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Practical Considerations for the Use of Circulating Tumor DNA in the Treatment of Patients With CancerA Narrative Review

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Importance  Personalized medicine based on tumor profiling and identification of actionable genomic alterations is pivotal in cancer management. Although tissue biopsy is still preferred for diagnosis, liquid biopsy of blood-based tumor analytes, such as circulating tumor DNA, is a rapidly emerging technology for tumor profiling.

Observations  This review presents a practical overview for clinicians and allied health care professionals for selection of the most appropriate liquid biopsy assay, specifically focusing on circulating tumor DNA and how it may affect patient treatment and case management across multiple tumor types. Multiple factors influence the analytical validity, clinical validity, and clinical utility of testing. This review provides recommendations and practical guidance for best practice. Current methodologies include polymerase chain reaction-based approaches and those that use next-generation sequencing (eg, capture-based profiling, whole exome, or genome sequencing). Factors that may influence utility include sensitivity and specificity, quantity of circulating tumor DNA, detection of a small vs a large panel of genes, and clonal hematopoiesis of indeterminate potential. Currently, liquid biopsy appears useful in patients unable to undergo biopsy or where mutations detected may be more representative of the predominant tumor burden than for tissue-based assays. Other potential applications may include screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring.

Conclusions and Relevance  This review found that liquid biopsy is increasingly being used clinically in advanced lung cancer, and ongoing research is identifying applications of circulating tumor DNA-based testing that complement tissue analysis across a broad range of clinical settings. Circulating tumor DNA technologies are advancing quickly and are demonstrating potential benefits for patients, health care practitioners, health care systems, and researchers, at many stages of the patient oncologic journey.

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Article Information

Accepted for Publication: July 14, 2022.

Published Online: October 20, 2022. doi:10.1001/jamaoncol.2022.4457

Corresponding Author: Christian Rolfo, MD, PhD, MBA, Center for Thoracic Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, One Levy Pl, Box 1079, New York, NY 10029 (christian.rolfo@mssm.edu).

Author Contributions: All authors had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Krebs, Malapelle, Paz-Ares, Schuler, Vainer, Yoshino, Rolfo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Krebs, Malapelle, Schuler, Thomas, Vainer, Yoshino, Rolfo.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Andre, Rolfo.

Administrative, technical, or material support: Malapelle, Paz-Ares.

Supervision: Paz-Ares, Schuler, Rolfo.

Conflict of Interest Disclosures: Dr Krebs reported nonfinancial support and grants from Roche during the conduct of the study; consulting and speaker fees from AstraZeneca, Bayer, Guardant, Janssen, Roche, and Seattle Genetics; travel expenses from BerGenBio, Immutep, and Janssen; institutional funding from AstraZeneca, Bayer, BerGenBio, Blueprint, Carrick, Chugai, Immutep, Janssen, Novartis, Nurix, Relay Therapeutics, Roche, Seattle Genetics, and Turning Point Therapeutics outside the submitted work. Dr Malapelle reported speaking and advisory fees from Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GlaxoSmithKline, Merck, AstraZeneca, Janssen, Diatech, Novartis, and Hedera, all outside the submitted work. Dr Andre reported grants from Novartis, Daiichi, Roche, Eli Lilly, AstraZeneca, and Pfizer compensated to the hospital, all outside the submitted work. Dr Paz-Ares reported speaking and/or scientific advisory fees from Amgen, AstraZeneca, Pfizer, Bristol Myers Squibb, Roche , Merck Sharp & Dohme, Mirarti, Bayer, Eli Lilly, PharmaMar, Ipsen, Guardant, Merck, and Novartis; grants from Pfizer, Bristol Myers Squibb, AstraZeneca, and PharmaMar; being a cofounder of Altum sequencing; and being a board member of Genómica, all outside the submitted work. Dr Schuler reported scientific consulting and presentation fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck, Serono, and Novartis; consulting fees from Roche and Sanofi; and grants to the institution from AstraZeneca and Bristol Myers Squibb, outside the submitted work; in addition, Dr Schuler reports a patent for a highly sensitive PCR method for mutation detection issued to the University Duisburg-Essen. Dr Thomas reported grants from Roche, AstraZeneca, Bayer, Amgen, Pfizer, BeiGene, Seattle Genetics, Sun Pharma, and Eisai; and being chief executive officer of Omico, during the conduct of the study. Dr Vainer reported personal fees from Roche, Pfizer, AbbVie, Takeda, Bayer, and AstraZeneca; and nonfinancial support from Bristol Myers Squibb, during the conduct of the study. Dr Yoshino reported personal fees from Chugai, Merck, Bayer, Ono, and Merck Sharp & Dohme; and grants from Merck Sharp & Dohme, Daiichi Sankyo, Ono, Taiho, Amgen, Sanofi, Pfizer, Genomedia, Sysmex, Nippon Boehringer Ingelheim, and Chugai, all outside the submitted work. Dr Rolfo reported advisory board, speaking fees, and nonfinancial medical writing support from Roche and nonfinancial support during the conduct of the study; advisory/committee fees from Bristol Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Pfizer, Mirarti, COR2ED, Daiichi Sankyo, Sanofi, Genzyme-Regeneron, Bayer, and Eisai; grants from the US National Institutes of Health’s SeroNet, the Lung Cancer Research Foundation, and Pfizer; and being on data safety monitoring/advisory boards for EMD, Merck Serono, ISLB president, the International Association for the Study of Lung Cancer, European School of Oncology, European Society for Medical Oncology, editor-in-chief of Critical Reviews in Oncology/Hematology at Elsevier, and former associate editor of ESMO Open, all outside the submitted work. No other disclosures were reported.

Additional Contributions: Research support in the form of third-party medical writing assistance and formatting for this narrative review—furnished by Blair Jarvis, MSc, on behalf of Health Interactions, and Islay Steele, PhD, Health Interactions—was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

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  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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