Department of Medical Oncology, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
Lung Cancer. 2021 May;155:20-27. doi: 10.1016/j.lungcan.2021.03.006. Epub 2021 Mar 9.
Transformation to small cell lung cancer (SCLC) is a resistance mechanism to tyrosine kinase inhibitor (TKI) treatment that develops in lung adenocarcinoma. The genomic and treatment outcomes in these populations have not been comprehensively reported in China.
We performed a retrospective study analyzing patients with advanced non-SCLC (NSCLC) from eight sites who were diagnosed with SCLC transformation after receiving epidermal growth factor receptor (EGFR)-TKI treatment including first/second- or third-generation EGFR-TKIs. We assessed the genomic features and clinical prognosis in these patients with EGFR-mutated lung cancer.
Thirty-two eligible patients with EGFR mutations were identified, 25 of whom had sufficient tumor tissues for detection of genes by next-generation sequencing. The median progression free survival (mPFS) for first/second-generation TKIs was 14.0 months. The most common mutations identified in samples with transformation to SCLC were in TP53 (17/25, 68.0 %), RB1 (9/25, 36.0 %), and PIK3CA (3/25, 12.0 %), and the incidence rates of RB1 and TP53 mutations were similar between patients receiving first/second-generation and third-generation TKI treatment. The estimated median time to SCLC transformation was 17.0 months. After SCLC transformation, platinum-etoposide was the most common treatment regimen, and the mPFS after platinum-etoposide treatment was 3.5 months. Anlotinib showed good efficacy in these patients (overall response rate, 66.7 %; mPFS, 6.2 months). The median overall survival after the initial diagnosis of metastatic lung cancer was 34.5 months, and patients with small cell transformation after third-generation TKI treatment had better prognosis than patients with transformation after first/second-generation treatment (49.4 months vs. 20.0 months, P = 0.013).
We observed that TP53 and RB1 mutations were common in Chinese patients with SCLC transformation, regardless of whether first/second-generation or third-generation EGFR-TKI treatments were used. Earlier occurrence of small cell transformation after EGFR-TKI treatment was associated with poorer prognosis of patients. After the standard chemotherapy regimens for the management of primary SCLC, anlotinib may be a therapeutic option.
小细胞肺癌（SCLC）的转化是肺腺癌对酪氨酸激酶抑制剂（TKI）治疗产生耐药的机制之一。在中国，尚未全面报道此类人群的基因组特征和治疗结果。
我们进行了一项回顾性研究，分析了来自 8 个研究中心的接受表皮生长因子受体（EGFR）-TKI 治疗后发生 SCLC 转化的晚期非小细胞肺癌（NSCLC）患者，这些患者接受的 EGFR-TKI 治疗包括第一代/第二代或第三代 EGFR-TKI。我们评估了这些 EGFR 突变型肺癌患者的基因组特征和临床预后。
共纳入 32 例 EGFR 突变患者，其中 25 例有足够的肿瘤组织进行下一代测序检测基因。第一代/第二代 TKI 治疗的中位无进展生存期（mPFS）为 14.0 个月。在发生 SCLC 转化的样本中最常见的突变是 TP53（17/25，68.0%）、RB1（9/25，36.0%）和 PIK3CA（3/25，12.0%），接受第一代/第二代和第三代 TKI 治疗的患者中 RB1 和 TP53 突变的发生率相似。SCLC 转化的估计中位时间为 17.0 个月。SCLC 转化后，铂类联合依托泊苷是最常见的治疗方案，铂类联合依托泊苷治疗的 mPFS 为 3.5 个月。安罗替尼在这些患者中显示出良好的疗效（总缓解率，66.7%；mPFS，6.2 个月）。转移性肺癌初始诊断后的中位总生存期为 34.5 个月，第三代 TKI 治疗后发生小细胞转化的患者预后优于第一代/第二代治疗后发生转化的患者（49.4 个月比 20.0 个月，P=0.013）。
我们观察到，无论使用第一代/第二代还是第三代 EGFR-TKI 治疗，TP53 和 RB1 突变在中国 SCLC 转化患者中均较为常见。EGFR-TKI 治疗后小细胞转化发生得越早，患者的预后越差。在原发性 SCLC 的标准化疗方案管理之后，安罗替尼可能是一种治疗选择。
