16 - 0.28]，特异性=0.94 [0.89 - 0.97]；+LR = 3.52；-LR = 0.84）。在检索到的68篇关于基于抗EGFR单克隆抗体治疗mCRC的手稿中，8项研究被认为符合最终分析的条件（817例k-RAS突变患者中的306例）。k-RAS突变的存在与对抗EGFR单克隆抗体治疗无反应显著相关（敏感性=0.47 [0.43 - 0.52]；特异性=0.93 [0.83 - 0.97]；+LR = 6.82；-LR = 0.57）。
该分析提供了实证证据，表明k-RAS突变是晚期NSCLC中对单药EGFR TKI反应（原发性耐药）的高度特异性阴性预测指标；在mCRC患者中，对单独或与化疗联合使用的抗EGFR单克隆抗体同样如此。k-RAS突变用于确定无反应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。
