Impact of EGFR Mutation Detection Methods on the Efficacy of Erlotinib in Patients with Advanced EGFR-Wild Type Lung Adenocarcinoma

IntroductionMethods used for epidermal growth factor receptor (EGFR) mutation testing vary widely. The impact of detection methods on the rates of response to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-wild type (wt) lung adenocarcinoma patients is unknown.MethodsWe recruited the Group-I patients to evaluate the efficacy of erlotinib in patients with EGFR-wt lung adenocarcinoma by either direct sequencing (DS) or mutant type-specific sensitive (MtS) methods in six medical centers in Taiwan. Cross recheck of EGFR mutations was performed in patients who achieved objective response to erlotinib and had adequate specimens. The independent Group-II lung adenocarcinoma patients whose EGFR mutation status determined by DS were recruited to evaluate the potential limitations of three MtS methods.ResultsIn Group-I analysis, 38 of 261 EGFR-wt patients (14.6%) achieved partial response to erlotinib treatment. Nineteen patients (50.0%) had adequate specimens for cross recheck of EGFR mutations and 10 of them (52.6%) had changes in EGFR mutation status, 5 in 10 by DS and 5 in 9 by MtS methods originally. In Group-II analysis, 598 of 996 lung adenocarcinoma patients (60.0%) had detectable EGFR mutations. The accuracy rates of the three MtS methods, MALDI-TOF MS, Scorpions ARMS and Cobas, were 87.8%, 86.8% and 85.8%, respectively.ConclusionsA significant portion of the erlotinib responses in EGFR-wt lung adenocarcinoma patients were related to the limitations of detection methods, not only DS but also MtS methods with similar percentages. Prospective studies are needed to define the proper strategy for EGFR mutation testing.**引言** 表皮生长因子受体（epidermal growth factor receptor, EGFR）突变检测的方法差异显著。目前尚不明确检测方法对EGFR野生型（wt）肺腺癌患者接受EGFR-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitors, TKIs）治疗的应答率的影响。 **研究方法** 本研究于中国台湾6家医学中心开展，招募第一队列患者，分别采用直接测序（direct sequencing, DS）或突变型特异性敏感检测（mutant type-specific sensitive, MtS）方法，评估厄洛替尼对EGFR野生型肺腺癌患者的疗效。对厄洛替尼治疗后获得客观应答且标本合格的患者，进行EGFR突变的复核检测。另招募经直接测序确定EGFR突变状态的独立第二队列肺腺癌患者，以评估三种MtS方法的潜在局限性。 **研究结果** 第一队列分析显示，261例EGFR野生型患者中，38例（14.6%）在厄洛替尼治疗后获得部分应答。其中19例（50.0%）标本合格可进行EGFR突变复核，10例（52.6%）的EGFR突变状态发生改变：最初经DS检测的10例中5例出现突变状态变化，最初经MtS方法检测的9例中5例出现突变状态变化。第二队列分析显示，996例肺腺癌患者中598例（60.0%）可检测到EGFR突变。三种MtS方法即基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）、蝎子ARMS（Scorpions ARMS）和Cobas的准确率分别为87.8%、86.8%和85.8%。 **研究结论** EGFR野生型肺腺癌患者中，相当比例的厄洛替尼应答与检测方法的局限性相关，不仅DS方法存在该问题，MtS方法亦是如此，且二者的影响比例相近。未来需开展前瞻性研究以确定合适的EGFR突变检测策略。