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Nat Med. 2014 May;20(5):548-54. doi: 10.1038/nm.3519. Epub 2014 Apr 6.

An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.

Author information

1
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA. [3].
2
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Department of Radiation Oncology, Stanford University, Stanford, California, USA. [3].
3
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
4
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
5
Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
6
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
7
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA. [3] Division of Hematology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
8
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Department of Radiation Oncology, Stanford University, Stanford, California, USA. [3] Stanford Cancer Institute, Stanford University, Stanford, California, USA.

Abstract

Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

PMID:
24705333
PMCID:
PMC4016134
DOI:
10.1038/nm.3519
[Indexed for MEDLINE]
Free PMC Article
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