Consider a simple blood test that may detect most malignancies at their earliest, most treatable stage. For decades, the concept of a “liquid biopsy” has been regarded as the holy grail of oncology. In theory, liquid biopsies may discover a malignancy long before it could be detected by touch, symptoms, or imaging. Blood testing could eliminate the need for surgeons to cut tissue samples from suspected lumps and lesions, allowing them to detect cancer in places where needles and scalpels can’t reach safely. They might also figure out what type of cancer is forming and what treatment would be most effective in eradicating it.
Because it’s difficult to identify definitive cancer signs in a tube of blood, the grail has yet to be found, but progress has been spectacular in recent years. The first large prospective research of a liquid biopsy for DNA and proteins from multiple types of malignancies, undertaken in 10,000 healthy older women, was published in the journal Science last year. Though far from perfect, the Johns Hopkins University-developed CancerSEEK blood test, which was licensed by diagnostics startup Thrive, uncovered 26 cancers that had gone undetected by traditional screenings such as mammography and colonoscopy. An even larger trial, involving 25,000 adults with a history of smoking and a blood test from the audaciously titled Grail, is currently ongoing in London.
Although no multicancer blood test is near to approval, the US Food and Drug Administration has designated CancerSEEK as a “breakthrough device” because of its life-saving potential. This year, some more narrowly targeted blood tests acquired that certification, including one (from Bluestar Genomics), geared at detecting pancreatic cancer in high-risk persons and others that check for glimmers of recurrence in cancer patients who have already been treated. According to Nickolas Papadopoulos, one of the Johns Hopkins experts who developed CancerSEEK, the breakthrough listing “speeds up the evaluation process.”
In addition to tumor DNA and proteins, liquid biopsies can use a range of indicators, such as free-floating cancer cells. “It’s thought that there’s a lot of turnover within a tumor,” says National Cancer Institute cancer researcher Ana Robles, “and as cells die, fragments are discharged into the blood.”
The search is complicated because “if you have early-stage cancer or certain types of cancer, there could not be a lot of DNA being shed,” according to Robles, and testing may miss it. The ideal blood test will be both highly specific (finding a mutation or other signal that can only be cancer) and highly sensitive (finding even small tumors). To address this issue, CancerSEEK searches for cancer-specific mutations in 16 genes and eight proteins linked to cancer for which highly sensitive assays exist. In a trial using an improved version of the test, it detected more than 95% of ovarian and liver tumors, as well as roughly 70% of stomach, pancreatic, and esophageal cancers, but only 33% of breast tumors and only 43% of stage 1 malignancies. Pan-cancer liquid biopsies will need more large, expensive studies to verify their efficacy for early diagnosis.
And detecting anything isn’t the entire goal. A good liquid biopsy will also pinpoint cancer’s likely site, allowing it to be treated. “Mutations are frequently shared among different types of cancer,” says Anirban Maitra, a pancreatic cancer investigator at M.D. Anderson Cancer Center in Houston. To address this issue, some recent liquid biopsies seek for changes in gene expression rather than changes in the genes themselves, such as whether they are switched on or off. Such alterations, according to Maitra, are “organ-specific.”
Liquid biopsies, which can aid those who have already been diagnosed with cancer, are on the horizon. The FDA approved the first two of these tests last year, which scan for tumor DNA to help doctors choose mutation-targeted treatments. Blood tests to detect the first signs of cancer recurrence in people who have completed treatment are being developed by scientists. According to Papadopoulos, the research on “minimum residual illness” is progressing quickly. “Does it save lives?” says the narrator.
That is the question that companies like Thrive and Grail must answer to carry out their large-scale screening tests. A high percentage of false positives or negatives, as well as a proclivity for detecting tumors that are slow-growing and insignificant, will be ineffective. “These businesses must demonstrate that they can detect early cancer and, more importantly, that early detection can affect cancer survival,” Maitra points out. “That is the holy grail of the holy grail,” says the narrator.