NATURE MEDICINE | TECHNICAL REPORT
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An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage
Aaron M Newman, Scott V Bratman, Jacqueline To, Jacob F Wynne, Neville C W Eclov, Leslie A Modlin, Chih Long Liu, Joel W Neal, Heather A Wakelee, Robert E Merritt, Joseph B Shrager, Billy W Loo Jr, Ash A Alizadeh & Maximilian Diehn
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Nature Medicine (2014) doi:10.1038/nm.3519
Received 15 August 2013 Accepted 06 November 2013 Published online 06 April 2014
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Abstract
Abstract• Accession codes• References• Author information• Supplementary information
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.