Beth Rogoyski
Most would consider a blood test a bit of a pain in the arm, but except for the fantastically needle-phobic, generally not something that would keep you awake at night. Contrast that to the sentiments that spring to mind when you hear the word chemotherapy, and the two couldn’t seem more dissimilar. Despite being at opposite ends of the medical spectrum, however, the two are finding overlap in the way we diagnose and treat cancer. Older chemotherapies simply work by poisoning fast-growing cells in the body; whilst this generally includes cancer cells, it also includes hair follicles (the tiny sacs that surround the root of hairs), and the stomach lining, which causes the characteristic hair-loss and sickness usually associated with cancer treatment. Emerging personalized medicine, further stratified with precision blood testing, is starting to eliminate these side-effects by utilizing drugs designed to exclusively target cancer, whilst leaving healthy cells unharmed.
AN UNWELCOME CHANGE
As previously mentioned on OncoBites, changes or mutations in certain parts of our DNA allow our cells to bypass the normal controls that would ordinarily keep them healthy, resulting in the unregulated growth and activity that we call cancer. Therefore, by definition, cancers must acquire properties that give them abnormal abilities, such as the ability to replicate indefinitely or remain hidden from our immune system. The mutations that allow them these seemingly death-defying properties, however, also have the potential to mark cancer cells out as dangerous and target them for precise medical destruction.
Whilst precision medicine is already changing the way we treat cancer, prevention is better than cure, and catching cancers early is key to improving survival. Using the same distinctive pro-cancer mutations that can target drugs to destroy dangerous cells, emerging blood tests are also working to pick up traces of these mutations in circulation, and diagnose cancer, long before a patient realizes anything is wrong.
AS GOOD AS GOLD
Despite being characteristically red, the majority of blood is composed of a golden-colored plasma, containing water, proteins, nutrients, hormones, amongst other constituents and debris. To remain healthy, normal cells will self-destruct if they become too old or damaged, and are subsequently digested, recycled, and replaced. Whilst cancer cells avoid this process and are therefore often referred to as immortal, some still die for their cause, perhaps having failed to migrate and metastasize, leaving behind debris in the plasma. This is one potential source of what is termed “circulating tumor DNA”, or “ctDNA”: fragments of tumor DNA that have been released from dead and dissolved cancer cells into the bloodstream. Like DNA left behind at a crime scene can be used to apprehend a culprit, ctDNA in the blood can be used to catch cancer.
FIRST BLOOD
Picking up signs of cancer in the blood would reduce the need for traditional biopsies, which involve physically removing a sample of the tumor and are often invasive, painful, and time-consuming. A blood-based or “liquid” biopsy not only resolves these issues but also gives a more complete tumor profile. Tumors often comprise an unstable mix of mutations and physically removing a small proportion of a tumor may not fully capture a complete picture of its genetic make-up. However, ctDNA shed into the blood is more likely to incorporate genetic information from across the tumor, which provides more comprehensive information on how to target the whole tumor for destruction, as well as prevent relapse and recurrence.
Despite exponential advances in cancer medicine, several factors still hamper successful treatment of cancer. Late diagnosis due to the slow progression of many cancers, drug resistance, ineffective treatment, and incomplete tumor removal are some of the foremost challenges in treating cancer. A liquid biopsy has the potential to resolve all of these problems.
USUAL SUSPECTS
There is no one region of cancer DNA, or “gene”, that be used universally to detect cancer. However, there are several genes which have a protective role against cancer and are therefore commonly mutated or deleted in cancers. Conversely, some genes which activate mechanisms that can be exploited by cancers, such as growth, blood supply, or migration, which are often found multiplied. Examples of such genes include p53, EGFR, and KRAS, and are found in the majority of cancers; by inspecting the blood for these usual suspects, a liquid biopsy can identify the presence and stage of the tumors.
Very early cancers only shed tiny amounts of DNA, so detecting ctDNA in amongst all the other components of blood is like looking for a needle in a haystack. However, in the recent year, a number of breakthrough experiments have been published which suggests routine liquid biopsies might be closer than predicted. One of the biggest and most ground-breaking of these studies tested eight proteins and over two thousand possible mutation sites in cancer DNA and were able to pick up eight different cancers. Even more impressively, all of the cancers were caught before they spread, making them far more treatable. By detecting ctDNA in blood samples, ovarian and early-stage liver cancer patients were able to be identified and diagnosed almost 100% of the time. However, for other cancers, its use was still fairly limited; in breast and early esophageal the test was only able to identify 30 and 20% of the tumors present respectively – a coin toss would have provided a more accurate diagnosis. Whilst the usage of this test is currently confined to a lab rather than a clinic, it provides one of the first tangible insights in the direction of future cancer medicine and a potential screening strategy for cancers which would otherwise stay undiagnosed. Plus, at an estimated $500, it is offering highly advanced science on a modestly low budget.
IN THE RIGHT VEIN
Early detection of cancer is only one use for liquid biopsies. For patients who have already received a diagnosis, ctDNA can be can be used to monitor and predict treatment response. New generations of precision cancer medicine deliberately target specific cancer mutations and prevent or undo the resulting cancerous characteristic, thereby eliminating the tumor. By identifying the specific combination of mutations, doctors can pinpoint a cancers vulnerability to chemotherapy, and destroy it. On the other hand, some mutations allow cancer to become resistant to a drug, meaning patients could be saved from enduring months of grueling treatment and hospitalization for a treatment that is unlikely to be effective.
In addition to these mutation-treatment pairings, liquid biopsies can be used to give a real-time update on patients’ conditions. Once cancer has been successfully treated through surgical removal or chemotherapy, ctDNA should become undetectable, if it does not, there may still be a residual tumor. By consistently monitoring these factors, we can gauge the success of the medical and surgical intervention in addition to detecting future relapses or acquired resistance, which may render a previously effective treatment as no longer beneficial.
GOOD BLOOD
DNA mutations and consequent cancers are inevitabilities that impact on many lives but armed with a scientific arsenal of understanding, we can use this information against them. Whilst the concept of a liquid biopsy is in its infancy, the science behind it is in its prime. Already seeping into treatment regimens, liquid biopsies have the potential to revolutionize cancer therapy towards personalized precision medicine. Whilst a cancer blood test isn’t yet imminent it may be that in the not so distant future, biopsies will little more than a pain in the arm!
Beth Rogoyski is a Cancer Research UK funded Ph.D. student at the University of Leicester. Beth specializes in chemoprevention, drug-repurposing, and genetics, with a long-standing background in education, outreach, and communication. All illustrations used in this piece are original artworks by her. You can find more of her work at PhDoodles.
Works discussed:
Cohen, J. D., Li, L., Wang, Y., Thoburn, C., Afsari, B., Danilova, L., . . . Papadopoulos, N. (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science, 359(6378), 926-930. doi: 10.1126/science.aar3247
O’Leary, B., Hrebien, S., Morden, J. P., Beaney, M., Fribbens, C., Huang, X., . . . Turner, N. C. (2018). Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun, 9(1), 896. doi: 10.1038/s41467-018-03215-x
Abbosh, C., Birkbak, N. J., Wilson, G. A., Jamal-Hanjani, M., Constantin, T., Salari, R., . . . Swanton, C. (2017). Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature, 545(7655), 446-451. doi: 10.1038/nature22364
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