Department of Pathology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
Department of Radiology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
Pathol Res Pract. 2019 May;215(5):946-951. doi: 10.1016/j.prp.2019.01.045. Epub 2019 Jan 30.
Recently, a low frequency of de novo T790M mutations existing in tumor tissues before TKIs therapy has been reported. However, the origin of T790M and its impact on clinical outcomes is still being debated. This study aimed to use highly sensitive methods to detect T790M before and after TKIs therapy and investigated the correlation of T790M with clinical prognosis.
Matched tumor samples before and after treatment were collected from 61 lung adenocarcinoma (LAC) patients in Beijing Chest Hospital between June 2014 to October 2017. Presence of the T790M mutation was simultaneously detected using amplification refractory mutation system-PCR (ARMS-PCR) assay and droplet digital PCR (ddPCR) assay.
Of the 61 enrolled patients, 46 were candidates for and received TKIs treatment based on their EGFR mutation status. When these samples were assayed, ddPCR identified significantly more T790M mutations than ARMS-PCR (before TKIs treatment: 19.6% (9/46) vs. 2.2% (1/46), P = 0.040; after TKIs treatment: 78.3% (36/46) vs. 50% (23/46), P < 0.001, respectively). Patients with first-line TKIs treatment harboring de novo T790M mutations showed a shorter PFS compared to those without de novo T790M mutations (median, 7.0 months vs. 11.7 months, p = 0.013). In multivariate analyses, de novo T790M mutation was an independent predictor of PFS in EGFR-mutant patients who received TKIs treatment (p = 0.031, HR 0.310, 95% CI: 0.107-0.900).
The ddPCR assay is an ultra-sensitive method to detect a minor amount of de novo T790M mutations in tumor samples. The de novo T790M mutation is a relatively unfavorable prognosis factor for patients receiving first-line TKIs treatment.
最近有报道称，在接受 TKI 治疗前，肿瘤组织中 T790M 突变的低频存在。然而，T790M 的起源及其对临床结果的影响仍存在争议。本研究旨在使用高灵敏度的方法检测 TKI 治疗前后的 T790M，并探讨 T790M 与临床预后的相关性。
收集 2014 年 6 月至 2017 年 10 月期间在北京胸科医院接受治疗的 61 例肺腺癌（LAC）患者治疗前后配对的肿瘤样本。使用扩增受阻突变系统-PCR（ARMS-PCR）和液滴数字 PCR（ddPCR）同时检测 T790M 突变的存在。
在纳入的 61 例患者中，根据 EGFR 突变状态，46 例患者为 TKI 治疗候选者，并接受了 TKI 治疗。在对这些样本进行检测时，ddPCR 检测到的 T790M 突变明显多于 ARMS-PCR（治疗前：19.6%（46/235）比 2.2%（1/46），P=0.040；治疗后：78.3%（36/46）比 50%（23/46），P<0.001）。一线 TKI 治疗中存在新出现的 T790M 突变的患者无进展生存期（PFS）明显短于不存在新出现的 T790M 突变的患者（中位 PFS：7.0 个月比 11.7 个月，P=0.013）。在多变量分析中，新出现的 T790M 突变是接受 TKI 治疗的 EGFR 突变患者 PFS 的独立预测因子（P=0.031，HR 0.310，95%CI：0.107-0.900）。
ddPCR 检测方法是一种检测肿瘤样本中少量新出现的 T790M 突变的超敏感方法。新出现的 T790M 突变是接受一线 TKI 治疗的患者预后不良的相对危险因素。
