Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Lung Cancer. 2018 Apr;118:1-5. doi: 10.1016/j.lungcan.2018.01.015. Epub 2018 Jan 31.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are promising targeted therapies for EGFR-mutated non-small-cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops. Comprehensive and dynamic companion genomic diagnosis can gain insights into underlying resistance mechanisms, thereby help oncologists and patients to make informed decision on the potential benefit of the treatment.
A 67-year-old male who was initially diagnosed of EGFR L858R-mediated NSCLC received multiple lines of chemotherapy and EGFR TKI therapies after surgery. The EGFR mutational status of individual metastatic lesion was determined by genetic testing of the tumor tissue biopsies using next generation sequencing (NGS) throughout the patient's clinical course. An acquired potentially drug-resistant EGFR mutation was functionally validated in vitro and its sensitivity to different EGFR TKIs was assessed simultaneously.
We have identified distinct resistance mechanisms to EGFR blockade in different metastatic lung lesions. Acquired EGFR T790M was first detected that leads to the resistance to the gefitinib treatment. Consequently, osimertinib was administrated and the response lasted until disease progressed. We identified a newly acquired EGFR L718V mutation in one lesion in conjunction with L858R, but not T790M, which showed stable disease on the following erlotinib treatment, while EGFR C797S together with L858R/T790M was detected in the other lesion that continuously progressed. In vitro functional studies demonstrated that EGFR-L858R/L718V confers resistance to osimertinib, but retains sensitivity to the second generation TKI afatinib.
We reported that distinct resistance mechanisms could arise in different metastases within the same patient in response to EGFR blockade. We also demonstrated in vitro that EGFR L718V mutation mediates resistance to osimertinib, but retains sensitivity to afatinib. We evidenced that dynamic companion genomic diagnosis offers valuable information to help define the mechanisms of drug resistance and to guide the selection of subsequent treatment.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）是 EGFR 突变型非小细胞肺癌（NSCLC）患者有前途的靶向治疗药物。然而，获得性耐药性不可避免地会发生。全面和动态的伴随基因组诊断可以深入了解潜在的耐药机制，从而帮助肿瘤学家和患者就治疗的潜在获益做出明智的决策。
一名 67 岁男性最初被诊断为 EGFR L858R 介导的 NSCLC，在手术后接受了多线化疗和 EGFR TKI 治疗。通过对肿瘤组织活检进行下一代测序（NGS）的基因检测，在整个患者的临床过程中确定了各个转移性病变的 EGFR 突变状态。在体外功能验证了获得性潜在耐药性 EGFR 突变，并同时评估了其对不同 EGFR TKI 的敏感性。
我们已经在不同的转移性肺病变中确定了对 EGFR 阻断的不同耐药机制。首先检测到获得性 EGFR T790M，导致对吉非替尼治疗的耐药性。因此，给予奥希替尼治疗，直到疾病进展为止。我们在一个病变中发现了新获得的 EGFR L718V 突变，与 L858R 一起，但不与 T790M 一起，这表明在随后的厄洛替尼治疗中疾病稳定，而在另一个病变中检测到 EGFR C797S 与 L858R/T790M 一起，疾病持续进展。体外功能研究表明，EGFR-L858R/L718V 对奥希替尼耐药，但保留对第二代 TKI 阿法替尼的敏感性。
我们报告说，同一患者的不同转移部位对 EGFR 阻断可能会产生不同的耐药机制。我们还在体外证明，EGFR L718V 突变介导对奥希替尼的耐药性，但保留对阿法替尼的敏感性。我们证明，动态伴随基因组诊断提供了有价值的信息，有助于确定耐药机制，并指导后续治疗的选择。
