@article{db6c58c15ed9462a857c7c04c48fb128,
title = "Integrating genomic features for non-invasive early lung cancer detection",
abstract = "Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed {\textquoteleft}lung cancer likelihood in plasma{\textquoteright} (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.",
author = "Chabon, {Jacob J.} and Hamilton, {Emily G.} and Kurtz, {David M.} and Esfahani, {Mohammad S.} and Moding, {Everett J.} and Henning Stehr and Joseph Schroers-Martin and Nabet, {Barzin Y.} and Binbin Chen and Chaudhuri, {Aadel A.} and Liu, {Chih Long} and Hui, {Angela B.} and Jin, {Michael C.} and Azad, {Tej D.} and Diego Almanza and Jeon, {Young Jun} and Nesselbush, {Monica C.} and {Co Ting Keh}, Lyron and Bonilla, {Rene F.} and Yoo, {Christopher H.} and Ko, {Ryan B.} and Chen, {Emily L.} and Merriott, {David J.} and Massion, {Pierre P.} and Mansfield, {Aaron S.} and Jin Jen and Ren, {Hong Z.} and Lin, {Steven H.} and Costantino, {Christina L.} and Risa Burr and Robert Tibshirani and Gambhir, {Sanjiv S.} and Berry, {Gerald J.} and Jensen, {Kristin C.} and West, {Robert B.} and Neal, {Joel W.} and Wakelee, {Heather A.} and Loo, {Billy W.} and Kunder, {Christian A.} and Leung, {Ann N.} and Lui, {Natalie S.} and Berry, {Mark F.} and Shrager, {Joseph B.} and Nair, {Viswam S.} and Haber, {Daniel A.} and Sequist, {Lecia V.} and Alizadeh, {Ash A.} and Maximilian Diehn",
note = "Funding Information: Competing interests D.M.K. reports paid consultancy from Roche Molecular Diagnostics. A.A.C. reports speaker honoraria and travel support from Roche Sequencing Solutions, Varian Medical Systems, and Foundation Medicine, a research grant from Roche Sequencing Solutions, and has served as a paid consultant for Fenix Group International. A.S.M. reports advisory for AbbVie, Genentech, and Bristol-Myers Squibb (honoraria paid to institution) and research funding from Novartis and Verily. J.J. is now employed by Celgene. S.H.L. reports paid advisory from AstraZeneca, speaker honoraria from Varian Medical Systems and research funding from BeyondSpring Pharmaceuticals Inc., Hitachi Chemical Diagnostics, Genentech, and New River Labs. S.S.G. reports paid consultancy from AbbVie, Ceremark, CytomX Therapeutics Inc., GPV, Life Molecular Imaging, Nusano, Spectrum Dynamics, and TPG, and ownership interest in Akrotome Imaging Inc., Cellsight Technologies, CytomX Therapeutics Inc., Earli Inc., Endra Inc., MagArray Inc., Nines, Nodus Therapeutics, Nusano, RefleXion Medical Inc., SiteOne Therapeutics Inc., Spectrum Dynamics, Vave Health, and Vor Biopharma. J.W.N. reports paid consultancy from AstraZeneca, Genentech, Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, and Calithera Biosciences, and research funding from Genentech, Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune and GSK. H.A.W. reports paid advisory from AstraZeneca, Xcovery, Janssen, and Mirati, unpaid advisory from Merck, Takeda, Genentech, Roche, and Cellworks, and research funding from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Xcovery. A.A.A. reports ownership interest in CiberMed and FortySeven Inc., patent filings related to cancer biomarkers, and paid consultancy from Genentech, Roche, Chugai, Gilead, and Celgene. M.D. reports research funding from Varian Medical Systems and Illumina, ownership interest in CiberMed, patent filings related to cancer biomarkers, and paid consultancy from Roche, AstraZeneca, RefleXion and BioNTech. The remaining authors declare no potential conflicts of interest. Funding Information: Acknowledgements We thank E. Kool for advice relating to ROS scavengers and E. Edell and A. Bungum from the Mayo Clinic Lung Tumor Specimen Registry for their assistance with sample collection. This work was supported by the National Cancer Institute (R01CA188298 and R01CA233975 to M.D. and A.A.A., 1-K08-CA241076-01 to D.M.K., R25CA180993 and T32-CA 121940 to M.S.E., U01 CA196405 to P.P.M., training grant T32 CA009302 to E.G.H., M.C.N. and D.A., and K12CA090628 and P30 CA015083-44S1 to A.S.M.), the US National Institutes of Health Director{\textquoteright}s New Innovator Award Program (1-DP2-CA186569 to M.D.), the US National Institutes of Health, the Virginia and D.K. Ludwig Fund for Cancer Research (M.D. and A.A.A.), the CRK Faculty Scholar Fund (M.D.), the Bakewell Foundation (M.D. and A.A.A.), the Damon Runyon Cancer Research Foundation (PST#09-16 to D.M.K.), the Tobacco-Related Disease Research Program Predoctoral Fellowship (T30DT0806 to E.G.H.), the Blavatnik Family Fellowship (E.G.H.), the American Cancer Society (134031-PF-19-164-01-TBG to B.Y.N.), the SDW/DT and Shanahan Family Foundations (A.A.A.), Stand Up To Cancer (M.D., A.A.A., D.A.H. and L.V.S.), and the NSF Graduate Research Fellowship (DGE-114747 to J.J.C., DGE-1656518 to D.A.). A.A.A. is a Scholar of The Leukemia & Lymphoma Society. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = apr,
day = "9",
doi = "10.1038/s41586-020-2140-0",
language = "English",
volume = "580",
pages = "245--251",
journal = "Nature",
issn = "0028-0836",
number = "7802",
}