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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers

Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients

Taylor J. Jensen, Aaron M. Goodman, Shumei Kato, Christopher K. Ellison, Gregory A. Daniels, Lisa Kim, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich and Razelle Kurzrock
Taylor J. Jensen
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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  • For correspondence: tjensen@sequenom.com
Aaron M. Goodman
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, California.
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Shumei Kato
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.Division of Precision Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, California.
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Christopher K. Ellison
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Gregory A. Daniels
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.
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Lisa Kim
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.
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  • ORCID record for Lisa Kim
Prachi Nakashe
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Erin McCarthy
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Amin R. Mazloom
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Graham McLennan
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Daniel S. Grosu
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Mathias Ehrich
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
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Razelle Kurzrock
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.
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  • ORCID record for Razelle Kurzrock
DOI: 10.1158/1535-7163.MCT-18-0535 Published February 2019
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Abstract

Inhibitors of the PD-1/PD-L1/CTLA-4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for noninvasive prenatal testing, to detect tumor-specific copy-number alterations, and the development of a new metric—the genome instability number (GIN)—to monitor response to these drugs. We demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease. Finally, we provide evidence for delayed kinetics in responses to checkpoint inhibitors relative to molecularly targeted therapies. Overall, these data demonstrate a proof of concept for using this method for monitoring treatment outcome in patients with cancer receiving immunotherapy.

This article is featured in Highlights of This Issue, p. 233

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received May 17, 2018.
  • Revision received September 5, 2018.
  • Accepted November 26, 2018.
  • Published first December 6, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (2)
February 2019
Volume 18, Issue 2
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Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients
Taylor J. Jensen, Aaron M. Goodman, Shumei Kato, Christopher K. Ellison, Gregory A. Daniels, Lisa Kim, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich and Razelle Kurzrock
Mol Cancer Ther February 1 2019 (18) (2) 448-458; DOI: 10.1158/1535-7163.MCT-18-0535

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Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients
Taylor J. Jensen, Aaron M. Goodman, Shumei Kato, Christopher K. Ellison, Gregory A. Daniels, Lisa Kim, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich and Razelle Kurzrock
Mol Cancer Ther February 1 2019 (18) (2) 448-458; DOI: 10.1158/1535-7163.MCT-18-0535
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Molecular Cancer Therapeutics
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