IMAGINE IF DIAGNOSING CANCER WAS AS simple as a blood test. Dubbed “liquid biopsies,” they analyze the proteins and DNA of cancerous tumors that circulate within the blood. They could allow for an earlier diagnosis, which gives patients the best chance to beat cancer and live longer.
According to the World Health Organization’s International Agency for Research on Cancer, over 14 million people will be diagnosed with cancer globally this year, and 8 million will die from the disease. And yet, many more are surviving. According to the American Society of Clinical Oncology, the majority of people diagnosed with cancer in the U.S. (64 percent) live over 10 years with their disease.
Diagnosing cancers before they grow and spread is key. Many cancer screens are familiar as routine, outpatient procedures, such as mammograms, colonoscopies, and Pap/HPV tests. Other screening tests are available for those at higher risk for lung and liver cancer. Unfortunately, there are many cancers for which there aren’t yet effective routine screens, such as pancreatic cancer. As Anna Jewell, director of operations at Pancreatic Cancer UK, said, “We urgently need to find new ways to diagnose pancreatic cancer earlier, because 80 percent of people with the disease are diagnosed at an advanced stage, when there are very few treatment options.”
The liquid biopsy gathers microscopic clues to identify and describe different cancers. The hope is this diagnostic tool will eventually be able to catch cancer early, before symptoms develop. Of primary importance is that these tests actually detect cancer (the test’s sensitivity) and do not falsely diagnose cancer (the test’s specificity). A liquid biopsy offers physicians a window into the complex makeup of genetic mutations of cancerous tumors. While it has long been known that cancer tumors shed cells and small molecules into the bloodstream, only recently have doctors possessed the analytical tools to detect them. Over the past decade, researchers learned to look in blood plasma for circulating free DNA (cfDNA), and then to apply various techniques to look for tumors or their genetic markers, circulating tumor DNA (ctDNA), in that material. Such information is valuable for doctors to decide which treatments might work best.
What makes the liquid biopsy a powerful tool is its ability to analyze microscopic molecules of DNA or RNA in the blood. Pathologists or laboratories analyze cfDNA through genomic analysis and distinguish one type of cancer from another. Even though DNA is microscopic, it contains billions of bits of information that require a lot of time and computing power to analyze.
New analysis methods, dubbed next-generation sequencing, have made the liquid biopsy possible. Sequencing pioneer Nick McCooke, formerly of Solexa, recently spoke to Labiotech.edu about this new science. “If you want to use conventional sequencing in diagnostics … it’s a long and complicated process that can only be done in a specialized laboratory with skilled operators,” said McCooke. “It takes days.” Next-generation sequencing takes hours, using a process where analysis is done in parallel and ultimately at a lower cost.
Could the liquid biopsy replace the tissue biopsy? Maybe, but not yet. Tissue biopsies remain the gold standard of cancer diagnosis, providing valuable information about tumors, which guide treatment decisions. Typically, a doctor removes tumor cells or tissue by needle aspiration, incision, or by endoscope. The tissue is examined under a microscope and undergoes tests to reveal information about a tumor. But there are downsides to this technique.
Tissue biopsies are more invasive due to their surgical nature. The procedure may require anesthesia, which comes with risks. Incisions take time to heal. Further, some tumors are hard to access, hidden deep within the body. Such tumors cannot be readily biopsied. Finally, patients may not tolerate having repeat tissue biopsies to judge the effectiveness of treatment over time.
Medically speaking, the hope for less-invasive liquid biopsies is that more and more sophisticated analytical methods will eventually detect cancer via blood sample, even in its early stages. For now, only one liquid biopsy test for non-small-cell lung cancer has been approved by the FDA. And the overall theory has only been tested in controlled study conditions, so such tech won’t be coming to doctors’ offices right away. Liquid biopsies will likely complement tissue biopsies for a while to come, rather than replace them outright.
But beyond clinical considerations, cost is another reason that effective liquid biopsies would be so attractive. Financial considerations are particularly important in ensuring access to quality cancer care. Developing nations shoulder a greater burden of mortality due to limited access to cancer detection technology and pathology services, according to the World Health Organization. Early diagnosis reduces costs of cancer treatment, so simpler detection methods could mean more effective treatment for more people.
Researchers at Johns Hopkins University announced a major advance in creating a single liquid biopsy to detect multiple cancers. The team developed CancerSEEK, a blood test that can detect eight types of cancer responsible for the majority of deaths in the United States. The team used the blood test on 1,005 patients who had confirmed cancers of the ovary, breast, lung, stomach, pancreas, colon or rectum, stomach, and esophagus. These cancers hadn’t yet spread (in other words, they were nonmetastatic) and were at stages I, II, or III.
According to results published in the journal Science, CancerSEEK was able to detect cancers at least 69 percent of the time, and this included ovarian, pancreatic, liver, stomach, and esophageal cancers— notoriously difficult to spot. Especially heartening was that the test detected ovarian and liver cancer correctly 98 percent of the time. These cancers aren’t often caught early, because patients may have few symptoms.
Also encouraging was the low false-positive rate (under 1 percent), which means few people would be forced to undergo difficult and unnecessary cancer treatment. “Very high specificity was essential because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” said Kenneth W. Kinzler, PhD, professor of oncology and co-director of the Ludwig Center at Johns Hopkins.
The team is eager to move the test into further trials, so it moves closer to real-world use. “A test does not have to be perfect to be useful,” lead researcher Dr. Nickolas Papadopoulos told Science. Even so, while the CancerSEEK results garnered national headlines, there is still work to be done before wider testing and use. For example, CancerSEEK was less effective in detecting cancer at its earliest stages, the most critical time to halt disease progression and metastasis.
Another ambitious effort is the Silicon Valley start-up Grail, which spun out of the biotechnology company Illumina. Grail has been mounting large studies to develop a single blood test capable of detecting any kind of cancer. The company has raised $1.1 billion for its research. Other companies developing their own liquid biopsy technologies include Genomic Health, Guardant Health, Roche AG, and TrovaGene Inc., according to Fierce Biotech.
While there has been progress, many physicians are urging caution—especially in light of the fallout from the collapse of Theranos, an early and well-funded med-tech company with a focus on experimental blood testing. The leading oncology expert groups, the American Society of Clinical Oncology and the College of American Pathologists, issued a joint release in March of this year saying the liquid biopsy is not ready for routine clinical practice. “There is very significant potential for many different applications of ctDNA tests in the future,” said Dr. Jason Merker, a physician representing the College of American Pathologists. “However, we need to make sure that we develop the body of evidence as part of clinical trials to support these applications in various tumor types. This is critical to ensure that we are providing the best care for our patients.”
Caution is certainly warranted, but the general sentiment is that earlier diagnosis for many cancers is visible on the scientific horizon. The positive results from CancerSEEK and significant investment in companies like Grail will encourage more advanced research, quite possibly yielding results that will save lives in the very near future.