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      Comprehensive characterization reveals sputum supernatant as a valuable alternative liquid biopsy for genome profiling in advanced non-small cell lung cancer

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          Abstract

          Background

          Sputum biopsies offer unique advantages such as non-invasiveness and convenient collection. The one investigation so far on sputum for genome profiling in advanced non-small cell lung cancer (aNSCLC) suggested promising performance. However, it remains undefined whether clinicohistologic characteristics were associated with performance and how this knowledge could help guide choice of liquid biopsy.

          Methods

          Targeted sequencing with a 520-gene panel was performed on prospectively collected matched tumor tissue (TIS), plasma (PLA), and sputum supernatant (SPU) from 71 aNSCLC patients (NCT05034445). Genomic alteration detection was characterized in a series of aspects and interrogated for association with 14 clinicohistologic features. Nomograms were constructed with logistic regression for predicting the liquid biopsy type with greater sensitivity.

          Results

          Compared with PLA, SPU showed comparable quality control metrics, mutation detection rate (SPU: 67.6%, PLA: 70.4%), concordance with tumor tissue (67.6% vs. 73.2%), and correlation with tissue-based tumor mutation burden levels ( r = 0.92 vs. 0.94). For driver alterations, detection was less sensitive with SPU (50.0%) than PLA (63.5%) in the entire cohort but similarly or more sensitive in patients with centrally located lung tumors or smoking history or for altered ALK or KRAS. Two nomograms were constructed and enabled predicting the probability of superior sensitivity with SPU with moderate to borderline high accuracy.

          Conclusion

          In addition to demonstrating comparable performance in multiple aspects, this study is the first to propose nomograms for choosing liquid biopsy based on clinicohistologic characteristics. Future research is warranted to delineate the clinical utility of sputum for genome profiling.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12931-022-02097-4.

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          Most cited references16

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          Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.

          Justin Gainor, Leila Dardaei, Satoshi Yoda … (2016)
          Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK(G1202R), increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.
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            Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy.

            Y.S. Li, B.Y. Jiang, J.J. Yang … (2018)
            Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
            Article 0 comments Cited 123 times – based on 0 reviews     Review now
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              Capture-Based Targeted Ultradeep Sequencing in Paired Tissue and Plasma Samples Demonstrates Differential Subclonal ctDNA-Releasing Capability in Advanced Lung Cancer.

              Xiaowei Mao, Zhou Zhang, Xiaoxuan Zheng … (2017)
              Circulating tumor DNA (ctDNA), which represents an unbiased way to assess tumor genetic profile noninvasively, facilitates studying intratumor heterogeneity. Although intratumor heterogeneity has been elucidated substantially in a few cancer types, including NSCLC, how it influences the ability of tumor cells harboring different genetic abnormalities in releasing their DNA remains elusive. We designed a capture-based panel targeting NSCLC to detect and quantify genetic alterations from plasma samples by using deep sequencing. By applying the panel to paired biopsy and plasma samples, we imputed and compared the ctDNA-releasing efficiency in subclones harboring distinct genetic variants.
              Article 0 comments Cited 80 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Chengzhi Zhou: doctorzcz@163.com
                Journal
                Journal ID (nlm-ta): Respir Res
                Journal ID (iso-abbrev): Respir Res
                Title: Respiratory Research
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-9921
                ISSN (Electronic): 1465-993X
                Publication date (Electronic): 1 July 2022
                Publication date PMC-release: 1 July 2022
                Publication date (Print): 2022
                Volume: 23
                Electronic Location Identifier: 175
                Affiliations
                [1 ]GRID grid.470124.4, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, , Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, ; 151 Yanjiangxi Road, Guangzhou, 510120 Guangdong China
                [2 ]GRID grid.488847.f, Burning Rock Biotech, ; Room 601, Building 6, Phase 2, Standard Industrial Unit, No. 7 LuoXuan 4th Road, International Biotech Island, Guangzhou, 510300 Guangdong China
                Article
                Publisher ID: 2097
                DOI: 10.1186/s12931-022-02097-4
                PMC ID: 9247971
                PubMed ID: 35778703
                SO-VID: 7350884c-698e-41a4-bde0-f0f5379ffaef
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 1 March 2022
                Date accepted : 7 June 2022
                Funding
                Funded by: State Key Laboratory of Respiratory Disease - the Open Project
                Award ID: SKLRD-OP-202111
                Funded by: Fundamental and Applied Fundamental Research Project of City-School (Institute) Joint Funding Project, Guangzhou Science and Technology Bureau
                Award ID: 202102010345
                Funded by: FundRef http://dx.doi.org/10.13039/100018904, Beijing Xisike Clinical Oncology Research Foundation;
                Award ID: Y-2019Genecast-076
                Funded by: Beijing Bethune Charitable Foundation
                Award ID: BQE-TY-SSPC(5)-S-03
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Respiratory medicine
                Keywords: nsclc,liquid biopsy,sputum supernatant,driver alterations,genomic profiling,next-generation sequencing
                Data availability:
                ScienceOpen disciplines: Respiratory medicine
                Keywords: nsclc, liquid biopsy, sputum supernatant, driver alterations, genomic profiling, next-generation sequencing

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