Romero Atocha, Serna-Blasco Roberto, Alfaro Cristina, Sánchez-Herrero Estela, Barquín Miguel, Turpin María Carmen, Chico Sofía, Sanz-Moreno Sandra, Rodrigez-Festa Alejandro, Laza-Briviesca Raquel, Cruz-Bermudez Alberto, Calvo Virginia, Royuela Ana, Provencio Mariano
Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Molecular Oncology Laboratory, Biomedical Sciences Research Institute Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain.
Transl Lung Cancer Res. 2020 Jun;9(3):532-540. doi: 10.21037/tlcr.2020.04.01.
Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced non-small-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome.
Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring the epidermal growth factor receptor () p.T790M resistance mutation and who were treated with osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR (dPCR) and next-generation sequencing (NGS).
The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile range (IQR): 4.6-18.0] months. The median treatment durations of sequential gefitinib + osimertinib, afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively. The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the original -sensitizing mutation after 3 months of treatment were associated with superior PFS (HR: 0.2, 95% CI: 0.05-0.7). Likewise, re-emergence of the original mutation, alone or together with the p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1-70.7 and HR: 5.9, 95% CI: 1.2-27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S-, and sensitizing+/T790M-/C797S-. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+) was 12.27 months compared with 4.87 months in patients in whom only the original sensitizing was detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found that mutations in exon 545 of the gene were the most frequent alteration detected upon disease progression in patients without acquired -resistance mutations.
Different molecular patterns identified by plasma genotyping may be of prognostic significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring.
多项临床试验已证明奥希替尼在晚期非小细胞肺癌（NSCLC）中的疗效和安全性。然而，治疗结果存在显著的无法解释的变异性。
对22例接受过治疗的IV期NSCLC患者进行观察性前瞻性队列研究，这些患者携带表皮生长因子受体（）p.T790M耐药突变并接受奥希替尼治疗。收集326份连续的血浆样本，通过数字PCR（dPCR）和下一代测序（NGS）进行分析。
自开始使用奥希替尼以来，中位无进展生存期（PFS）为8.9[四分位间距（IQR）：4.6 - 18.0]个月。序贯吉非替尼 + 奥希替尼、阿法替尼 + 奥希替尼和厄洛替尼 + 奥希替尼治疗的中位持续时间分别为30.1、24.6和21.1个月。在19份（86%）治疗前血液样本中检测到p.T790M突变。治疗3个月后未检测到原始敏感突变与较好的PFS相关（HR：0.2，95%CI：0.05 - 0.7）。同样，原始突变单独或与p.T790M突变一起再次出现与较短的PFS显著相关（HR分别为：8.8，95%CI：1.1 - 70.7和HR：5.9，95%CI：1.2 - 27.9）。基于血液的监测显示，在进展为奥希替尼治疗时出现三种分子模式：敏感+/T790M+/C797S+、敏感+/T790M+/C797S-和敏感+/T790M-/C797S-。呈现三联体模式（敏感+/T790M+/C797S+）的患者的中位进展时间为12.27个月，而仅检测到原始敏感突变的患者为4.87个月，呈现双重模式（敏感+/T790M+）的患者为2.17个月。最后，我们发现基因第545外显子的突变是在没有获得性耐药突变的患者疾病进展时检测到的最常见改变。
血浆基因分型确定的不同分子模式可能具有预后意义，表明使用液体活检是肿瘤监测的一种有价值的方法。
