Abstract
Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74–2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52–0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.
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Data availability
Genomic and clinical data are available on cBioPortal (https://www.cbioportal.org/study/summary?id=nsclc_ctdx_msk_2022). The raw sequencing data for MSK-IMPACT and MSK-ACCESS are protected and are not broadly available due to privacy laws. Researchers at MSK with appropriate IRB permission may request the data from the Center for Molecular Oncology (skicmopm@mskcc.org).
Code availability
No software was used for data collection.
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Acknowledgements
This work was supported by a grant from the Antidote Health Foundation for Cure of Cancer (BTL), the National Institutes of Health (T32-CA009207 (J.J.), CTSA UL1TR00457 (M.R.M.-G.), P50 CA247749 01 and P30 CA008748), the Molecular Diagnostics Service in the Department of Pathology, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology.
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Conception: J.J. and B.T.L. Radiomic analysis: J.J., E.S.L., R.Y. and J.P.D. Patient accrual: J.J., A.N., P.K.P., J.E.C., Y.R.M.-G., B.D., H.A.Y., M.O., M.D.H., K.C.A., M.G.Z., M.G.K., K.K.N., J.E., I.P., W.V.L., J.J.F., A.I., D.M., G.R., B.J.P., D.L.C., C.I.D., M.I., S.C., N.P., A.L., N.R., J.C., W.D.T., G.J.R., V.W.R., A.R., D.G., A.D., D.R.J., C.M.R., J.M.I. and B.T.L. Genomic data collection and analysis: J.J., G.J., A.R.B., R.B., A.Z., M.D., N.S., D.C., R.K., R.M., S.P.S., M.F.B., M.E.A., M.L., R.L., L.P.L. and M.L. Clinical data collection and analysis: J.J., E.S.L., N.S., Y.R.M.-G., H.-Y.T., C.-R.X., C.T.-L. and M.D.S. Administration: A.M., J.G., D.B.S., A.D., H.I.S., P.L., L.P.L., M.F.B., M.E.A., M.L., P.R., J.S.R.-F., D.R.J., C.M.R., J.M.I. and B.T.L. Statistical plan: J.J., M.G., R.S. and S.P.S. Writing: J.J., C.W., P.R., J.S.R.-F. and B.T.L. All co-authors reviewed and approved the final draft of the manuscript.
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J.J. has a patent licensed by MDSeq. A.N. reports serving as a one-time paid consultant for Bayer. P.K.P. receives compensation for consulting or advisory board participation from Bicara Therapeutics, Boehringer Ingelheim, EMD Serono, GlaxoSmithKline, Takeda Pharmaceuticals, WC Communications and Xencor and receives honoraria for participation in CME educational programs from PeerVoice, ACE Oncology Research to Practice, Clinical Care Options, Spring to Life and Touch Independent Medical Education. J.E.C. has served as a consultant for Astra Zeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health and Janssen and has received research funding to her institution from Astra Zeneca, Bristol-Myers Squib, Genentech and Merck. A.R.B. has stock ownership in Johnson & Johnson. R.B. reports a grant from Archer, honoraria for advisory board participation from Loxo oncology and speaking fees from Illumina. A.Z. has received speaking fees from Illumina. D.C. has consulted with/received honoraria from Pfizer, Loxo/Lilly Oncology, BridgeBio, FORE Therapeutics, Scorpion Therapeutics and Vividion Therapeutics. Y.R.M.-G. acknowledges receipt of training through an institutional K30 grant from the NIH (CTSA UL1TR00457). She has received funding from a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation, funded by Charles M. Baum and Carol A. Baum. She reports travel, accommodation and expenses from AstraZeneca and honoraria from Virology Education. She acknowledges research funding to the institution from Loxo Oncology at Eli Lilly, Elucida Oncology, Taiho Oncology, Hengrui USA/Jiangsu Hengrui Pharmaceuticals and Endeavor Biomedicines. She acknowledges royalties from Rutgers University Press and Wolters Kluwer. H.-Y.T. has received academic travel support from Resolution Bioscience. C.X. has received honoraria from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck & Co., Novartis, Pfizer and Roche; has received research support from BeiGene and Hengrui Pharmaceutical; and has received reimbursement for travel and accommodation expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck & Co., Novartis, Pfizer and Roche. B.D. reports equity interest in Eli Lilly and Company, Roche and CVS Health and family member involvement with Eli Lilly and Company and CVS Health. H.A.Y. has consulted for AstraZeneca, Blueprint Medicine, Janssen Oncology, Cullinan and Daiichi. Her institution has received research funding for clinical trials from AstraZeneca, Daiichi, Pfizer, Novartis, Cullinan Oncology and Lilly. M.O. reports personal fees from PharmaMar, personal fees from Novartis, personal fees from Targeted Oncology, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Jazz Pharmaceuticals and personal fees from Astro Pharmaceuticals, outside the submitted work. M.D.H. reports grants from BMS and personal fees from Achilles, Adagene, Adicet, Arcus, AstraZeneca, Blueprint, BMS, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs and Regeneron, as well as equity options from Factorial, Immunai, Shattuck Labs and Arcus. A patent filed by Memorial Sloan Kettering related to the use of TMB to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. P.L. is listed as an inventor on patent applications filed by MSKCC that describe approaches to treat KRAS or BRAF-mutant tumors. K.C.A. reports personal fees from AstraZeneca and nonfinancial support from Takeda and Novartis outside the submitted work. In the last 3 years, M.G.Z. has received consulting fees from Takeda, GlaxoSmithKline, Expert Connect, Aldeyra Therapeutics, Novocure and Atara and honoraria from Research to Practice, Medical Learning Institute and OncLive. Memorial Sloan Kettering receives research funding from the Department of Defense, the National Institutes of Health, Precog, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium/Takeda, Curis and Atara for research conducted by M.G.Z. M.G.Z. serves as chair of the board of directors of the Mesothelioma Applied Research Foundation, uncompensated. M.G.K. receives personal fees from Novartis, Sanofi-Genzyme, AstraZeneca, Pfizer, Janssen and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems and AstraZeneca; received travel support from AstraZeneca, Pfizer and Genentech; and received editorial support from Hoffman La-Roche. Memorial Sloan Kettering has received research funding from the National Cancer Institute (USA), the Lung Cancer Research Foundation and Genentech Roche for research conducted by M.G.K. I.P. has consulted or served on the advisory boards of Pfizer, AstraZeneca, Blueprint Medicine, DavaOncology, Eli Lilly and Curio Science. W.V.L. receives institutional research funding from Daiichi Sankyo, Amgen and Abbvie and has been a compensated consultant for PharmaMar, G1 Therapeutics, AstraZeneca and Jazz Pharmaceuticals. D.M. is a consultant for AstraZeneca, Johnson & Johnson, Boston Scientific, Bristol Myers Squibb and Merck. G.R. receives royalties from Scanlan International. B.J.P. is a consultant for AstraZeneca. L.P.L. is an employee and shareholder of Agilent Technologies. M.L. is an employee and shareholder of Agilent Technologies. C.I.D. reports serving on the advisory board for Amgen and Ipsen, honoraria for Merck and academic travel support from Roche. M.I. reports serving on the advisory boards of Pfizer and Takeda; receiving honoraria from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Pfizer, Takeda and Novartis; and travel support from Roche, AstraZeneca and MSD. S.C. reports advisory board fees from Roche and Astra Zeneca and travel support from Bristol Myers Squibb, outside the submitted work. N.P. has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. A.L. reports personal fees and travel funding from Mundipharma/Helsinn, personal fees from Bayer and personal fees from Eisai. G.J.R. reports grants from National Institutes of Health/National Cancer Institute, has been an uncompensated consultant to Daiichi, Pfizer and Mirati and has institutional research support from Mirati, Takeda, Merck, Roche, Pfizer and Novartis. In addition, G.J.R. has pending patents US20170273982A1 and WO2017164887A8. D.B.S. has served as a consultant for/received honoraria from Loxo Oncology, Lilly Oncology, Pfizer, QED Therapeutics, Vivideon Therapeutics and Illumina. M.L. has received honoraria for advisory board participation from Merck, Astra-Zeneca, Bristol Myers Squibb, Blueprint Medicines, Janssen Pharmaceuticals, Takeda Pharmaceuticals, Lilly Oncology, LOXO Oncology, Bayer, ADC Therapeutics, Riken Genesis and Paige AI and research support from LOXO Oncology, Merus, and Helsinn Therapeutics. Marc Ladanyi reports honoraria for ad-hoc advisory board participation from Merck, AstraZeneca, Bristol Myers Squibb, Takeda, Bayer, and Lilly Oncology; and research support from LOXO Oncology, Merus and Helsinn Therapeutics. V.W.R. reports grants from Genelux, grants from Genentech, other from DaVinci Surgery, nonfinancial support from Bristol Myers Squibb and personal fees from NIH/Coordinating Center for Clinical Trials, outside the submitted work. A.R. reports grants from Varian Medical Systems, grants and personal fees from AstraZeneca, grants and personal fees from Merck, grants and personal fees from Boehringer Ingelheim, grants from Pfizer, personal fees from Research to Practice, personal fees from Cybrexa, personal fees from More Health and nonfinancial support from Philips/Elekta, outside the submitted work. D.G. reports grants from Varian, AstraZeneca, Merck and Bristol Myers Squibb and personal fees from Varia, AstraZeneca, Merck, US Oncology, Bristol Myers Squibb, Relfexion, WebMD, Vindico and Medscape and has served on the advisory board for AstraZeneca. A.D. has received honoraria or worked on the advisory boards of Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica, ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Nuvalent, Merus, AXIS, Chugai Pharm and EPG Health; has received funding through his institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho and PharmaMar; has received research support from Foundation Medicine; receives royalties from Wolters Kluwer; has received other support from Boehringer Ingelheim; has received food/beverage from Merck, Puma and Merus; and has received CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME and Clinical Care Options. H.I.S. reports the following support: compensated consultant/advisor to Ambry Genetics, Konica Minolta, Bayer, Pfizer, Sun Pharmaceuticals and WCG Oncology; uncompensated consultant/advisory to Amgen, ESSA Pharma, Janssen Research & Development, Janssen Biotech and Sanofi Aventis; he has received research funding (to his institution) from Epic Sciences, Illumina, Janssen, Menarini Silicon Biosystems, Prostate Cancer Foundation and ThermoFisher; intellectual property rights from BioNTech, Elucida Oncology, MaBVAX and Y-mAbs Therapeutics; and nonfinancial support from Amgen, Asterias Biotherapeutics, Bayer, ESSA Pharma, Menarini Silicon Biosystems, Phosplatin, Pfizer, Prostate Cancer Foundation and WCG Oncology. S.P.S. is a shareholder and consultant of Canesia Health. M.F.B. reports a consulting/advisory role with PetDx and Eli Lilly; research support from Grail; and a patent pending related to cfDNA profiling. R.L. is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Syndax. Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics and Isoplexis for which he receives equity support. He receives research support from Ajax and Abbvie and has consulted for Incyte, Janssen, Morphosys and Novartis. He has received honoraria from Astra Zeneca and Kura for invited lectures and from Gilead for grant reviews. P.R. received institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences and ArcherDx and consultation/ad board/honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera and Tempus. J.R.-F. is a paid consultant of Goldman Sachs, Paige.AI and REPARE Therapeutics, a member of the scientific advisory board of Goldman Sachs, Paige.AI and Volition RX, and an ad hoc member of the scientific advisory board of Roche, Genentech, Roche Tissue Diagnostics, Ventana, Novartis, InVicro and GRAIL. D.R.J. serves as a consultant for AstraZeneca and Merck. C.M.R. reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines and Harpoon Therapeutics, outside the submitted work. J M.I. reports equity in LumaCyte and has served as an uncompensated member of a steering committee for Genentech. B.T.L. has served as an uncompensated advisor and consultant to Amgen, Genentech, Boehringer Ingelheim, Lilly, AstraZeneca and Daiichi Sankyo. He has received research grants to his institution from Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health and Bolt Biotherapeutics. He has received academic travel support from MORE Health and Jiangsu Hengrui Medicine. He is an inventor on two institutional patents at Memorial Sloan Kettering (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. The remaining authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Turnaround time of plasma and tissue sequencing.
Boxplots showing median (center) +/−25%ile (boxes) and 95%ile (whiskers) of turnaround time for liquid biopsy (MSK-ACCESS and ctDx Lung, N independent samples = 2,162) and tissue (MSK-IMPACT, N independent samples = 612) sequencing from date of blood collection. Tissue start time is the date of white blood cell control collection. The turnaround time for plasma ctDNA sequencing was significantly faster than for tissue sequencing (*two-sided Mann-Whitney U, p < 0.001).
Extended Data Fig. 2 Correlates of ctDNA alteration levels.
Histograms showing the proportion of patients with either number of ctDNA alterations or maximum mutation variant allele frequency (VAF) per sample. P-values are from Mann-Whitney U tests or Kruskal-Wallis tests for histologic subgroups. Raw VAFs of zero are set to the minimum value of the log axis.
Extended Data Fig. 3 Survival of patients without tissue sequencing matched to targeted therapy by ctDNA.
Kaplan-Meier survival curves for patients without tissue sequencing matched or not matched to targeted therapy. Number at risk in each category is adjusted for left truncation and time-dependent nature of targeted therapy variables.
Supplementary information
Supplementary Information
Supplemental text and Supplementary Figs. S1–14.
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Jee, J., Lebow, E.S., Yeh, R. et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat Med 28, 2353–2363 (2022). https://doi.org/10.1038/s41591-022-02047-z
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DOI: https://doi.org/10.1038/s41591-022-02047-z
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