Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department I of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
GenePlus-Beijing, Beijing, China.
Clin Cancer Res. 2020 Feb 15;26(4):892-901. doi: 10.1158/1078-0432.CCR-19-0556. Epub 2019 Nov 6.
The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value.
Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced stage incurable disease who received first-line chemotherapy.
The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 patients with LCNEC were classified into small-cell lung cancer (SCLC)-like and non-small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared with pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared with etoposide-platinum or pemetrexed-platinum in patients with NSCLC-like LCNEC.
Genomic subtyping has potential in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.
肺大细胞神经内分泌癌（LCNEC）的最佳全身治疗仍存在争议。既往研究表明，具有不同基因组特征的 LCNEC 可能对不同的化疗方案有不同的反应。本研究旨在通过分析晚期 LCNEC 患者的游离 DNA（cfDNA）来进行基因组亚型分析，并评估其潜在的预后和预测价值。
对 63 例 LCNEC 患者的肿瘤 DNA 和 cfDNA 进行靶向捕获测序分析。对 54 例接受一线化疗的不可治愈晚期疾病患者进行生存和反应分析。
cfDNA 中 LCNEC 中频繁突变的癌症基因的突变图谱与肿瘤 DNA 非常相似，这导致基因组亚型的一致性达到 90%。根据来自肿瘤 DNA 和/或 cfDNA 的相应基因组特征，将 63 例 LCNEC 患者分为小细胞肺癌（SCLC）样和非小细胞肺癌（NSCLC）样 LCNEC。总体而言，SCLC 样 LCNEC 患者的总生存期短于 NSCLC 样 LCNEC 患者，尽管化疗的反应率（RR）较高。此外，与培美曲塞联合铂类药物和吉西他滨/紫杉醇联合铂类药物相比，依托泊苷联合铂类药物治疗 SCLC 样 LCNEC 可获得更好的反应和生存，而吉西他滨/紫杉醇联合铂类药物治疗 NSCLC 样 LCNEC 患者的生存时间短于依托泊苷联合铂类药物或培美曲塞联合铂类药物。
基因组亚型分析对 LCNEC 患者的预后和治疗决策具有潜在价值，cfDNA 分析可能是 LCNEC 基因组分析的可靠替代方法。
