Latest News

Setting Standards For Measuring Circulating Tumor DNA

February 11, 2020 | Is it possible to come to global consensus on liquid biopsy measurements? Can circulating tumor DNA (ctDNA) be measured accurately and concordantly with DNA in solid tumors?

Angela Pia Sanzone believes so. Sanzone, Blood Biomarkers Group Leader, Advanced Therapies Division, National Institute for Biological Standards and Control (NIBSC), UK, is working with the World Health Organization on international reference standards for ctDNA that will enable harmonized reporting in diagnostics and patient monitoring.

On behalf of Diagnostics World, she spoke with Kaitlin Searfoss Kelleher about the WHO efforts to develop these standards, the challenges ahead, and how they may impact the field of liquid biopsy.

Editor’s Note: Angela Pia Sanzone will be presenting her work at the Diagnostics Innovation Summit, May 19-21, in Lisbon Portugal. She will speak in program dedicated to Enabling Technologies for Liquid Biopsy and Beyond.

Diagnostics World News: Tell us a little bit about the WHO international standards for ctDNA that are being developed by NIBSC. What standards are being developed and what benefits do you see being realized?

Angela Pia Sanzone: World Health Organization (WHO) International Standards are the “gold standards” from which countries and manufacturers can calibrate their own working standards and assays for biological testing.

At NIBSC we have recently started a new program to develop standards for ctDNA that not only match the physical characteristics but also the biological characteristics of ctDNA. At the moment we are focusing on developing WHO ctDNA International Standards for EGFR variants (L858R, exon 19 deletions, and T790M) with complementary development of genomic DNA WHO International Standards but we aim to expand our portfolio to other clinically relevant biomarkers.

Once successfully developed and adopted by the scientific community, such WHO ctDNA International Standards will enable the harmonization of diagnostic ctDNA quantification and the calibration, kits and assays, and other reference material; in other words, the interpretation of ctDNA analysis results as well as a more successful clinical research, therapy, and regulatory-related decision making and reimbursement applications will be possible.

What challenges do you foresee in widespread adoption of these standards once finalized? Any advice for a successful implementation?

To be fair, the first real challenge is already to develop, in a timely manner, the most stable and commutable WHO ctDNA International Standards that are able to mimic the real patient-like scenario. By this I mean International Standards that enable users to assess the concordance with solid tumor biopsy, that have similar sizes to the natural ctDNA, that contain the clinically relevant variants that are difficult to detect in the most commutable matrix, and that ideally will act as calibrant also below the current clinical cutoff.

Once this is done, as it has happened with other WHO ISs, we will have to liaise with the different stakeholders including industry, hospitals, governmental organization, academic institutions and regulators for the full implementation.

How do you see this affecting the liquid biopsy field in the years to come?

The lack of fully commutable standard materials to assess results’ concordance between liquid biopsy and tissue is one of the main challenges in the adoption of ctDNA in the clinical routine. The availability of WHO ctDNA International Standards will allow not only the harmonization of diagnostic ctDNA quantification but also speed up novel liquid biopsy technologies regulatory approval and consequently their uses to improve patients’ health. In addition, the development of the WHO ctDNA International Standards for EGFR variants with complementary development of genomic DNA WHO International Standards is just the first in a series of standards and as such will act as a prototype for the development and validation of the standards for other assays evaluating genomic material.