晚期非小细胞肺癌患者血浆基因分型与奥希替尼（AZD9291）治疗结果的相关性
Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer.
作者信息
Oxnard Geoffrey R, Thress Kenneth S, Alden Ryan S, Lawrance Rachael, Paweletz Cloud P, Cantarini Mireille, Yang James Chih-Hsin, Barrett J Carl, Jänne Pasi A
机构信息
Geoffrey R. Oxnard, Ryan S. Alden, Cloud P. Paweletz, and Pasi A. Jänne, Dana-Farber Cancer Institute, Boston; Kenneth S. Thress and J. Carl Barrett, AstraZeneca, Waltham, MA; Rachael Lawrance and Mireille Cantarini, AstraZeneca, Macclesfield, United Kingdom; and James Chih-Hsin Yang, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
出版信息
J Clin Oncol. 2016 Oct 1;34(28):3375-82. doi: 10.1200/JCO.2016.66.7162. Epub 2016 Jun 27.
PURPOSE
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib.
METHODS
Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients.
RESULTS
Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months).
CONCLUSION
In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M.
目的
第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）已显示出对由EGFR T790M介导的TKI耐药具有强大活性。我们研究了游离血浆DNA（cfDNA）的无创基因分型是否是预测第三代EGFR-TKI奥希替尼治疗结果的有用生物标志物。
方法
在奥希替尼的首次人体研究中收集了所有患者的血浆。纳入的患者已获得EGFR-TKI耐药且有常见EGFR敏感突变的证据。使用BEAMing对游离血浆DNA进行基因分型。以中心实验室的肿瘤基因分型作为参考评估血浆基因分型的准确性。对所有T790M阳性或T790M阴性患者分析客观缓解率（ORR）和无进展生存期（PFS）。
结果
血浆基因分型检测T790M的敏感性为70%。在58例T790M阴性肿瘤患者中，18例（31%）的血浆中检测到T790M。T790M血浆阳性（ORR，63%；PFS，9.7个月）或T790M肿瘤阳性（ORR，62%；PFS，9.7个月）的患者的ORR和中位PFS相似。虽然T790M血浆阴性的患者总体预后良好（ORR，46%；中位PFS，8.2个月），但肿瘤基因分型区分出了T790M阳性且预后较好的患者亚组（ORR，69%；PFS，16.5个月）以及T790M阴性且预后较差的患者亚组（ORR，25%；PFS，2.8个月）。
结论
在这项回顾性分析中，血浆中T790M阳性的患者使用奥希替尼的治疗结果与基于组织检测为阳性的患者相当。这项研究表明，在有经过验证的血浆T790M检测方法后，一些患者可以避免进行T790M基因分型的肿瘤活检。由于血浆基因分型有30%的假阴性率，那些血浆T790M检测结果为阴性的患者仍需要进行肿瘤活检以确定是否存在T790M。
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