A tumor is not an isolated island in the body. Regularly, small pieces are released, which end up in the blood, urine or other body fluids. These pieces could be entire tumor cells, but also separate DNA fragments from the tumor. The latter is also called cell-free DNA. John Martens, professor of translational genomics of cancer, has devoted his scientific career to detecting these tumor fragments, with the aim of drawing conclusions about the course of the disease or determining the right choice of treatment.
Martens’ research revolves around liquid biopsies which involves taking a sample of blood or another body fluid regularly from cancer patients. Liquid biopsies are derived from the “classic” biopsy, in which the tumor is punctured with a needle. This is a painful and stressful procedure and not a viable option for all patients. Consider, for example, patients with tumors or their metastases in the brain or lungs: organs that are difficult or impossible to reach with a needle.
Moreover, it is mostly simply not justifiable for a patient to undergo multiple biopsies, while practitioners like to know how the tumor develops during treatment. Liquid biopsies do not have such problems, Martens believes. ‘They can easily be drawn more than once, because they are not considered to be too burdensome. Moreover, we know that liquid biopsies are often just as informative as the classic variant, and sometimes being even more informative.’
However, detecting tumor cells or cell-free tumor DNA in such a liquid biopsy is not an easy task, Martens explains. ‘We usually start with a standard 10-milliliter blood tube. This contains only few tumor cells among billions of blood cells. The same applies to cell-free tumor DNA: of all the cell free DNA fragments in the blood, often less than 1 percent originates from the tumor.’ For the detection of tumor-specific properties, you therefore need very sensitive equipment and detection methods.
The Erasmus MC Cancer Institute has ultra-sensitive devices to detect tumor cells and fragments thereof in liquid biopsies. By mixing the liquid biopsy with a tumor-specific antibody coupled to small iron beads, scientists can selectively fish the tumor cells from the blood using a strong magnet. Martens: ‘With a second device, we can even get our hands on pure tumor cells and look at individual tumor cells in great detail.’
Liquid biopsies are often just as informative as the classic variant, and sometimes even more informative
Meanwhile, Martens and his group are even going a step further. They take liquid biopsies from cancer patients before start of treatment and after treatment failure. ‘This allows us to find out what genetic changes occur as a result of the treatment. We are also trying to grow tumor cells outside of the body so that we can test drugs on them.’
For colon cancer patients, a liquid biopsy potentially means they can be spared from non-effective treatment, Martens and his team discovered. ‘With a liquid biopsy for tumor DNA, we can determine in advance, at a personal level, whether someone is eligible for treatment with the drug cetuximab. If not, we can spare someone from undergoing an ineffective treatment. This is because we already know that cetuximab only works in tumors lacking certain gene mutations that cause resistance to the drug. In the study we found that in a liquid biopsy we can determine in advance whether the tumor carries such a resistance causing mutation or not.’
The liquid biopsy turned out to give even more information about colon cancer than the current routine diagnostics using tumor biopsies. ‘The additional advantage of a liquid biopsy is that we can take blood regularly to monitor how the colon tumor responds to the treatment. We know that a tumor cell continuously adapts to its environment and, as a results can become resistant. Our study showed that in the blood, we can observe whether this happens and even which resistance mechanism the tumor utilizes to escape sensitivity to a cetuximab, which might be useful for the next treatment to follow up with.’
For patients with lung cancer, a liquid biopsy is now since 2016 a standard part of the diagnosis. This means that liquid biopsies have – for the first time in the Netherlands – taken the step from Martens’ research laboratory to the diagnostic laboratories and consulting rooms of the Erasmus MC Cancer Institute. From every patient who qualifies for targeted therapy with EGFR inhibitors, blood is taken for a liquid biopsy. Upon progression, treatment is adjusted based on molecular research performed on the liquid biopsy.
The story of liquid biopsies has only just begun
This application is just the beginning, Martens believes. There are also possibilities in the field of early detection of cancer and its metastases. Martens: ‘Even before someone develops symptoms, tumor DNA may be present in the blood. In the future I can imagine liquid biopsies being used as a screening as well as a monitoring instrument. Based on the characteristics of the tumor DNA found, it should then be possible to determine which organ the tumor DNA originated from and what treatment is most appropriate.’
The story of liquid biopsies has only just begun, Martens believes. ‘Fifteen years ago we started with one PhD student, but now at the Erasmus MC Cancer Institute alone there are already more than twenty researchers working on this subject. And this research field and the number of applications for it are only increasing.’
Watch the video below for more information about liquid biopsies as innovative biomarkers.