Cancer DNA blood tests validated by researchers

An international research team has assessed five commercially available assays for tumour DNA sequencing — a fast, cheap and less invasive method to diagnose and monitor cancer.

Published in the journal Nature Biotechnology, their study marks a major milestone for the use of such assays as cancer diagnostics, outlining best-practice guidelines and uncovering key areas of future development.

When cancer cells develop, they accumulate mutations in their DNA, fragments of which enter the bloodstream when cancer cells break down. Thanks to assays employing next-generation sequencing, these so-called circulating tumour DNA (ctDNA) fragments can now be detected in a patient’s blood samples, which could be used to identify and monitor cancer as an alternative to more invasive tissue biopsies.

However, while ctDNA assays are already being adopted in precision oncology clinical trials, researchers and clinicians still lack a thorough understanding of how accurate current assays are, and which aspects of the technology still need to be improved. This knowledge helps define what applications ctDNA sequencing is suitable for and is needed before ctDNA sequencing can be implemented widely in clinical practice.

“In order for ctDNA assays to be of benefit to patients in the clinic, they need to accurately and consistently detect cancer mutations across different labs and samples,” noted first author Dr Ira Deveson from the Garvan Institute of Medical Research. “Our study is the most comprehensive evaluation of analytical performance among ctDNA assays to date.”

Led by the Garvan Institute, the US FDA’s National Center for Toxicological Research and the University of Arkansas for Medical Sciences, researchers from 12 participating laboratories in Europe, Asia and the United States evaluated the performance of current industry-leading ctDNA assays, from companies Roche Sequencing Solutions, Illumina, Integrated DNA Technologies, Burning Rock Dx and Thermo Fisher Scientific. They tested the assays using synthetic experiments and mock-ctDNA reference samples.

Analysis revealed that all laboratories detected ctDNA mutations above 0.5% relative frequency (consistent with late-stage and metastatic tumours) with high sensitivity, precision and reproducibility using all participating assays. However, the assays detected lower levels of ctDNA (consistent with early-stage cancer or early signs of disease relapse) unreliably and inconsistently between different tests.

“Understanding the current assays’ detection limits was a crucial step towards a future where blood tests can be routinely used as a cancer screening tool,” said Dr Joshua Xu from the National Center for Toxicological Research. “This critical study is a thorough analytical evaluation of ctDNA assays … which has been called for by government, regulatory and clinical organisations.”

The researchers’ paper also outlines priorities for the future development of ctDNA assays, which they say will help advance the technology for clinical applications in monitoring tumour progression, response to therapy and cancer relapse. As noted by Associate Professor Donald Johann Jr, from the University of Arkansas for Medical Sciences, “Our findings indicate that the participating ctDNA assays may be suitable for molecular stratification and profiling tumour evolution in advanced cancer patients. This should help clear a path for more advanced clinical trials of ctDNA assays.”

“Our independent performance analysis is a crucial mechanism to drive advances in next-generation sequencing approaches for their use in cancer detection and management,” concluded co-senior author Associate Professor Tim Mercer, from the Garvan Institute and the Australian Institute for Bioengineering and Nanotechnology at The University of Queensland.

“We expect it will help improve the tests’ sensitivity and reliability for diagnosing tumours at early stages.”

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