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. 2020 Feb 15;26(4):892-901.
doi: 10.1158/1078-0432.CCR-19-0556. Epub 2019 Nov 6.

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

Minglei Zhuo #  1 , Yanfang Guan #  2   3   4 , Xue Yang #  1 , Lingzhi Hong  5 , Yuqi Wang  2   3   4 , Zhongwu Li  6 , Runzhe Chen  5   7 , Hussein A Abbas  8 , Lianpeng Chang  2   3 , Yuhua Gong  2   3   4 , Nan Wu  9 , Jia Zhong  1 , Wenting Chen  2 , Hanxiao Chen  1 , Zhi Dong  1 , Xiang Zhu  10 , Jianjie Li  1 , Yuyan Wang  1 , Tongtong An  1 , Meina Wu  1 , Ziping Wang  1 , Jiayin Wang  4 , Emily B Roarty  5 , Waree Rinsurongkawong  11 , Jeff Lewis  11 , Jack A Roth  12 , Stephen G Swisher  12 , J Jack Lee  11 , John V Heymach  5 , Ignacio I Wistuba  13 , Neda Kalhor  14 , Ling Yang  2   3 , Xin Yi  2   3   4 , P Andrew Futreal  7 , Bonnie S Glisson  15 , Xuefeng Xia  16 , Jianjun Zhang  15   7 , Jun Zhao  17
Affiliations

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

Minglei Zhuo et al. Clin Cancer Res. .

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.

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Conflict of interest statement

Conflicts of interest:

Y.F.G., Y.Q.W., L.P.C., Y.H.G., L.Y., and X.Y are current employees of Geneplus-Beijing. J.V.H. is a consultant for AstraZeneca, Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Medivation, ARIAD, Synta, Oncomed, Novartis, Genentech, and Calithera Biosciences, holds stock in Cardinal Spine LLC and Bio-Tree, and has received funding from AstraZeneca. I.I.W. receives honoraria from Roche/Genentech, Ventana, GlaxoSmithKline, Celgene, Bristol-Myers Squibb, Synta Pharmaceuticals, Boehringer Ingelheim, Medscape, Clovis, AstraZeneca, and Pfizer, and research support from Roche/Genentech, Oncoplex, and HGT. J.Z. serves as a consultant for AstraZeneca and Geneplus-Beijing and received honoraria and funding from Bristol-Myers Squibb, Merck, Roche, OrigiMed, Innovent, Bristol-Myers Squibb, Merck & Co. and Adaptive Biotechnologies Inc. outside the submitted work. The other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Cancer gene mutation landscape of LCNEC tumors from BJ-Cohort derived from NGS of tumor DNA(n=28) (A) and cfDNA(n=39) (B).
Patients were arranged along the x-axis. Mutation burden (number of mutations) is shown in the upper panel. Genes with somatic mutations detected in more than one patient were shown. Mutation frequencies of each gene were shown on the left.
Figure 2.
Figure 2.. Cancer gene mutations detected in paired tumor DNA and cfDNA from 20 patients.
Genes with somatic mutations are listed on the x-axis, and samples are shown on the y-axis. Mutations detected in tumor tissue DNA only, in cfDNA only or shared were shown in blue, red and orange, respectively.
Figure 3.
Figure 3.. Genomic subtyping was associated with response to different chemotherapy regimens.
DCR: disease control (complete response + partial response + stable disease) rate. RR: response (complete response + partial response) rate. Criterion 1: LCNEC tumors with RB1+TP53 co-alterations were classified as SCLC-like LCNEC (n=15), otherwise as NSCLC-like (n=) (39). Criterion 2: LCNEC tumors harboring any of the following alterations: RB1 mutation or loss, PTEN loss/mutation, FGFR1/FGFR4 mutation/amplification, TP53 loss were classified as SCLC-like LCNEC (n=27), otherwise as NSCLC-like (n=27). SCLC-PE: etoposide-platinum doublets. NSCLC-GEM/TAX: gemcitabine or taxane-platinum doublets. NSCLC-PEM: pemetrexed-platinum doublets. Note: Only 2 SCLC-like LCNEC patients based on criterion 1 were treated with NSCLC-GEX/TAX, who were not included in the statistical analysis.
Figure 4.
Figure 4.. Genomic subtyping was associated with survival of LCNEC patients treated with different chemotherapy regimens.
A-D: the genomic subtyping was based on the presence (SCLC-like) or absence (NSCLC-Like) of co-alterations in TP53 and RB1 (Criterion 1). E-H: the genomic subtyping was based on the presence (SCLC-like) or absence (NSCLC-Like) of any of the following alterations: RB1 mutation or loss, PTEN loss/mutation, FGFR1/FGFR4 mutation/amplification, TP53 loss (Criterion 2). SCLC-PE: etoposide-platinum doublets. NSCLC-GEM/TAX: gemcitabine or taxane-platinum doublets. NSCLC-PEM: pemetrexed-platinum doublets. 54 patients with first line chemotherapy were included in survival analysis.
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