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标题及作者 Lung adenocarcinoma patient with an EGFR kinase domain duplication (KDD) and the response to icotinib You-Cai Zhu 1 , Wen-Xian Wang 2 , Chun-Wei Xu 3 , Qing-He Tan 4 , Jian-Ying Li 4 , Wu Zhuang 5 , Zheng-Bo Song 2 , Kai-Qi Du 1 , Gang Chen 3 , Tang-Feng Lv 6 , Yong Song 6 1 Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing 314000, China; 2 Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou 310022, China; 3 Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, China; 4 Department of Oncology, Nantong Tumor Hospital, Nantong 226361, China; 5 Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, China; 6 Department of Respiratory Medicine, Jinling Hospital, Nanjing 210002, China Correspondence to: Chun-Wei Xu, MD, PhD. Department of Pathology, Fujian Cancer Hospital, Fujian Medical University, No. 420, Fuma Road, Fuzhou 350014, China. Email: xuchunweibbb@163.com; Wen-Xian Wang, MD, PhD. Department of Chemotherapy, Zhejiang Cancer Hospital, No.1 Banshan East street, Gongshu District, Hangzhou 310022, China. Email: helen-0407@163.com. Journal of Thoracic Disease. All rights reserved. 患者基本情况 63岁女性肺腺癌患者，不抽烟，左肺肿瘤伴有远处转移，经ARMS检测EGFR状态为野生，再次NGS检测后发生了EGFR-KDD基因，经过盐酸埃克替尼片（凯美纳）125mg tid治疗后目前PFS已经到达11月（截止发稿时未进展）。 A 63-year-old Chinese female, who was a non-smoker,presented to our hospital for evaluation of a left lung mass on physical examination. A computed tomography (CT) scan showed a mass in the superior lobe of the left lung, and close to a pleural nodule (Figure 1). For staging purposes,surgery was performed. Hematoxylin and eosin staining of the surgical specimen showed a typical morphology for adenocarcinoma cells and surgical specimens from the left lobe tumor and pleural nodes (2.3 cm × 1.3 cm× 1.0 cm) showed lung adenocarcinoma (Figure 2). The immunohistochemical results [TTF-1 (+), NapsinA (+),CK7 (+)] According to the 7 th edition of TNM staging, the patient was classified as stage IV (T1N0M1). The patient was wild-type for sensitive EGFR variants, including EGFR 18–21, by ARMS(AmoyDx, Xiamen, China) detection.Using an NGS assay (Illumina, San Diego, CA, USA), we found that the tumor had EGFR-KDD (3D Medicines,Shanghai, China) (Figure 3), and the most common types of EGFR mutations were wild. The patient received icotinib (125 mg/tid) treatment and showed a stable tumor response according to the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1). During treatment with icotinib, there were no treatment-related adverse events, including hepatic and renal function, gastrointestinal reactions, rashes, and cordis damage. To date, the disease is stable after 11 months and she is continuing treatment with icotinib. Our case is the first report of an EGFR-KDD mutation in the Asian population. Considering this rare EGFR mutation and response to TKI treatment, we conclude that the incidence of rare EGFR gene mutations in NSCLC patients should be studied. Figure 1 Computed tomography (CT) scans show: (A) lung window before surgery and (B) mediastinal window before surgery. Figure 2 The gross morphology and microscopic morphology of lung tumor. (A) Surgery of left lung tumor; (B) hematoxylin and eosin(H&E) staining showed a typical morphology for adenocarcinoma cells (H&E, ×100) 讨 论 EGFR exons 18–25 KDDs were first described in a glioblastoma (11), and now are known to be a driver gene in lung cancer. In 2015, EGFR-KDD was first reported in a patient with lung adenocarcinoma (12). A female patient with metastatic adenocarcinoma, but without a known activating EGFR mutation based on initial polymerase chain reaction testing, underwent a repeat biopsy which was evaluated with a NGS platform. She was shown to have an EGFR-KDD mutation and demonstrated remarkable disease control with erlotinib therapy. In addition, Gallant et al. (9) reported a male patient with lung adenocarcinoma and an EGFR-KDD mutation detected with NGS. The patient had a partial response to afatinib therapy. These findings were studied in vitro and EGFR-KDD expression had significantly increased colony formation compared to the EGFR wild type and oncogenic EGFR-L858R mutation.Therefore, EGFR-KDD is an oncogenic alteration. Gallant et al. (9) also analyzed whether or not EGFR-TKIs is an effective therapeutic strategy for tumors harboring the EGFR-KDD mutation. Third-generation EGFR-TKIs (erlotinib, afatinib, and AZD9291) are able to inhibit EGFR-KDD tyrosine phosphorylation in a dose-dependent manner, albeit to different levels, and afatinib is the most potent inhibitor of EGFR-KDD autophosphorylation to decrease cell viability. The current report describes the first Asian patient with an EGFR-KDD mutation who derived a sustained anti-tumor response from treatment with the EGFR-TKI, icotinib. We have summarized the lung cancer patients who have been reported to have EGFR-KDD mutations in Table 1. Therefore, for this type mutation in NSCLC patients, EGFR inhibitors may be a first-line therapy, as in sensitive EGFR mutation patients.（部分，未完........） 既往国际上关于EGFRKDD突变患者的报道： |
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