Cancer Center of People's Liberation Army of China, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
J Exp Clin Cancer Res. 2011 Dec 6;30(1):111. doi: 10.1186/1756-9966-30-111.
Epidermal growth factor receptor (EGFR) mutation is strongly associated with the therapeutic effect of tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable. Body fluid was considered to be a feasible substitute for the analysis, but arising problems in clinical practice such as relatively lower mutation rate and poor clinical correlation are not yet fully resolved.
In this study, 50 patients (32 pleural fluids and 18 plasmas) with TKIs therapy experience and with direct sequencing results were selected from 220 patients for further analysis. The EGFR mutation status was re-evaluated by Amplification Refractory Mutation System (ARMS), and the clinical outcomes of TKIs were analyzed retrospectively.
As compared with direct sequencing, 16 positive and 23 negative patients were confirmed by ARMS, and the other 11 former negative patients (6 pleural fluids and 5 plasmas) were redefined as positive, with a fairly well clinical outcome (7 PR, 3 SD, and 1 PD). The objective response rate (ORR) of positive patients was significant, 81.3% (direct sequencing) and 72.7% (ARMS) for pleural fluids, and 80% (ARMS) for plasma. Notably, even reclassified by ARMS, the ORR for negative patients was still relatively high, 60% for pleural fluids and 46.2% for plasma.
When using body fluids for EGFR mutation analysis, positive result is consistently a good indicator for TKIs therapy, and the predictive effect was no less than that of tumor tissue, no matter what method was employed. However, even reclassified by ARMS, the correlation between negative results and clinical outcome of TKIs was still unsatisfied. The results indicated that false negative mutation still existed, which may be settled by using method with sensitivity to single DNA molecule or by optimizing the extraction procedure with RNA or CTC to ensure adequate amount of tumor-derived nucleic acid for the test.
表皮生长因子受体（EGFR）突变与非小细胞肺癌（NSCLC）患者酪氨酸激酶抑制剂（TKI）的治疗效果密切相关。然而，用于突变分析的肿瘤组织通常不可用。体液被认为是分析的一种可行替代品，但在临床实践中仍存在一些问题，例如相对较低的突变率和较差的临床相关性等问题尚未得到完全解决。
本研究从 220 例患者中选择了 50 例（32 例胸腔积液和 18 例血浆）有 TKI 治疗经验且有直接测序结果的患者进行进一步分析。采用扩增受阻突变系统（ARMS）重新评估 EGFR 突变状态，并回顾性分析 TKI 的临床疗效。
与直接测序相比，ARMS 确认了 16 例阳性和 23 例阴性患者，前 11 例阴性患者（6 例胸腔积液和 5 例血浆）重新定义为阳性，且临床疗效较好（7 例 PR、3 例 SD 和 1 例 PD）。阳性患者的客观缓解率（ORR）较高，胸腔积液直接测序和 ARMS 分别为 81.3%和 72.7%，血浆为 80%。值得注意的是，即使经 ARMS 重新分类，阴性患者的 ORR 仍然相对较高，胸腔积液为 60%，血浆为 46.2%。
当使用体液进行 EGFR 突变分析时，阳性结果始终是 TKI 治疗的良好指标，且预测效果不亚于肿瘤组织，无论采用何种方法。然而，即使经 ARMS 重新分类，阴性结果与 TKI 临床疗效之间的相关性仍不理想。结果表明，仍存在假阴性突变，可通过使用对单 DNA 分子敏感的方法或优化提取过程来解决，以确保有足够量的肿瘤衍生核酸进行检测。
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