Dr Miles Levy, consultant endocrinologist, Leicester


Research project: The use of circulating cell-free tumour-derived DNA (ctDNA) in the diagnosis and monitoring of thyroid cancer

Recent advances in the diagnosis and management of thyroid cancer have seen the five-year survival rate rise to 98%. However, thyroid cancer recurs in up to one in five patients. Currently, thyroglobulin (Tg)  and calcitonin are the two most commonly used biomarkers for detecting recurrence of papillary and medullary thyroid cancer respectively. However, they are imperfect. So there is a need for more sensitive and specific testing (biomarkers) for thyroid cancer.

This study will investigate the use of circulating cell-free tumour DNA (ctDNA) in the diagnosis and monitoring of thyroid cancer. It will build on the pioneering work already done at the Leicester Cancer Research Centre using ctDNA in the diagnosis and treatment of lung, breast and bowel cancer.

The researchers will be studying the DNA of each person’s thyroid cancer to look for mutations that have occurred in their cancer. Using these findings, researchers will design a bespoke blood test for each patient to look for this mutation-containing ctDNA in their blood. They will then track the levels over time to see whether this ‘liquid biopsy’ can detect recurrence of thyroid cancer. It has the potential to detect worsening cancer before it is shown on the scans and to guide treatment choices, individualised to the patient.

We asked Dr Levy about his research study:

Why there is a need for a more sensitive biomarker for thyroid cancer?

Currently, the blood tests we have available to monitor patients with thyroid cancer are not perfect. For example, thyroglobulin levels are often used to detect the presence of thyroid tissue after thyroid surgery or radioiodine treatment. However, these are not always reliable in patients with more aggressive tumours and levels might be falsely low due to the presence of antibodies in about one in three patients. Calcitonin is another blood test that is used to monitor patients with medullary thyroid cancer. However, calcitonin levels can also be raised in other conditions like infection, kidney disease and other types of cancer. Furthermore, calcitonin levels vary with the patient’s age, gender and level of physical activity and therefore can be difficult to interpret.

What is the aim of the study?

We will investigate the use of circulating cell-free tumour DNA (ctDNA) in the diagnosis and monitoring of thyroid cancer. CtDNA is released into the blood from all cells in the body, including cancer cells. We will be looking closely at the DNA of each person’s thyroid cancer to look for mutations that have occurred specifically in each individual’s cancer. Using what we find, we will then design a bespoke blood test (‘the magnet’) for each patient to look for this mutation-contacting ctDNA in their blood. We will track the levels over time and see if this ‘liquid biopsy’ can detect recurrence of thyroid cancer and track changes in the cancer over time. We will also look to see whether the mutations we find can help choose treatments for individuals to help make the medicines we offer patients more precise.

Can you explain about circulating cell-free tumour DNA (ctDNA)?

All cells in the body are made up of DNA which provides the building blocks of life. DNA sits in the nucleus of the cell, which is in the centre where this code resides. DNA is made up of a huge library of information that tells each cell what to do. Each cell has a different function because different sequences of DNA are switched on and off in different parts of the body.

When new cells are made, the DNA is copied from the old cell into the new cell and should be identical. But sometimes this copying goes wrong and mistakes are made, similar to misspelling or a sentence stopping too soon, which then affects the function of the cell, usually for the worse. This abnormality in DNA copying is called a ‘mutation’. Cancers develop usually because of the accumulation of mutations and as a result, cells do not know when to stop growing and go out of control.

It is possible to biopsy a cancer to diagnose it and see how bad it is, and with new powerful techniques, we can look at the sequence of DNA within the cancer to see exactly where the abnormal sequence of DNA (the mistakes) differs from normal cells. Using this information, we can also sometimes try and predict what molecular treatments the specific cancer would respond to.

Because cancer cells break down and release DNA into the circulation just like all cells, we are able to find the DNA from the cancer as it looks different to the rest of the normal DNA fragments in the blood. This is like looking for a needle in a haystack but because we know the exact sequence of DNA from the biopsy specimen, we can find it by designing a special tool, something akin to a special magnet. Our laboratory is well known for this technique, having a proven track record in other cancers such as breast, lung and bowel cancer, and we have developed techniques to isolate circulating tumour (ct)DNA in a simple blood test that can be taken in a clinic setting. This is often referred to as ‘liquid biopsy’.

This ‘liquid biopsy’ has been shown to be a sensitive and specific biomarker in a variety of cancers that can provide very useful information, for example by detecting worsening cancer before it is shown on scans and changing alongside changes in the tumour over time. The information gained from genetic analysis of the mutations can also be useful in guiding treatment choices.

Has any research already been done in this area?

The use of ctDNA has not been widely tested in thyroid cancer before. The few studies that have been performed only used a selected group of DNA mutations to look for in tumour cells and ctDNA. It may therefore be that the reported accuracy of ctDNA and correlation with tumour behaviour has not been as successful or useful as it could be, because the techniques being used are not as advanced as in our laboratory. We wish to use a more individualised way of detecting ctDNA, looking for mutations that have occurred specifically within each patients’ thyroid cancer and then using these to detect and track ctDNA

How will the research be conducted?

Initially, we will recruit 10 patients with thyroid cancer from our Leicester Endocrine clinic. With their consent, we will monitor their blood samples for ctDNA quantification before, during and after treatment such as thyroid surgery (thyroidectomy) and ablative radioiodine. We will also collect blood at each clinical visit over at least 12 months.

What will the BTF Research Award pay for?

The award will play a vital role in funding our project. The grant will allow us to purchase the necessary consumables and services to conduct our research.

What potential does your work have for thyroid cancer patients in the future?

This potentially provides a non-invasive way of accurately picking up cancer recurrence that is more sensitive and specific than any other current way of doing so.

We hope this work, combined with our work investigating ctDNA in neuroendocrine tumours, will significantly contribute towards more substantial grant applications to develop the technique of ctDNA as a biomarker for thyroid cancer. This project fits well with NHS England’s long-term plan to sequence the DNA of all cancers so we are hopeful it will lead to more funding and ultimately improve diagnosis, and monitoring of treatment of thyroid cancer.

Please see Dr Miles Levy's progress report from July 2023 

Read about past BTF Research Award-funded studies

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