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For many years, the only way to get a definitive cancer diagnosis has been through tissue biopsy. Doctors take a sample directly from the suspected tumour and look at the tissue through a microscope to look for cancer cells. Depending on where the suspected tumour is located, a tissue biopsy might involve surgery or another invasive and painful procedure. In some cases, doctors need to take repeated biopsies if the cancer returns or if a treatment fails, and the patient is exposed to the risks of tissue biopsy again and again.
Tissue biopsy, important as it is for cancer diagnosis, is not used for early detection of cancer. Usually, an individual has already started to notice symptoms of something unusual, and potential tumours need to be large enough that doctors will be able to find them in order to get a biopsy.
Yet, we know that early detection of cancer is very important, because when cancer is found at an early stage, treatments are usually less aggressive and more effective. In some cases, a tumour can be removed with surgery, with no chemotherapy or radiation needed. Survival also tends to be higher when cancer is diagnosed early.
One potential way to improve early cancer detection is through liquid biopsy, which looks for signs of cancer in blood or other bodily fluids. This approach is already used in some cases to get information about a tumour that has already been diagnosed, but research is progressing to a point where the technology may be able to be applied to early cancer detection or even screening. This approach holds a lot of promise for cancers like those of the lung and pancreas, which are currently often diagnosed at later stages, and it has the potential to save many lives.
What is a liquid biopsy?
A liquid biopsy looks for signs of cancer in a person’s bodily fluid – most often blood, but also urine, saliva, semen or other fluids. A significant benefit of using these fluids is that they can be easily accessed and collecting them is generally quick and “non-invasive,” causing relatively little pain or discomfort.
In recent years, research into liquid biopsy has flourished. While it isn’t routinely used for cancer diagnosis yet, it is starting to be used in people who have already been diagnosed with cancer for a couple of purposes:
Monitoring whether a cancer is growing. Liquid biopsy is a relatively quick and easy test, especially compared to a tissue biopsy, and doctors do not need to access the tumour directly to get information about the cancer. As a result, doctors are able to take multiple biopsies over time and monitor whether a tumour is continuing to grow, which allows them to learn in real time whether or not a treatment is working and change approaches if necessary.
Identifying the tumour’s genetic mutations. Because liquid biopsy looks for signs of cancer that have come directly from the tumour, some tests can analyze the tumour’s genetic material. Researchers and doctors may be able to use this analysis to learn the genetic mutations present in the tumour, understand its aggressiveness and likelihood of spreading, and even recommend treatments that work against specific genetic mutations.
These same reasons are what make researchers excited about the potential of using liquid biopsy for early cancer detection. “Liquid biopsy is already being used for treatment selection, but the applications for it will expand,” says Dr Shana Kelley, a professor and researcher at the University of Toronto who leads research developing liquid biopsy technology. “Clinical data is showing that it is a very powerful tool, and technology is advancing very rapidly and becoming more sensitive.”
At this point, there are still some significant hurdles to overcome in order to develop a reliable and practical early cancer detection and screening test:
Sensitivity: The technology that detects cancer in the blood needs to be highly sensitive to the presence of cancer to reduce the risk that it will miss some. It needs to be able to detect the smallest amounts of cancer in the blood if it is going to be used when there are no symptoms.
Precision: The test must also detect signs of cancer, also known as markers, that are highly specific and do not signal any other condition, in order to reduce the risk that it will misdiagnose people who do not actually have the disease.
Variation: Cancers can be immensely different from each other – not just different types of cancer, but also the same type of cancer in different people, and even different cells within the same tumour. These differences make it difficult for researchers to develop a practical diagnostic test that relies on identifying only a small set of cancer signals to make a diagnosis.
As research progresses, though, scientists are coming closer to solving these technical challenges. “The main challenge is that the markers of cancer are really quite rare. We could get billions of normal cells in a sample and just one cancer marker,” says Dr Kelley. “We have to push technology to be very sensitive and very specific and find a way to get a strong cancer signal even in the presence of a lot of background noise.”
With Canadian Cancer Society funding, Dr Kelley and her team developed a device that uses a microchip to detect signals in a drop of blood when cancer is present. Over the last couple of years, they have been refining the system to look for more cancer-related genetic mutations and have also made adjustments so that the test is faster and more cost-effective. These are important considerations if the test is going to be used regularly in a clinic.
Developing and refining the technology that detects cancer signal is critical. At the same time, researchers are also studying the cancer markers that the technologies are built to detect – what these tests actually look for that alerts them that someone has cancer. A variety of markers exist that give different kinds of information and are better fits for different types of cancer. Three well-studied examples are circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and exosomes.
Circulating tumour cells (CTCs)
As a tumour grows, it releases whole cells that enter the bloodstream and travel around the body. These cells, called circulating tumour cells (CTCs) can be detected in a blood sample and indicate that cancer is present.
Using current technology, researchers are able to count CTCs to learn about the cancer, how advanced it is and whether it is growing or spreading. A test approved by the US Food and Drug Administration (FDA) and Health Canada called CellSearch counts CTCs in patients with advanced breast, colorectal and prostate cancers. By measuring CTCs at different time points, for example before and after starting treatment, doctors can get an early picture of whether a particular treatment is working.
There is potential, though, to use CTCs for early cancer detection, since CTCs may be present in the blood even before someone has cancer symptoms.
One study looked at whether CTCs could signal the presence of lung cancer in people with Chronic Obstructive Pulmonary Disease (COPD), a condition that greatly increases a person’s risk of lung cancer. The researchers looked for CTCs in people with COPD who had no detectable lung cancer. A small number of people in their study were found to have CTCs and were monitored closely, and each of these people developed lung cancer between 1 and 4 years later. Because these participants were monitored so closely, in each case the tumour was diagnosed at a very early stage when it could be removed with surgery and needed no further treatment. Importantly, none of the participants with no detectable CTCs developed lung cancer 5 years after the study started. These results demonstrate that CTCs may have value for early cancer detection in a high-risk group, even when there are no symptoms of cancer.
Current technology looks at the counts of CTCs, but as research progresses, researchers may be able to gain so much more information about the tumour from these cells. They contain the same genetic and biological material as the tumour, so researchers might be able to identify the genetic mutations and other features of a cancer through these cells. They could learn about how aggressive a tumour is, whether it may be resistant to certain treatments, and whether there may be targeted treatments that could work on that particular tumour.
Circulating tumour DNA (ctDNA)
As cancer cells die, they release fragments of their genetic material into the blood, which is known as circulating tumour DNA (ctDNA). These bits of cancer DNA can be detected by specialized equipment and alert researchers to cancer’s presence.
Similar to CTCs, ctDNA can be counted to determine whether cancer is present and how much cancer there is, but researchers are most excited by its potential to provide more detailed information about the tumour.
Some tests detecting ctDNA are used in the clinic already, but these applications are only used in people with a known cancer diagnosis. For example, one test screens ctDNA from people with advanced cancer to look for mutations in a selection of genes that could be treated by available drugs that target those mutations. This test is used when material from a tissue biopsy is unavailable or does not give this level of detail. Another test is used in lung cancer to look for mutations in one specific gene called EGFR, indicating whether EGFR-targeted drugs could work against the cancer.
Building on these tests, researchers are working on ambitious projects to use ctDNA for early cancer detection.
Early this summer, researchers from New York presented results from a clinical study that demonstrated a new technology with promising potential for cancer screening. The researchers tested a technology that is more extensive and accurate than previous tests, scanning ctDNA for mutations in more than 508 genes. The researchers compared ctDNA mutations found in the blood of people with advanced breast, lung and prostate cancers with mutations found in DNA directly from the tumour tissue. In 89% of patients, at least one mutation identified in the blood sample was also identified in the tumour tissue, demonstrating that the test is able to detect tumour mutations accurately and has potential for cancer screening. While the test still needs to be refined and tested in larger groups of people, this was a major step forward in showing that it may be possible to use ctDNA for cancer screening.
Cells commonly pinch off a part of themselves, creating a bubble-like structure called an exosome. Exosomes have a variety of biological uses, including communication between cells and transporting waste from cells. When a cancer cell pinches off an exosome, it contains fluid from the cell, along with genetic material and proteins. While most cells, healthy or unhealthy, secrete exosomes, researchers have found that cancer cells tend to release far more. They can also be detected and measured in body fluids, similar to CTCs and ctDNA, as a signal that cancer is present.
Exosomes from cancer cells can be detected in a variety of bodily fluids, not just blood. For example, a cancer located close to the mouth could potentially be detected by exosomes in saliva, or a cancer developing close to the urinary system (e.g., bladder) could potentially be detected in urine.
Because exosomes contain a variety of components, researchers are exploring different strategies for using exosomes as a signal of cancer:
Genetic material: Similar to CTCs and ctDNA, genetic material in cancer exosomes can provide information about the tumour. One study looked at exosomes released from the brain cancer glioblastoma. The study found a subset of people with the disease had exosomes circulating in their blood that contained a distinct genetic marker that has potential to be used for improved diagnosis.
Proteins: In a study of exosomes in pancreatic cancer, researchers found that a protein located on the surface of exosomes was a highly specific marker of the disease. The protein, called GPC1, could identify people with pancreatic cancer, even among people with other pancreatic diseases. It could also provide information about tumour stage and even survival.
Challenges of liquid biopsy for finding cancer early
Despite the differences in each of these cancer markers, the main challenges to using them for early cancer detection are highly similar.
Tumour markers are very rare in the blood. Regardless of the specific marker, each one is present in low concentrations when a person is known to have cancer, and at even lower concentrations in someone with an early stage cancer that has not yet given rise to symptoms. Blood contains cells, genetic material and exosomes even when a person is healthy, and it can be very challenging for current technology to pick up on a cancer signal amid the background noise.
Tumours have many different types of cells and a variety of genetic mutations. Far from being a collection of identical cells, tumours actually have many different cells that may have a variety of genetic mutations depending on where in the tumour they were located and how the tumour has evolved. Genetic material from one CTC, ctDNA or exosome may not be completely representative of the entire tumour.
While these are significant challenges, they are not insurmountable. Researchers are developing technology, and in some cases using nanotechnology, that is more sensitive and able to separate cancer signals from background noise, allowing detection of cancer material at ever lower levels in the blood. With continued investment and support for this emerging research, we will continue to see progress.
Conclusions and future research
Liquid biopsy has a variety of uses, and though using it for early cancer detection may be years away, it holds a lot of potential. “Screening is a big unmet need,” says Dr Kelley. “We’ve made significant progress with cancer treatment, but many of the treatments are best for early-stage cancer, not advanced tumours. We really need new screening tests for cancer.”
Significant technical challenges need to be overcome to address the sensitivity and specificity of potential screening tests, but as genetic sequencing and computerized analysis improve, we are likely to see these methods being studied in clinical trials. Trials comparing liquid biopsies to current methods of cancer detection require many people to participate and are difficult to coordinate, but they are necessary to demonstrate that the new methods are effective.
These challenges, though, are worth the effort. “People already diagnosed with cancer will get much more tailored treatments if liquid biopsy can be used to monitor them,” says Dr Kelley. “And all the people who have not been diagnosed and who are at high risk could be screened more effectively. They wouldn’t have the uncertainty hanging over their heads.”
For cancers that have traditionally been hard to diagnose at early stages like lung, brain and pancreatic cancers, liquid biopsy may be a life-saving technique. For this to happen, more research is needed to improve the technology to a point where it is fast and cost-effective, as well as accurate and sensitive.
Eileen Hoftyzer, BSc, and Carolyn Goard, PhD