ASCO 2013：香港中文大学莫树锦等证实pEGFR mut能有效预测非小细胞肺癌患者的预后

在FASTACT 2中，研究者对肿瘤生物标记物的分析证实了在晚期非小细胞肺癌患者中，EGFR突变有助于预测厄洛替尼联合化疗作为一线治疗对上述患者所带来的治疗获益。然而，在该研究中的肿瘤标本有限。最近技术的发展能够促使从不含细胞的血浆DNA中检测到EGFR突变状态（pEGFRmut）。在本研究中，研究者们旨在评估pEGFRmut和来自肿瘤组织的EGFR mut之间是否存在一定关联，同时也评估pEGFR mut作为晚期非小细胞肺癌患者无进展生存期和总体生存期预测指标的价值。

研究者采用两套等位基因特异的PCR序列、cobas EGFR_FFPET检测和cobas EGFR血测试来回顾性的进行EGFR mut测试。其目的都是确定EGFR突变（外显子19缺失、L858R和G719X）。FFPET的一部分被用于组织测试，而2ml的血浆样本被用于血液测试。

在研究纳入的451名患者中，研究者共得到了268个肿瘤样本，其中241个样本（90%）可被用于进一步分析。在241个可供分析的样本中，有96个（40%）存在至少一个激活的EGFR突变。在451名中有427份血浆样本可用于分析。其中136份（32%）存在激活的EGFR突变。经过两项测试，有224个样本呈现一致性表现，详见下表。如果将组织检测法作为标准的话，那么血浆测试的敏感性为76%（68/89）而其特异性为96%（130/135）。而对激活的EGFR突变的阳性预测值和阴性预测值分别为93% （68/73）和86% （130/151）。

在pEGFR mut的患者中，与仅接受化疗的患者相比，同时接受厄洛替尼和化疗的患者的中位无进展生存期显著延长，前者为6.1月而后者为13.8月，两组差异具有显著统计学意义。而对于pEGFR野生型的患者而言，上述两个治疗组的无进展生存期则分别为6.0月和6.7月，差异不具有显著统计学意义。在pEGFRmut的患者中，与仅接受化疗的患者相比，同时接受厄洛替尼和化疗的患者的中位总体生存期显著延长，前者为19.0月而后者为32.4月，两组差异具有显著统计学意义。而对于pEGFR野生型的患者而言，上述两个治疗组的无进展生存期则分别为13.3月和16.1月，差异不具有显著统计学意义。

本研究结果指出，cobas EGFR血检测能可靠的确定血浆中EGFR突变状态。在FASTACT 2中，pEGFR mut能有效预测与生存期相关的预后情况。临床研究信息：CTONG0902。

Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C).
Abstract
Background: Biomarker analysis of tumor from FASTACT 2 confirmed predictive power of EGFR mut on the benefit of intercalated combination of E and C as 1st line in advanced NSCLC (T. Mok, ESMO 2012). However, only limited tumor were available. Recent development allowed us to detect EGFR mut in cell-free DNA from plasma (pEGFRmut). In this study, we studied the concordance between pEGFRmut and EGFR mut in tumor (tEGFRmut), and the role of pEGFRmut as predictor of PFS and OS. Methods: Retrospective EGFR mut testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific PCR assays, cobas EGFR_FFPET test and cobas EGFR_blood test (in development). Both tests are designed to detect EGFR activating mut (exon 19 deletions, L858R, G719X). One FFPET section was used for tissue test and 2-ml plasma was used for blood test. Results: Among 268 tumors from 451 enrolled pts, 90% (241/268) were analyzable. 40% (96/241) harbored at least one activating EGFR mut. All 427 plasmas from 451 enrolled pts were analyzable. 32% (136/427) were positive for EGFR activating mut. The concordance of two tests from 224 matched tissue and plasma samples was summarized below. Using tissue as comparator, the sensitivity of plasma test was 76% (68/89) and the specificity of plasma test was 96% (130/135) respectively. Positive and negative predictive values for EGFR activating mut were 93% (68/73) and 86% (130/151) respectively. Median PFS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 13.8 vs. 6.1 m (HR=0.21 p<0.0001), and for pEGFR wild-type, 6.7 vs. 6.0 m (HR=0.80, p=0.06). Median OS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 32.4 vs. 19.0 m (HR=0.51, p=0.0035), and for pEGFR wild-type, 16.1 vs 13.3 m (HR=0.89, p=0.39). Conclusions: cobas EGFR_blood test can be used to reliably detect EGFR mutations in plasma. pEGFRmut is a potent predictor of survival outcomes in FASTACT 2. Clinical trial information: CTONG0902.