When liquid biopsy was first introduced in 2010, it was hailed as a revolutionary way to guide cancer treatment. Now, 14 years later, liquid biopsy still holds great promise, including for early cancer detection, but understanding its place in cancer care and its limitations is essential.
What Liquid Biopsy Looks For
Oncology, or cancer care, can be parsed into three broad categories: prevention/detection through screenings, curative intent with the goal of eradicating the cancer, and treating people most effectively though cure isn’t possible. Liquid biopsy can provide different types and degrees of information about someone’s cancer throughout this continuum of care.
Quite simply, a liquid biopsy uses a blood sample as opposed to a tissue sample (the traditional form of biopsy) to detect the presence of cancer and that cancer’s characteristics, or markers. This is possible because tumors shed cells that circulate in the bloodstream. Tumor cells and normal cells shed free floating “naked” DNA into the bloodstream. We’ve known this for some time but didn’t have technologies to act on it until relatively recently.
The first liquid biopsy tests looked for circulating tumor cells or CTCs. These are cells that come directly from the tumor. Historically, it’s been hard to retrieve a lot of them from a few tubes of blood unless the cancer is in a metastatic stage, so that’s when this test is more likely to be used these days.
Used more often are tests that look for cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA), which is cfDNA derived from tumor cells. These tests allow us to look for mutations without taking another tissue biopsy, which typically is still used initially to diagnose a tumor. Cancer is really a disease of DNA mistakes—or DNA gone bad—and by isolating the DNA mutations we hope to find that cancer’s Achilles heel, the faulty DNA we can target. Through clinical trials, we know that there are some specific mutations that we can attack with targeted therapies while sparing normal cells. That’s the ideal scenario. In real life, it’s not as clean-cut. Most of our drugs will have off-target or side effects. But still, there’s a lot of really amazing information found in liquid biopsy tests that we can act on.
Other Uses
Cell-free DNA tests have other important current uses. The technology has revolutionized genetic testing during pregnancy because we can sequence fetal DNA from mom’s blood and look for genetic mistakes that used to require testing with invasive procedures like amniocentesis or chorionic villi sampling. It can also be used to detect the earliest signs of rejection of a transplanted organ, such as a liver, based on the cells that organ sheds, since DNA from the donated organ is distinct from the DNA of the receipient.
Liquid biopsy can also be used to assess how well cancer treatment has worked. For instance, it can show the existence of microscopic disease, which isn’t visible on a PET or CT scan. Once we can see evidence on a scan, it’s not going to be curable for the most part. However, if we detect microscopic disease only (negative scans but positive ctDNA), usually this indicates that the cancer is likely to return. The limitation here is that we don’t have clear direction yet on what to do about that finding. On one hand, there’s the opportunity for potentially curing more patients. On the other, we don’t always know what additional therapies are needed because we’d be treating a number on a blood test rather than disease we can see. Also, even if we had a possible treatment, there’s the question of whether insurance would pay for it in this situation.
At the other end of the spectrum, the test might be negative for any signs of cancer, indicating there’s a high likelihood that a person is probably cancer-free. But we don’t yet know how definitive that is. Could it come back later on? How often should we retest—every three months, six months, yearly? These are questions we’re grappling with right now in oncology.
Finding Cancer Early
Because we can see evidence of cancer in a liquid biopsy, there’s a lot of interest in using it to find signs of cancer in its earliest stages. The Galleri test, for instance, is a first attempt at preemptively identifying what we call pan-cancer or all cancer types using cfDNA/ctDNA, no easy feat because cancer types are so different. Galleri is a cfDNA/ctDNA methylation test: It aims to detect which organ or tissue the cancer is coming from by looking for abnormal patterns of what’s called methylated cell-free DNA (denoted by carbon-hydrogen molecules that attach to DNA) in an otherwise healthy person. If it finds early warning signs, that’s an indication to get a diagnostic workup. But it’s not foolproof. It does a better job at pinpointing the organ the cancer’s coming from than the stage of the cancer. One study found it detected just 39 percent of stage 1 cancers. There have also been false negatives, meaning it didn’t find cancer that was already present. (Galleri costs close to $1,000 and is not covered by insurance.)
To determine whether tests like Galleri are sensitive enough and specific enough to be truly useful involves the type of study that can take decades. That being said, there are academic institutions that have developed methylation tests using their own technology. At the University of Toronto, for instance, they’re currently looking at families who are known to have familial inherited cancer syndromes like BRCA-1 or BRCA-2, following and screening them to see whether or not methylation cfDNA/ctDNA tests can detect these cancers and make a difference in their outcomes.
Clinically, the current situation is a bit like the wild, wild west, meaning that we don’t have great data that liquid biopsy screening is actually going to affect outcomes in terms of cancer survival. And that’s why there’s a big push right now toward personalized screening. For instance, rather than universally testing every man for prostate cancer, we should test those at the highest risk, with elevated PSA and a family history, and the same for women with a family history of breast cancer.
