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The Prognostic and Therapeutic Role of Genomic Subtyping by Sequencing Tumor or Cell-Free DNA in Pulmonary Large-Cell Neuroendocrine Carcinoma.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Zhuo M

PROVIDER: S-EPMC7024651 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The Prognostic and Therapeutic Role of Genomic Subtyping by Sequencing Tumor or Cell-Free DNA in Pulmonary Large-Cell Neuroendocrine Carcinoma.

Zhuo Minglei M Guan Yanfang Y Yang Xue X Hong Lingzhi L Wang Yuqi Y Li Zhongwu Z Chen Runzhe R Abbas Hussein A HA Chang Lianpeng L Gong Yuhua Y Wu Nan N Zhong Jia J Chen Wenting W Chen Hanxiao H Dong Zhi Z Zhu Xiang X Li Jianjie J Wang Yuyan Y An Tongtong T Wu Meina M Wang Ziping Z Wang Jiayin J Roarty Emily B EB Rinsurongkawong Waree W Lewis Jeff J Roth Jack A JA Swisher Stephen G SG Lee J Jack JJ Heymach John V JV Wistuba Ignacio I II Kalhor Neda N Yang Ling L Yi Xin X Futreal P Andrew PA Glisson Bonnie S BS Xia Xuefeng X Zhang Jianjun J Zhao Jun J

Clinical cancer research : an official journal of the American Association for Cancer Research 20191106 4

<h4>Purpose</h4>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.<h4>Experimental design</h4>Tumor DNA and cfDNA from 63 patients w ...[more]

PMID: 31694833

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Project description:PurposePulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.Experimental designLCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242).ResultsCommonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation.ConclusionsLCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618-29. ©2016 AACR.

Dataset Information

The Prognostic and Therapeutic Role of Genomic Subtyping by Sequencing Tumor or Cell-Free DNA in Pulmonary Large-Cell Neuroendocrine Carcinoma.

Publications

The Prognostic and Therapeutic Role of Genomic Subtyping by Sequencing Tumor or Cell-Free DNA in Pulmonary Large-Cell Neuroendocrine Carcinoma.

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