What if colon cancer screening didn’t involve poop?

From the NEJM data, Guardant’s Shield blood test had an 87.5 percent sensitivity for stage 1, 2, or 3 colorectal cancer, which passes the CMS threshold. But it has only a 13.2 percent sensitivity for advanced precancerous lesions. The fecal immunochemical test can detect these advanced precancerous adenomas with a sensitivity rate of around 20 to 30 percent. Cologuard, which combines FIT with stool DNA detection, has a 42 percent sensitivity for adenomas. Colonoscopies can detect adenomas larger than 6 millimeters with a 75 to 93 percent sensitivity. (Small polyps or outgrowths are usually harmless, and 6 millimeters is the standard lower limit for identifying advanced adenomas that are likely to grow into cancer.)

Detecting and cutting off such advanced adenomas is key to preventing colorectal cancer from developing. “If you can only detect cancer and you can’t detect pre-cancer, then it’s not going to be as effective,” Hur said.

Colon cancer forms on the interior surface, or lumen, of the colon “tube,” Hur explained. “As the stool is created, it sloughs off cancer cells or blood. If you’re trying to look for some type of cancer cell, circulating tumor cells, or DNA from a cell, stool is much better [than blood]. In order for it to be picked up by blood, it has to go into the bloodstream. Early cancer hasn’t invaded through the wall of the colon.”

Early detection matters because the more time a cancerous cluster of cells has to grow and spread, the harder it is to treat and cure. The five-year survival rates for colorectal cancer plummet drastically as it progresses past stage 3, falling from roughly 70 percent in stage 3 to 12 percent in stage 4. According to the American Cancer Society, stage 3 is when the colon cancer has spread to nearby lymph nodes, but not to other parts of the body. Stage 4 is when it is metastatic, and has spread to other tissues and organs in the body.

According to Lieberman, CMS didn’t set any minimum sensitivity rate at which new blood tests need to find advanced precancerous adenomas in order to approve them for coverage. In an email statement to Vox, a CMS spokesperson said that while they acknowledge the utility and potential clinical benefit of screening for advanced adenomas, there is limited available evidence on the accuracy of blood-based tests to detect advanced adenomas. The agency noted the sensitivity of fecal tests for advanced adenoma is also fairly low. For now, to maximize early pre-cancer detection, colonoscopies remain the best option for patients.

Experts believe that blood tests will become more accurate as science advances. But how much they can be improved will dictate their long-term value to medicine.

Some of that depends on the kind of cancer doctors are looking to find. Unsurprisingly, for liquid tumors that affect the blood, bone marrow, or lymphatic system, an early-detection liquid biopsy “totally makes sense,” Hur said. “The tumor is in the bloodstream.” But it’s unclear whether or not a liquid biopsy will ever be sensitively attuned enough that it will be able to consistently detect an adenoma inside a person’s colon.

There could be a scenario where scientists can identify a more specific immune response to a growing polyp that can be targeted with a blood test. But that carries a risk of more false positives, since a wide range of conditions, including something as innocuous as a cold, could trigger a similar immune response. Inflammation is our immune system’s response to trauma or the presence of a pathogen such as a virus, bacteria, or toxin. Scientists have known since the 19th century that cancer can cause an inflammatory response that sends specialized immune cells into disarray. Elevated white blood cells are a telltale sign of all kinds of infection, but they can also be a sign of leukemia.

Despite the hype, experts caution that additional research is needed to improve liquid biopsies. If scientists can learn more about the biology and genomics of tumors, they could identify more specific biomarkers or a combination of biomarkers that could make these tests more accurate and therefore more valuable.

Lieberman acknowledged that scientists are becoming more sophisticated in how they analyze the genomes of cancer cells, which means they could identify more genes that are present in patients at higher risk of colon cancer, and that can be detected before the cancer starts to develop.

“This is still a ripe new area for development,” he said. “I think this first [Guardant] study is exciting in the sense that we can detect cell-free DNA in patients with colon cancer at an early enough stage that it can make a difference for those individuals.”

In the long run, blood might not always be the most revealing substance circulating through the human body when it comes to finding early markers of disease. The accuracy of blood tests will likely vary based on the type of cancer and the organs in which they’re located. For cancers in which blood tests are less effective, the goal is still to develop less invasive diagnostics, but the mechanism might be different.

Urine is also being investigated for its potential to detect circulating tumor DNA in urological and non-urological cancers. It has already shown promising sensitivity rates for non-small cell lung cancer and breast cancer in clinical trials. In an April study in JAMA, a urine test that scans for 18 genes showed a 95 percent sensitivity in patients with more aggressive prostate cancer. In January, a urine-based test using bioengineered bacteria was able to detect colorectal adenomas in mice.

Despite the limited utility of the current tests, the pursuit of better liquid biopsies is unlikely to slow down because they continue to hold enormous theoretical potential. For cancers with no established screening tests at all — like pancreatic cancer, which has an average five-year survival rate of 13 percent — a viable blood test with clinically significant sensitivity for early signs of disease would be a game-changer.

Earlier in April, a new study presented at the American Association for Cancer Research's annual meeting found that an exosome-based blood test combined with another protein as an added biomarker identified stage 1 and stage 2 pancreatic cancer with 97 percent accuracy. Cells use tiny vesicles called exosomes to communicate with one another, and they’re commonly shed by both cancer cells and healthy cells. Researchers developed a signature associated with pancreatic cancer based on eight microRNAs “uniquely found in exosomes shed from pancreatic cancer” and five cell-free DNA markers found in the blood of patients with pancreatic cancer, according to AACR.

An advantage of these noninvasive blood and stool tests is that they’re a relatively cheap way to get a lot of people screened. However, much of the value of these tests is lost if patients who receive an abnormal result don’t follow up with a colonoscopy to confirm whether or not they have cancer.

“The Achilles’ heel of noninvasive testing is that many patients don’t follow up and get the colonoscopy after they get a positive stool test,” Lieberman said.

A 2023 study in JAMA found that only 56 percent of patients followed up with a colonoscopy after receiving a positive stool-based test. “We don’t really know yet what it will be like with a positive blood test,” he said.

Even with the limitations, there are upsides to having a blood test as another screening option. Prepping the bowels in the lead-up to a colonoscopy is unpleasant and inconvenient, requiring a special preparation for days before the procedure. And too often, people avoid them altogether — the US adherence rate for colorectal cancer screening guidelines is around 65 percent. With the recommended age for colorectal cancer screening recently dropping from 50 to 45, there may be more demand for a less invasive test.

Fast and easy blood tests, along with proper education on the importance of screening for colorectal cancer, could also be beneficial in regard to achieving health equity. Colon cancer deaths, estimated by the American Cancer Society to reach 53,010 in 2024, are highest in Black patients, and screening rates are lower compared to white patients.

“There’s an expression in colon cancer screening: The best colon cancer screening test is the one that gets done,” Hur said. “There’s potential to do good. ... People want this ... They don’t want to do the scope test. But people just need to know what they’re getting.”