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Mol Cancer Ther. 2019 Feb;18(2):448-458. doi: 10.1158/1535-7163.MCT-18-0535. Epub 2018 Dec 6.

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

Author information

1
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California. tjensen@sequenom.com.
2
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.
3
Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, California.
4
Division of Precision Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, California.
5
Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
#
Contributed equally

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.

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