Screening can prevent colorectal cancer through detection of precancerous growths, or polyps, which can be removed before they become cancerous. It can also allow colorectal cancers to be detected early, before they cause symptoms and when treatment may be more effective.

Colorectal cancer screening tests. These include colonoscopy, sigmoidoscopy, stool-based tests to detect hidden blood (fecal immunochemical testing (FIT) or fecal occult blood testing (FOBT)), and virtual colonoscopy. (See Screening Tests to Detect Colorectal Cancer and Polyps for more information.)

Despite the availability of effective colorectal cancer screening tests, some people choose not to get screened. Some reasons may be because of the personal nature of the procedures, a lack of recommendation by their doctor, perceived costs or lack of insurance, or the preparation involved for a colonoscopy.

Although not currently recommended for screening, there are new techniques under development such as:

• finding technologies that improve the genetic analysis of stool samples, which may reveal the presence of tumor DNA
• looking at changes in the gut microbiome and trying to identify specific bacteria that could potentially help identify patients at risk for colorectal cancer

Repeat screening or follow-up. The guideline for getting a screening colonoscopy is every 10 years. However, people who have noncancerous polyps detected at colonoscopy are generally asked to return for a repeat colonoscopy earlier than that.

NCI’s FORTE Colorectal Cancer Prevention Trial, is now looking at whether some people with one or two small polyps can wait 10 years before returning for another colonoscopy. By comparing two study groups, one with repeat colonoscopy after 5 years, and one with repeat colonoscopy after 10 years, researchers hope to learn whether waiting 10 years is as good at preventing colorectal cancer as follow-up exams after 5 years. 

For colorectal cancer screening to be effective, people need to follow up on abnormal test results. In one study, researchers found that people who had a positive at-home stool test to screen for colorectal cancer, but did not have a follow-up colonoscopy, were twice as likely to die from colorectal cancer as those who did have a follow-up colonoscopy.

NCI is funding research to better understand the many factors that can contribute to why a person may not have a follow-up test and how to increase repeat screening and follow-up colonoscopy after abnormal stool tests. Researchers are also studying how the many levels of the healthcare delivery system affect the decision to get screened.

Surgically removing the cancer is the most common treatment for many stages of colorectal cancer. Chemotherapy, radiation, targeted therapy, radiofrequency ablation, and cryosurgery are other treatments that may be used to treat colorectal cancer, depending on the stage.

Because of an increased risk of recurrence, differences in anatomy, and poorer prognosis, the treatment of rectal cancer may differ from that of colon cancer. Although surgery remains a common type of treatment for local and locally advanced rectal cancer, people with some stages may be treated with radiation, chemotherapy, and/or targeted therapy with or without surgery.

In addition to these standard treatments for rectal cancer, researchers continue to study both new treatments, such as immunotherapies, and new combinations of existing treatments in clinical trials.

One trial is comparing a standard treatment (chemoradiation followed by combination chemotherapy) with chemoradiation followed by combination chemotherapy that includes an additional chemotherapy drug. The goal is to find out whether the additional chemotherapy drug may increase the likelihood of the cancer responding and possibly avoid the need for surgery. 

Immunotherapy for patients with Lynch syndrome or MSI-H colorectal cancer

Approximately 5% of colorectal cancer cases are due to Lynch syndrome, an inherited DNA repair disorder. People with this disorder have an increased risk of developing colorectal cancer, typically before they reach the age of 50. Lynch syndrome colorectal cancer tumors have many mutations, which may make them more susceptible to immunotherapies.

A genetic feature known as microsatellite instability-high (MSI-H) is seen in about 15% of patients with stages II and III colorectal cancer and about 5% with stage IV. MSI-H means that there are mistakes in the way the DNA is copied in cancer cells, which can make them grow out of control.

The immune checkpoint inhibitors nivolumab (Opdivo), ipilimumab (Yervoy), and pembrolizumab (Keytruda) have all been approved for the treatment of metastatic colorectal cancer in patients with Lynch syndrome and in patients with MSI-H cancers. 

The NCI-sponsored COMMIT study is testing the addition of atezolizumab (Tecentriq) to the combination of chemotherapy and the targeted therapy bevacizumab (Avastin), for treating patients that have defective DNA mismatch repair. The hope is that combining drugs that work in different ways will improve treatment results in patients with colorectal cancer.

Another NCI-sponsored trial is studying whether atezolizumab will improve outcomes in people with earlier-stage disease (specifically, stage III colon cancer) that is deficient in DNA mismatch repair. This trial will compare combination chemotherapy with or without atezolizumab.

For people with locally advanced rectal cancer who have MSI-H cancer, one trial is studying the effects of nivolumab and ipilimumab when given together with short-course radiation therapy. 

Combining immunotherapy with other treatments for patients without Lynch syndrome

Immune checkpoint inhibitors have been less effective in colorectal cancer patients without Lynch syndrome and whose cancers don't have mismatch repair deficiency. Scientists are currently testing various agents, such as chemotherapy drugs, targeted therapies and viruses, in combination with immune-based therapy to determine whether combining treatments would be effective in killing cancer cells.

Using targeted therapies for metastatic colorectal cancer

Using targeted therapies against genetic mutations that may drive tumor growth is another key area of research for metastatic colorectal cancer. The goal is to find agents that can block the activity of the abnormal proteins produced by these mutations. For example:

• The drug encorafenib (Braftovi), which targets the BRAF protein, is approved for the treatment of some patients with colorectal cancer. This drug is used in combination with cetuximab (Erbitux) in adults with metastatic colorectal cancer whose tumors have a certain mutation in the BRAF gene and who have already undergone treatment.
• An NCI-supported trial showed that colorectal cancer that contains mutations in the BRAF gene responds to treatment with the drug vemurafenib (Zelboraf) in combination with cetuximab and irinotecan (Camptosar). Vermurafentib targets mutant B-Raf proteins when combined with these two drugs.
• The NCI-sponsored SOLARIS trial is testing the addition of vitamin D3 to the combination of chemotherapy and bevacizumab for treating patients with metastatic colorectal cancer. 
• In January 2023, the Food and Drug Administration (FDA) approved the combination of two targeted drugs, tucatinib (Tukysa) and trastuzumab (Herceptin) for people with advanced colorectal cancer that produces an excess amount of a protein called HER2. (3% or less of people with advanced colorectal cancer have tumors that overexpress this protein.) In the clinical trial that led to the approval, called MOUNTAINEER, more than one third of people who received the drug combination had their tumors shrink or disappear. For another third, tumors stopped growing for some time.

Testing liquid biopsies

Liquid biopsies are a promising new approach being explored to detect, analyze, and track DNA, cells, and other substances shed from tumors into bodily fluids, such as blood and urine. Scientists are testing this method to detect colorectal cancer early, measure treatment responses, identify treatment resistance, and monitor for disease recurrence.

One example is the COBRA trial, which found that testing blood for fragments of genetic material (DNA) shed by tumors, known as circulating tumor DNA (ctDNA), could identify patients with stage IIA colon cancer who might benefit from additional treatment with chemotherapy after surgery.

An ongoing trial is studying ctDNA in people with stage II or III colon cancer. The goal is to determine whether and what type of chemotherapy will benefit patients who have had surgery for their colon cancer based on the presence or absence of ctDNA. 

Artificial intelligence, or AI, is suddenly everywhere. From ChatGPT to automated customer service "representatives,” the ability of computers to perform increasingly complicated tasks is transforming society. 

AI is also rapidly making its way into health care. One area where it’s being widely tested is in screening for cancer, to help interpret imaging-related tests like mammography for breast cancer and, increasingly, colonoscopy for colorectal cancer. But is it ready to assume a leading role?

According to a pair of new studies, when it comes to screening for colorectal cancer, that answer appears to be: Not yet. 

One of the studies was the largest ever clinical trial to evaluate whether AI-based technology called computer-aided detection (CAD) can improve colonoscopy. Use of CAD, the study showed, didn’t increase the rate of detection of advanced adenomas—the growths most likely to become cancer—by experienced doctors.

Incorporating CAD into the screening procedure did increase the overall number of adenomas detected, but the increase was driven by the detection of much smaller growths, those least likely to become cancer. 

The value of finding and removing these smaller growths, also called polyps, remains controversial. But the researchers, led by Rodrigo Jover, M.D., Ph.D., of the Hospital General Universitario in Spain, wrote that removing them does pose small but real risks, such as damage to the colon.

Their study was published August 29 in the Annals of Internal Medicine.

A different study in the same issue reported similar results from an analysis of 21 previous clinical trials that had tested the addition of CAD to standard colonoscopy. Overall, the addition of AI increased the rate of polyp detection, but again, this was driven by an increase in detection of small polyps, not larger, more threatening growths.

The AI-based CAD used in these studies was not as advanced as the AI used to power newer tools like ChatGPT, explained Asad Umar, D.V.M., Ph.D., of NCI’s Division of Cancer Prevention, who was not involved in the new studies. 

The systems used in these trials “are still kind of primitive AI—they’re not like what we’ve seen in 2022, 2023,” Dr. Umar said. Once more leading-edge AI technologies become integrated into CAD systems, he continued, they could potentially have a role in improving screening for colorectal cancer. 

“The next versions are likely to be way better,” he said.

Does AI boost the performance of experienced doctors?

During a colonoscopy, a long, thin tube with a high-definition camera on the end of it, called a colonoscope, is guided through the anus, into the rectum and throughout the colon. A doctor performing the procedure doesn’t work alone, explained Dennis Shung, M.D., Ph.D., from Yale University, who wrote an editorial that accompanied the new studies. 

“If I’m pulling out the colonoscope during the procedure and the nurse in my endoscopy suite says, ‘I think I saw something,’ I would go back and look every time,” he said. 

Over the last decade, AI-based computer systems have been designed to perform a similar role for gastroenterologists, doctors who perform colonoscopies.

These systems are based on software that, as the colonoscope snakes through the colon, scans the tissue lining it. The CAD software is “trained” on millions of images from colonoscopies, allowing it to potentially recognize concerning changes that might be missed by the human eye. If its algorithm detects tissue, such as a polyp, that it deems suspicious, it lights the area up on a computer screen and makes a sound to alert the colonoscopy team.

Studies of these systems to date have provided conflicting evidence about whether they improve endoscopists’ performance. And previous clinical trials haven’t been large enough to determine if they make a meaningful difference in detecting advanced adenomas.

Finding small, not larger, polyps

To fill this data gap, researchers in Spain launched the CADILLAC trial in 2021. Researchers from six major colonoscopy centers enrolled more than 3,000 people who had blood in their stool found by fecal immunochemical test (FIT). People who test positive on a FIT are advised to get a follow-up colonoscopy because they’re at increased risk of having advanced adenomas or colorectal cancer.

Participants were randomly assigned to receive either a standard colonoscopy (the control group) or colonoscopy with CAD. A total of 64 endoscopists from the six centers participated in the study.

Overall, advanced adenomas or colorectal cancers were found in about 34% of participants in both groups. 

These results differ from those of some earlier, smaller studies that found that adding CAD to the procedure increased the detection of advanced adenomas and colorectal cancers.

This difference may be, at least in part, because of the extensive experience of the participating endoscopists and the correspondingly high detection rate of advanced adenomas in the control group, the study team wrote.

“It is possible that in contexts of lower or in groups of endoscopists considered … “low detectors” there may be more effect of computer-aided detection systems,” they wrote.

Computer-aided detection did increase the number of small—less than 5 millimeters in diameter—polyps removed, even by experienced doctors.

Similar results were seen in the second study, carried out by a European research team, which analyzed the results of 21 previous randomized clinical trials testing CAD added to colonoscopy. The study, called a meta-analysis, included data on more than 18,000 people who had participated in the earlier trials. 

As in the CADILLAC study, the meta-analysis showed that adding CAD increased the detection of small polyps—in this case, by more than 50%—but not of advanced adenomas. 

Any polyp found on colonoscopy will be taken out during the procedure. So with increased detection of small polyps “we might be removing too many things that don’t necessarily need to be removed,” explained Dr. Umar. This is a phenomenon called overtreatment.

Any time a polyp is removed “there’s a risk of perforation and bleeding, because we’re taking a chunk out of the colon,” he continued. “It’s rare, but it does happen.”

A team member in the future?

That CAD didn’t improve detection of advanced adenomas in these studies was somewhat disappointing, because technologies that can speed up and streamline the workflow for screening colonoscopy need to be developed further, Dr. Umar explained.

Currently, the number of people who get a screening colonoscopy is far fewer than national guidelines recommend. “But we don’t have enough gastroenterologists to do as many colonoscopies as we need to do” he said. In some regions, such as some rural areas, the lack of trained specialists is already impacting the ability of people to get screened in a timely manner.

If AI-based systems could eventually speed up the process of colonoscopy, it could potentially help compensate for the workforce shortages in the field, Dr. Umar said. 

In the current randomized trial, adding computer-aided detection didn’t slow the process, which is an important first step, he explained.

The technology may also eventually help with similar procedures, such as checking people with a condition called Barrett’s esophagus for early signs of esophageal cancer, Dr. Umar added. 

Because precancerous areas in the esophagus tend to be flat, they are even harder to identify than growths in the colon and rectum. “But it’s the same problem everywhere : How do we identify lesions that are going to go on to become a cancer?” he said.

For now, AI systems may have a role to play in training much-needed new endoscopists, who will naturally miss more concerning polyps because they’re less experienced, Dr. Umar explained. 

A truly game-changing advance would be a computer system that can provide some real-time certainty about whether polyps identified during colonoscopy are potentially dangerous, said Dr. Shung. Right now, tissue removed during the procedure needs to be sent to a pathologist for analysis, which can take days.

“On my wish list is an algorithm that could detect all the polyps and tell me if they’re cancerous . … Then I’d be able to spend more time with the patient and counsel them about what they need to do ,” Dr. Shung said.

Such systems won’t be in the clinic soon, but companies that produce colonoscopy equipment are already starting to build AI directly into their systems, added Dr. Shung. 

“It’s going to come directly with the endoscope—I think that’s going to be the future,” he said. 

“People worried that AI will take their jobs,” Dr. Shung added. “But I think of AI as a team member, something complementary, that could to let humans take care of humans,” he said.

The human gut contains trillions of bacteria. Some play helpful roles, like helping to digest food. Others can be problematic, causing conditions like stomach ulcers.

Tumors that arise in the lower intestines, which includes the colon and rectum, are constantly exposed to a wide range of gut bacteria. This intimate physical relationship has led researchers to wonder if some species of bacteria could be affecting the growth of colorectal tumors.

Over the last decade, one such species, called Fusobacterium nucleatum, has been strongly implicated as a potential contributor to colorectal cancer growth. Although F. nucleatum is normally found in the mouth, studies have also found increased numbers of it in the intestines of people with colorectal tumors compared with people without cancer.

In a new study, published on March 20 in Nature, NCI-funded researchers have pinpointed a single type of F. nucleatum that appears to be the cancer-fueling culprit scientists have been searching for.

In studies in the lab, they showed that this type of F. nucleatum could survive for an extended time in conditions that mimicked the stomach’s acidic environment. And in mice, its presence increased the number of precancerous growths called adenomas in the large intestine. It also produced compounds that can create a beneficial environment for tumor growth.

In tissue samples taken from people with colorectal cancer, this type of F. nucleatum was the only type more likely to be found in tumor tissue than in nearby healthy tissue. And people with colorectal cancer were five times as likely to have this bacterium in their stool than people without the disease.

“It sounds scary, but this is good information to have,” said Susan Bullman, Ph.D., of Fred Hutch Cancer Center, who co-led the study. “Microbes are manipulatable—you can target them. So we see that this microbe is getting to tumors and may be contributing actively to disease progression, we can harness that information and think about how to prevent that.”

The findings highlight the need for a more comprehensive understanding of the behavior of different microbes in the lower intestines, added Phil Daschner, a program director with NCI's Division of Cancer Biology who was not involved with the study.

“The microbes in our gut include bacteria, but also fungi and viruses,” Daschner said. “And may be helping to promote tumor growth.”

From the mouth to the gut

Even in its natural home, the mouth, F. nucleatum is not our friend. “In the oral cavity, it’s considered a ‘bridging’ organism,” explained Christopher Johnston, Ph.D., the study’s other co-leader, also from Fred Hutch. That means it helps bind together other microorganisms in the mouth to produce the sticky, cavity-causing substance called dental plaque, which in turn can help cause gum disease.

Previous studies have found F. nucleatum in and around colorectal tumors—not just those located in the colon and rectum, but also in colorectal cancer that has metastasized elsewhere in the body.

“But not all F. nucleatum are the same,” Dr. Bullman explained. “There’s high variation within these organisms and in what they’re capable of doing.”

To get a more specific picture of which types of F. nucleatum may be attracted to colorectal tumors, the researchers first analyzed the genomes of F. nucleatum types taken from human colorectal tumors and from the mouths of people without cancer. Out of its several known subspecies, only one, called F. nucleatum animalis (or Fna), was routinely found in the tumor samples.

Additional genetic analyses revealed that Fna could be divided even further, into two separate groups. While both groups were found in about equal proportions in the mouth, only one, dubbed Fna C2, was found in colorectal tumor samples in substantial numbers.

As expected, the two groups were genetically very similar. However, by sequencing their complete genomes, the team was able to tease out several genetic differences among them that could explain Fna C2’s ability to set up shop in tumors.

Those differences included Fna C2’s higher resistance to acid, which could allow it to potentially reach the intestines directly from the mouth, through the stomach. Fna C2 also had the ability to hide inside certain tumor cells, which could protect it from the immune system. And it was able to use nutrients found in the gastrointestinal tract, which are very different from those found in the mouth.

“These are unique features that allow to survive this transit and to set up house in the lower gastrointestinal tract,” said Dr. Bullman.

Does Fna C2 help start as well as fuel tumors?

The team next conducted experiments in mice to try to get a better handle on Fna C2’s ability to help tumors form and grow.

That work showed that Fna C2 could slightly increase the formation of adenomas in the colon. It also produced changes in energy availability for cancer cells in the intestines that could create an environment favorable to tumor formation.

To date, no mouse model has been able to closely mimic bacterial behavior in the human colon, Dr. Bullman explained. For example, some of the human proteins that the bacteria binds to or uses to grow aren’t found in mice.

This has made studying the contribution of bacteria to the early formation of tumors difficult, she added. “So while we think this microbe is important in cancer progression, for its role in cancer initiation, the jury’s still out,” she said.

Going back to humans, the team looked for the two Fna groups in tissue samples taken from more than 300 people with colorectal cancer. Only Fna C2 was found in greater numbers in tumor tissue than in samples taken from adjacent normal tissue.

The researchers also measured Fusobacterium types found in stool samples from people with colorectal cancer and people without the disease. Whereas almost 30% of people with colorectal cancer had Fna in their stool, less than 5% of people in the healthy comparison group did.

Targeting a problematic bacterium

“What’s probably the most important about this research is the potential to identify treatments,” Daschner said. “If you can inhibit Fna C2, you might be able to either prevent polyps from progressing to cancer or prevent already-formed tumors from getting worse.”

Previous research in mice showed that using antibiotics to knock out Fusobacterium could slow the growth of colorectal cancer. But antibiotics can kill other bacteria as well, which could lead to unexpected effects on a tumor or on beneficial bacteria in the rest of the body, said Dr. Bulllman.

“But identifying this specific may allow us to identify that can specifically target this subgroup, because it’s genetically distinct,” she said.

Dr. Johnston’s team hopes to eventually use Fna C2 to create what they call microbial cellular therapies, using the bacterium like a Trojan horse to deliver cancer drugs into a tumor.

“Because this has such an intimate relationship with cancer, if we can strip out the parts that make it but keep the parts that allow it to travel to and colonize tumors, that could be a new strategy for delivering drugs directly into these tumors,” he explained.

The discovery of this type of F. nucleatum may eventually have implications for colorectal cancer screening, said Daschner.

The presence of Fna C2 alone in stool wouldn’t be enough to diagnose cancer or polyps, he explained. But future studies could look at whether adding it to existing tests that look for blood or cancer DNA in the stool may potentially help identify more people who need a follow-up colonoscopy, he added.

The relationships between microbes that can cause gum problems and the risk of diseases elsewhere in the body are still under study. “But maintain your oral health,” said Dr. Johnson.

Previous research has found that people with gum disease had an increased risk of several different cancer types, he explained. “So a link between oral health and cancer is certainly there.”

“The mouth is such a unique environment; it’s the gateway into the body for most pathogens,” Dr. Johnson added. “It makes sense to keep it protected.”

New cases of colorectal cancer in people under the age of 50 have been rising at an alarming rate over the past several decades. But younger adults aren’t routinely screened for colorectal cancer because the disease is still relatively rare in younger adults. 

Now, a study has identified four warning signs that, according to the investigators, could help encourage younger adults to seek medical care so they can potentially catch the disease at an earlier and more treatable stage. 

To conduct the study, the research team analyzed insurance claims data on more than 5,000 people diagnosed before age 50, called early-onset colorectal cancer, and more than 22,000 people without cancer (controls).

The analysis showed that, in the period of 3 months to 2 years before people with colorectal cancer were diagnosed, four signs were more commonly reported in people who developed colorectal cancer than in matched controls:

• abdominal pain
• rectal bleeding
• diarrhea
• iron deficiency anemia

Having just one of these signs during this period was associated with nearly twice the likelihood of being diagnosed with early-onset colorectal cancer as having none of the signs.

Having three or more of these signs was associated with six times the likelihood of being diagnosed with the disease. The findings were published May 4 in the Journal of the National Cancer Institute.

“Colorectal cancer is no longer a disease of just the older population,” said the study’s senior investigator Yin Cao, Sc.D., of the Washington University School of Medicine in St. Louis. “For younger adults, we really want to raise awareness that, if you have any of these signs or symptoms, don’t wait to see a doctor.” 

Clinicians also need to be aware of these signs, Dr. Cao continued, because it may help them identify cancers in younger people “as early as possible.” 

Confronting the rise in early-onset colorectal cancer

Colorectal cancer is the third most common cancer in the United States among both men and women. The widespread adoption of screening in the mid-1980s has led to a steady decline in cases of colorectal cancer among adults aged 50 and older. However, new cases of early-onset colorectal cancer, while still relatively rare, have been rising since the mid-1990s. 

In response to this trend, cancer screening guidelines now recommend people start getting screened for colorectal cancer at age 45 instead of 50. But half of early-onset colorectal cancers are diagnosed in people under 45 years old, for whom screening is not routinely recommended (except for those with inherited mutations in specific cancer-related genes, such as people with Lynch syndrome, or with a first-degree relative who has had colorectal cancer).

Younger adults are also more likely to ignore early signs of the disease, increasing the likelihood that their cancers aren’t caught until common colorectal cancer symptoms seen in older adults, such as weight loss and rectal bleeding, become severe.

Dr. Cao noted that many early-onset colorectal cancers aren’t diagnosed until the cancer is at an advanced stage. For colorectal cancer that has spread to distant organs, only 14% of people will live for 5 years or longer. If caught at localized stage, 5-year survival is 90%. In addition to improving survival, earlier diagnosis also reduces the need for aggressive treatments, which can greatly impact a younger person’s quality of life, she said. 

To help improve early diagnosis in younger adults, Dr. Cao and her colleagues wondered whether they could identify certain warning signs associated with a diagnosis of early-onset colorectal cancer.    

Identifying the warning signs 

In the new study—funded in part by NCI—the researchers used a US insurance database that includes claims data from about 113 million adults between ages 18 and 64.

Among adults with at least 2 years of data, they identified 5,075 people ages 18–49 with colorectal cancer and 22,378 people without colorectal cancer. The two groups were matched by age and other factors, such as sex and where they live. The average age was 43. 

The researchers then checked the claims data for 17 prespecified signs of colorectal cancer to see if any of these were found more frequently in the cancer group in the period between 3 months and 2 years before diagnosis than in the control group.

The four signs turned out to be more common among those who were diagnosed with early-onset colorectal cancer than those who weren’t over a similar time period.

The investigators conducted a similar analysis of older adults aged 50–64 and found that abdominal pain and rectal bleeding were only slightly more common in those with colorectal cancer. The stronger association in younger adults suggests that “there’s an avenue for early detection” among this population, Dr. Cao said.

Nearly 20% of the younger adults with early-onset colorectal cancer had one or more of these four signs between 3 months to 2 years before diagnosis. Abdominal pain was the most common sign, appearing in 11.6% of people with cancer versus 7.7% in the controls. But rectal bleeding had the strongest association with a diagnosis of early-onset colorectal cancer, followed by iron deficiency anemia. The more signs a person had, the more likely they were to have been diagnosed with the disease.

The investigators also looked at the length of delay between when warning signs appeared and when a person was diagnosed. Among those with one sign between 3 months to 2 years before diagnosis, the median delay to diagnosis was 9.7 months. Each additional sign shortened the time to diagnosis.

However, even people with 3 or more signs had a median delay of 4.8 months before diagnosis. People with rectal bleeding had a shorter delay in diagnosis than those with other signs, but the median delay was still 7 months. 

Overall, though, nearly 50% of the patients with early-onset colorectal cancer experienced their first sign within 3 months of their diagnosis, with a median delay of less than a month. 

Getting diagnosed as early as possible 

Dr. Cao said that it’s unclear why half the patients had a much shorter delay to diagnosis than the nearly 20% diagnosed between 3 months and 2 years of diagnosis. The claims data did not provide details on the severity of the signs at the time of diagnosis.

That sort of information, she noted, could potentially offer insights into whether it was severe symptoms that drove individuals to seek medical care. The claims data also did not provide data on cancer stage at the time of diagnosis, so the researchers couldn’t tell whether any of the signs might be associated with more advanced disease at the time of diagnosis. 

Nevertheless, Dr. Cao said, the findings underscore the importance of recognizing warning signs early. They may also potentially help doctors and their patients under 50 with any of these signs make decisions about whether to seek diagnostic testing, she continued, particularly if they have more than one sign, if the signs don’t go away, or if they come back. 

When a younger adult notices these warning signs, “they should at least go to their primary care doctor, and, if needed, the primary doctor will refer them to a gastroenterologist,” Dr. Cao said. 

In some instances, doctors may advise that younger adults showing these warning signs get an at-home stool test commonly used for colorectal cancer screening, said Gary Della'Zanna, D.O., a gastrointestinal cancer expert in NCI’s Division of Cancer Prevention, who was not involved in the study. “It’s easy, it's reasonably affordable, and it's not invasive,” Dr. Della'Zanna said. 

But ultimately, he noted, more research is needed to identify younger adults who are at increased risk for early-onset colorectal cancer at the population level. Accumulating this sort of data “will help us better identify the at-risk population, because we don’t have the resources to screen everybody,” he said. “And colonoscopies are not without risk.” 

New research underlines the importance of following up with a colonoscopy exam after a positive (abnormal) result on an at-home stool test to screen for colorectal cancer. The test, known as the fecal immunochemical test (FIT), checks for traces of blood in patient-collected stool samples, which can be an early sign of cancer. 

Screening for colorectal cancer, the second leading cause of cancer-related deaths in the United States and other high-income countries, has been shown to reduce deaths from this disease. 

In the new study, researchers found that people who had a positive FIT result (signs of blood in the stool) but did not have a follow-up colonoscopy were twice as likely to die as those who did have a follow-up colonoscopy.

“This study emphasizes that cancer screening is really a process, not a single step, and shows the importance of completing all steps of the process,” said gastroenterologist Douglas Corley, M.D., Ph.D., of Kaiser Permanente, Northern California, who was not involved in the study.

Until now, there hasn’t been much information on how a lack of follow-up testing after a positive FIT result may affect people’s risk of dying from colorectal cancer, Dr. Corley noted. Findings from the study, which was conducted in Italy, were published March 31 in Gut.

“The study points to the importance of more closely monitoring people who do not follow recommendations after a positive FIT result,” said Erica Breslau, Ph.D., M.P.H., of NCI’s Healthcare Delivery Research Program, who also was not involved in the study. The findings also highlight the need to “identify opportunities to improve what is currently being done” to ensure that people get the follow-up tests they need, Dr. Breslau said.

FIT is one of the most widely used colorectal cancer screening tests worldwide. Experts generally recommend that people repeat this test every 1 to 2 years. People with a positive FIT test result are advised to have a colonoscopy to investigate the cause of the bleeding because a FIT test alone cannot diagnose cancer.

A follow-up, or diagnostic, colonoscopy can find not only colorectal cancer but also precancerous growths, or polyps, that doctors can remove during the procedure, reducing the risk of future cancers. If cancer is detected, treatment is usually the next step.

Many successful colorectal cancer screening programs, including those in the United States, use some combination of stool-based tests, such as FIT, and screening colonoscopy, Dr. Corley said, so the new study results “are very relevant to settings in the United States.”

Delayed diagnosis of colorectal cancer leads to higher risk of death

For the study, Manuel Zorzi, M.D., M.Sc., of the Veneto Tumour Registry in Padua, Italy, and his colleagues, examined the medical records of participants in a regional colorectal screening program who took a FIT test between January 1, 2004, and September 30, 2017.

The program offers free FIT testing once every 2 years to people 50–69 years old. Stool samples collected at home are sent in for analysis. People with a positive FIT result are contacted by phone by trained individuals and a follow-up colonoscopy exam is offered free of charge.

The study included 111,423 people who had a positive FIT test, of whom 88,013 people had a follow-up colonoscopy as part of the program (colonoscopy group) and 23,410 did not (no-colonoscopy group). Nearly all of the people who had a follow-up colonoscopy did so within a year of the positive FIT result.

The researchers compared the numbers of new colorectal cancer cases diagnosed, deaths from colorectal cancer, and deaths from any cause in the two groups over time for up to 10 years after an initial positive FIT result.

During the study period, fewer than 1% of people in each group died of colorectal cancer. However, those who did not get a follow-up colonoscopy were about twice as likely to die of colorectal cancer over a 10-year period as those who did have a follow-up colonoscopy. 

In the colonoscopy group, the number of new colorectal cancers diagnosed went up sharply in the first 6 months or so after a positive FIT result and leveled off after that.

The initial sharp rise was expected, the researchers noted, due to colorectal cancer being found during follow-up colonoscopy. The low incidence of colorectal cancer after that was likely due to the early detection of cancers and the removal of precancerous lesions during colonoscopy, Dr. Breslau explained.

“This demonstrates the longer-term protective value of completing the screening process, which is another new piece of information provided by the study,” Dr. Corley said.

By contrast, in the no-colonoscopy group, new cases went up more gradually but continued rising over 10 years. People in this group were more likely to have their cancer detected only after symptoms appeared, when the cancer was more advanced. This delayed diagnosis likely explains the higher death rate from colorectal cancer in this group, Dr. Breslau said.

Room for improvement

Many colorectal cancer screening programs, including some in the United States, “struggle to ensure timely colonoscopy completion among those with a positive FIT, with rates as low as 50%,” Dr. Zorzi and his colleagues wrote. But the program in northeast Italy, which started in 2002, has maintained colonoscopy rates of 80% at just 3 months after a positive test result, they noted.

This follow-up rate “is comparable to some of the best follow-up rates in the United States and elsewhere,” Dr. Corley said.

Yet there’s clearly room for improvement.

“This study doesn’t help us understand why people aren’t following up,” Dr. Corley said. “Understanding why some people are willing to be screened but do not follow up can lead to improvements in the effectiveness of the screening process.”

Multiple factors can contribute to people not getting follow-up colonoscopy exams, both he and Dr. Breslau said. 

In the United States, cancer screening is a complex process that involves multiple steps and can be affected by many factors, Dr. Breslau said. Such factors include the patient’s personal circumstances (for example, access to transportation), whether they have health insurance, whether they can get timely access to colonoscopy, and whether they have had an adequate conversation with their doctor about screening. 

“In Italy, unlike in the United States, all citizens are entitled to care that is mostly free through Italy’s National Health Service. This study shows that even with a national health service that provides universal coverage, there are other barriers to obtaining care,” Dr. Breslau said. For example, people’s fears about the preparation for colonoscopy continue to be a major barrier.

Dr. Zorzi’s team found that people in the no-colonoscopy group were at higher risk of dying from all causes, not just from colorectal cancer. This points to one possible reason why people in this group, on average, were less likely to get follow-up colonoscopy exams, Dr. Corley said. 

“Some people may have had other illnesses that precluded them from having a colonoscopy or made them feel that they were more likely to die from causes other than colorectal cancer,” he explained. 

The ongoing NCI-funded PROSPR program aims to better understand how to improve the cancer screening process and reduce disparities in colorectal and other cancer screening in community health care settings in the United States.

Dr. Corley, who is the lead investigator for the colon cancer component of PROSPR, stressed the effectiveness of colorectal cancer screening.

“One study we published showed that by increasing screening rates from 40% to 80%, we could cut the incidence of colorectal cancer deaths in half,” he said. “ raises the importance of being able to get the individual steps correct and completed as best you can ... because every step where you lose some people in follow-up can have a big impact.”

From the untimely death of “Black Panther” star Chadwick Boseman, to a recent photo essay in GQ magazine, the rapid rise in the rate of colorectal cancer among younger adults has been in the news lately. This increase played a key role in the new recommendation by an independent US advisory panel to start screening for colorectal cancer at age 45 instead of 50.

Screening for colorectal cancer, which can detect cancer and precancerous lesions before symptoms develop, has been shown to reduce deaths from the disease. But while the US Preventive Services Task Force (USPSTF) just updated its guidance to recommend screening for all adults aged 45 to 75, the panel concluded that the “net benefit” of screening after age 75 is small, and did not change its guidance for this age group.

Now, a new study provides some evidence that screening for colorectal cancer appears to be beneficial for people beyond age 75 as well. Although the study’s findings don’t contradict the advisory panel’s screening recommendations for older Americans—that is, that the decision should be made on a case-by-case basis—the researchers believe their results provide helpful information for physicians to use in discussing whether their older patients should get screened for colorectal cancer.

Because the task force suggests that decisions about screening people 76 to 85 years old be made selectively, “it’s been a bit of a gray area for physicians, and for patients, to know what to do,” said Andrew Chan, M.D., M.P.H., a professor of medicine at Massachusetts General Hospital. 

Dr. Chan co-led the new study assessing the impact of colorectal cancer screening in more than 56,000 people aged 75 or older. His team found that the risk of dying from colorectal cancer was reduced by more than a third in people over age 75 who had been screened by colonoscopy or sigmoidoscopy, compared with people in the same age group who did not undergo either of these screening tests. The findings were published May 20 in JAMA Oncology.

The study's results are noteworthy because they provide some of the first real-world evidence suggesting that people might benefit from screening beyond age 75, said Shivan Mehta, M.D., a gastroenterologist and health policy researcher at the University of Pennsylvania, who was not involved with the new study. 

Nevertheless, the decision to screen people aged 76 to 85 should still be made on a case-by-case basis by considering the potential benefits and harms for each patient, said Asad Umar, D.V.M., Ph.D., of NCI’s Division of Cancer Prevention, who also was not involved with the new study.

The new findings, which came out after the latest USPSTF guidance was developed, might make physicians a bit more likely to recommend screening for their older patients, “but these recommendations should still be personalized to the patient,” Dr. Mehta said.

Concrete Data from Two Long-Term Studies

In its latest recommendations on colorectal cancer screening, USPSTF concluded that, for people 76 to 85 years old, “patients and clinicians should consider the patient's overall health, prior screening history, and preferences” in deciding whether screening is appropriate. 

The panel’s guidance for people over age 75 is based mainly on studies that use computer modeling to calculate the benefits and harms of screening for people in this age group, Dr. Umar explained.

“There are risks involved with colonoscopy, such as bleeding and perforation of the colon, and also risks involved with the preparation, especially in older people,” Dr. Umar said.

Preparing for a colonoscopy requires a thorough cleansing of the entire colon before the test, which can lead to dehydration and other problems. And the risk of these possible harms tends to be greater in older people, Dr. Umar added.

To get more concrete information on the impact of colorectal cancer screening with colonoscopy or sigmoidoscopy beyond age 75, Dr. Chan’s team used data from two large, long-term studies of US health care professionals, the Nurses’ Health Study and the Health Professionals Follow-up Study. Study participants receive questionnaires every 2 years about their health and health-related behaviors, such as diet and exercise. 

From 1988 through 2014, participants were asked whether they had undergone either colonoscopy or sigmoidoscopy in the past 2 years and, if so, why the tests were done.

Colonoscopy examines the inside of the colon using a thin, tube-like instrument with a light and a lens for viewing. Sigmoidoscopy is a similar procedure that examines only the lower part of the colon and involves a less extensive preparation. However, this procedure is not widely available in the United States. Both procedures can be used to remove precancerous lesions, or polyps, if they are detected.

Evidence Suggests Benefits of Screening Beyond Age 75

Among more than 56,000 participants who reached age 75 during the study, the team identified 661 new cases of colorectal cancer and 323 deaths from the disease. They then compared the rates of new colorectal cancer diagnoses and deaths from the disease among participants who reported having a screening colonoscopy or sigmoidoscopy after age 75 and those who did not undergo either test.

There are other, less invasive screening tests for colorectal cancer, but this study “focused on colonoscopy because that has been and continues to be the primary mode of screening” in the United States, Dr. Chan said. And most study participants reported undergoing screening colonoscopies rather than sigmoidoscopies.

Screening after age 75 was linked with a 39% reduction in the incidence of colorectal cancer and a 40% decrease in the risk of death from the disease. The researchers found similar reductions in the risk of death from colorectal cancer, whether or not participants had ever undergone screening before age 75. 

Among participants who had a history of cardiovascular disease or multiple underlying health conditions, no clear reduction in colorectal cancer–related deaths was seen with screening. However, these findings were less definitive than the overall results, Dr. Umar said.

“Our data provide additional support for the USPSTF recommendations. And they give people more confidence that if they decide to continue screening beyond age 75, or even to start screening for the first time after age 75, there are data to support that decision,” Dr. Chan said. 

More Research Questions to Address

The study's results are far from the last word on this subject, researchers said. Because this was an observational study, “it is not completely clear if the improved outcomes are from the screening or from the selection of patients to get screened,” Dr. Mehta said.

The researchers could not account for factors that may have influenced doctors’ decisions on whether to suggest screening to certain patients and people’s decisions to undergo screening, he explained.

For example, because colonoscopy is invasive and the preparation can be difficult, it’s possible that only the older participants who were fit and healthy underwent this screening test. And that could explain the lower death rate seen in the group that was screened.

Additional studies will be needed to guide future recommendations on colorectal cancer screening in older adults, Dr. Umar said.

“I hope we will reach a point where we can start to think about more sophisticated ways to help guide” decisions about colorectal cancer screening—for example, by looking at certain lifestyle factors or genetic risk factors that predispose some people to the disease, Dr. Chan said.

Although this study focused on colonoscopy, “there is increasing evidence of the value of noninvasive screening tests for colorectal cancer, such as stool-based testing,” which people can do at home and don’t require cleansing the colon, Dr. Chan said. “And how those tests fit into screening recommendations for people over age 75 remains an area for future research.”

Studying the role that stool tests may play in screening people of all screening-eligible ages will also be important because the number of specialists (gastroenterologists) in the United States available to do colonoscopies for people aged 45 to 75 is already limited, Dr. Umar said.

Finally, because most participants in the new study were White, the investigators note the need for studies in older people of other racial and ethnic groups to see if disparities in the benefits of screening exist between groups.

“To date, we’ve seen that the impact of screening on colorectal cancer rates and mortality appear to be consistent across different racial and ethnic groups,” Dr. Chan said. But “additional real-world data will always be welcome.”

Colorectal cancer often spreads to the liver, and once it does, it becomes incredibly difficult to treat. Cancer is even more likely to set up camp in the liver when patients have fatty liver disease, but scientists don’t know why. Now, a new study has shown that fatty liver disease appears to create the perfect environment for metastatic colorectal cancer to thrive in the liver.

Fatty liver disease happens when excess fat builds up in the liver. Around 25% of US adults have the most common type of fatty liver disease, called nonalcoholic fatty liver disease (NAFLD), and that number is going up. In addition to being linked with colorectal cancer metastasis, NAFLD is also associated with an increased risk of several cancers, including liver cancer.

The NCI-funded study, largely conducted in mice, found that fatty livers sent fat-coated “message bubbles” to colorectal cancer cells. The message bubbles, called extracellular vesicles (EVs), encouraged colorectal cancer to grow in the liver and prevented immune cells from attacking metastatic tumors in the liver. The findings were published May 9 in Cell Metabolism.

“What this study shows is that NAFLD can impact the aggressiveness of metastatic cancer—specifically of colorectal cancer that metastasizes to the liver,” said Joanna Watson, Ph.D., of NCI’s Division of Cell Biology, which partially funded the study.

The findings also raise the possibility that people with colorectal cancer and fatty liver disease might need different treatments than people with colorectal cancer and healthy livers, said the study’s lead scientist, Ekihiro Seki, M.D., Ph.D., of Cedars-Sinai Medical Center in Los Angeles.

Extracellular vesicles from fatty liver

The cells in our bodies can’t whip phones out of their pockets and text each other when they need to communicate. But they can send out EVs, which can travel through the blood to deliver messages to cells in other parts of the body. The messages are typically encoded by proteins or RNA tucked inside the vesicles.

Countless studies have shown that cancer cells rely on EVs to sweet-talk other cells, often as a means of getting their way. Among other things, tumor-derived EVs have been found to tell distant organs—like the liver—to get ready for the cancer’s arrival.

But little attention has been paid to EVs produced by the liver itself and whether they interact with cancer as it spreads, Dr. Seki said. The research team was curious whether EVs from fatty liver disease might help colorectal cancer spread to the liver.

First, the team studied mice with fatty livers. Colorectal cancer cells injected into the spleens spread and formed more tumors in the livers of mice with fatty livers than in those without, they found. 

Mice with fatty livers also had more EVs in their blood than their counterparts without fatty livers, the researchers found. Likewise, people with NAFLD had higher levels of EVs in their blood than in people without NAFLD.

EVs from mice with fatty livers and people with NAFLD appeared to tell colorectal cancer cells to grow and spread. For example, when the researchers took those EVs and mixed them with colorectal cancer cells in lab dishes, the cancer cells grew aggressively.

But in mice that were genetically engineered to lack the ability to make EVs in their livers, colorectal cancer cells formed far fewer metastatic liver tumors than in mice with livers that could make EVs.

These findings are novel, Dr. Watson said, because “they focus on liver-produced extracellular vesicles rather than cancer cell–produced extracellular vesicles to create the pro-metastatic niche” (an area in a distant organ that has been prepped to support metastatic cancer growth).

A message for cancer cells and immune cells

The team’s next question was: What’s the message EVs from fatty livers are carrying?

The message, they discovered, came in the form of microRNAs, small pieces of RNA that limit or stop the production of specific proteins in cells. They identified three microRNAs that launched a cascade of actions in colorectal cancer cells that ultimately helped the cells grow and form tumors in the liver. Turning this cascade off in colorectal cancer cells slowed the growth of tumors in mice with fatty livers.

But that’s not all this cascade—controlled by a protein called YAP—appeared to do. It also prompted colorectal cancer cells to alter immune cells in the liver, the researchers reported. More specifically, the cancer cells convinced nearby immune cells not to attack metastatic tumors in the liver.

For example, in mice with fatty livers, colorectal cancer cells released a protein that made immune cells called macrophages migrate into the liver. These macrophages, in turn, sent signals that encouraged cancer cells to grow and cancer-killing T cells to stand down.

Nonalcoholic fatty liver disease and cancer

The next question was: Are EVs from the livers of people with colorectal cancer and NAFLD doing the same thing? To get at the answer, the researchers examined colorectal cancer tumors that had spread to the liver in 16 people with and 18 people without NAFLD.

In people with NAFLD, the YAP signaling cascade was turned on in metastatic liver tumors. There were also more cancer-friendly macrophages and T cells in the metastatic liver tumors of people with NAFLD.

Because NAFLD generally doesn’t cause any symptoms, it “tends to be diagnosed by chance as a consequence of tests for other health problems,” Dr. Watson noted.

Doctors tend to look out for severe forms of fatty liver disease like cirrhosis, Dr. Seki added, and pay less attention to the mildest form, simple steatosis.

“However, I want to tell clinicians, please do not ignore simple steatosis, which can also increase the risk of cancers and cancer metastasis,” he emphasized.

Not only that, but the study suggests that fatty liver disease might also affect how certain cancer treatments work, Dr. Seki said. Given the immune cell changes they observed, the researchers “strongly expect” that immunotherapies may not work as well in people with fatty liver disease, he explained. 

The good news is that fatty liver disease may be improved by losing weight, switching to a low-fat diet, and exercising, he added. And researchers are testing potential drug treatments for NAFLD.

The study also points to the need for a shift in how cancer research is done, said Dr. Watson.

Scientists know “a tremendous amount about the changes that occur within the cancer itself” and the microenvironment right around the tumor, she noted. But scientists also need to think about the “macroenvironment” of the whole body, and how multiple organs and systems are in communication with tumors, she emphasized.

People with obesity are at increased risk for type 2 diabetes and other health problems. Certain drugs that help keep diabetes symptoms in check also promote weight loss. These are called GLP-1RAs. Examples include Ozempic, Trulicity, Wegovy, and Zepbound.

People with obesity are also at higher risk for colorectal cancer. Scientists wondered whether people who take GLP-1RAs for diabetes also have a reduced risk for colorectal cancer.

To find out, researchers examined the medical records of more than 1.2 million people with type 2 diabetes. They followed available patient records for up to 15 years. They compared the risk of colorectal cancer among people taking seven different types of drugs.

The analysis showed that people with diabetes who took GLP-1RAs had a lower risk of colorectal cancer than those taking other diabetes drugs. The protection was greatest in people with overweight or obesity. People in this group who took GLP-1RAs had a 50% lower risk of colorectal cancer than those who took insulin to manage their diabetes. They had a 42% lower risk than those who took the common diabetes drug metformin.

“This research is critically important for reducing incidence of colorectal cancer in patients with diabetes, with or without overweight and obesity,” says Dr. Nathan Berger, who co-lead the study along with Dr. Rong Xu at Case Western Reserve University. More research is needed to confirm these results and learn more about how these drugs work.

After surgery for colorectal cancer that’s started to spread beyond its initial location, many people go straight to treatment with chemotherapy. The idea behind this postsurgery, or adjuvant, treatment is to reduce the likelihood that the cancer will come back in other places in the body, resulting in more people being cured of the cancer.

But there hasn’t been a method to predict who really needs this extra treatment and who could safely skip it—and avoid any associated side effects.

Results from a new study suggest that there may now be a promising way to identify who does and doesn’t need postsurgical chemotherapy.

In the study, the presence of fragments of genetic material that have escaped from tumors into the bloodstream, or circulating tumor DNA (ctDNA), seemed to predict which patients would benefit from the chemotherapy they received. That is, among patients who were ctDNA-positive, those who got chemotherapy lived longer without their cancer coming back (a recurrence) than those who didn’t get chemotherapy.

And, importantly, a negative ctDNA test picked out people who likely hadn’t needed chemotherapy immediately after surgery—in other words, there was no evidence that chemotherapy helped them live longer without a recurrence.

Findings from the study, called BESPOKE CRC and funded by Natera, Inc., which makes the ctDNA test it used, were presented January 20 at the ASCO Gastrointestinal Cancers Symposium. Results from another study using the same test, presented at the symposium by a research team from Japan, showed similar capabilities for ctDNA testing in colorectal cancer.

The ctDNA measurements taken in the study, captured with a test called a liquid biopsy, weren’t used to initially choose treatment for individual patients. However, results of the liquid biopsies were provided back to participants and their care teams, to see if those results would change previously decided treatment plans, explained Pashtoon Murtaza Kasi, M.D., M.S., of Weill Cornell Medicine, one of the study’s lead investigators.

But the findings from BESPOKE and the Japanese study are strong enough, he said, to provide assurance that ongoing clinical trials testing ctDNA-driven decisions about whether to use adjuvant chemotherapy are safe and very reasonable to pursue.

“We know that about 60% of people are cured by surgery,” said Carmen Allegra, M.D., special advisor on gastrointestinal cancer therapeutics in NCI’s Division of Cancer Treatment and Diagnosis, who was not involved with the study. “And we don’t want to expose those patients to chemotherapy and its side effects if we don’t have to.”

But ctDNA may also help identify people who would benefit from even more aggressive treatment after surgery, or who may want to join clinical trials of experimental therapies, said Dr. Kasi.

Two ctDNA tests are already being marketed for monitoring colorectal cancer recurrence and are being used in some clinics. “The problem is, we don’t really know how to use them yet,” said Dr. Allegra.

Currently, if a patient has a positive ctDNA test but imaging tests show no signs that their cancer has come back, there’s uncertainty about whether to start additional treatment right away, he explained.

The ongoing trials will hopefully provide the guidance needed to understand how to best use ctDNA test results to guide patient care, he added.

Tracking a signature of hidden cancer cells

The idea of liquid biopsies that measure ctDNA isn’t a new one. The technology is being widely tested to monitor people with cancer and to potentially detect some cancers early, before symptoms develop.

In terms of guiding treatment, there are two potential uses for such technology: as prognostic tests and as predictive tests. Tests that are prognostic can measure how likely a cancer is to recur after treatment. Tests that are predictive can help inform whether a specific treatment will be effective against an individual’s cancer.

Together, these two types of information could potentially be used to better tailor treatment for colorectal cancer. Researchers have hoped that ctDNA testing could fill these roles, but its actual prognostic and predictive capabilities had remained open questions.

Beginning in 2020, researchers led by Dr. Kasi enrolled almost 1,800 people into the BESPOKE CRC study. The results from their first 623 participants were presented at the 2024 ASCO symposium.

All BESPOKE participants had stage II or stage III colorectal cancer. Cancer at these stages has spread into or through the wall of the colon or rectum and, in some cases, to nearby lymph nodes, but not to distant sites in the body.

The study was not a clinical trial that randomly assigned participants to different groups. All participants underwent surgery and, if decided on by their care team, chemotherapy.

In addition to standard monitoring for cancer recurrence, which includes imaging and blood tests for a protein called CEA, study participants underwent ctDNA testing 1 month after surgery, every 3 months for the next year, then every 6 months for the duration of the study or until their cancer recurred.

A clear difference in benefit from chemotherapy

Of the 623 study participants, 381 received chemotherapy starting about 3 months after surgery, based on how abnormal the cancer cells removed during surgery looked under a microscope and other risk factors.

Of the participants who received chemotherapy, 85 had at least one positive ctDNA test. The other 296 patients who received chemotherapy had negative ctDNA tests.

For people with a positive ctDNA test, chemotherapy provided an obvious benefit. Those patients lived for a median of almost 18 months without their disease returning (a measurement called disease-free survival) compared with about 7 months for people with positive ctDNA tests who didn’t get adjuvant chemotherapy.

But for people with negative ctDNA tests, chemotherapy didn’t make much of a difference. More than 90% of people without measurable ctDNA lived for a median of over 2 years without their disease returning, regardless of whether they received chemotherapy after surgery.

Of the more than 500 participants whose initial ctDNA tests were negative, 14 eventually had a positive test result. These patients were more likely to have their disease recur than patients whose tests remained negative. By 15 months after surgery, however, the likelihood of a patient going from ctDNA-negative to ctDNA-positive dropped sharply.

Out of the 101 patients whose cancer eventually recurred in other organs during follow-up, 40 had what is called oligometastatic disease. This is where a patient has only a few, usually small metastases. A substantial number of these tumors were first picked up by ctDNA testing during the study, Dr. Kasi explained.  

For some people with oligometastatic disease, treatment options like surgery or radiation to the sites of metastases are still an option, he continued. “And we know from prior experience that does help improve survival. So ctDNA may help increase the number of people who may benefit from such an approach.”

How Do Patients Feel About ctDNA Testing?

As part of BESPOKE CRC, the research team also asked patients about how ctDNA testing impacted their mental health—whether it provided peace of mind or more stress.

Overall, participants reported satisfaction with the testing. Scores on tests of anxiety and depression didn’t differ between people whose tests were negative or positive. Almost three-quarters stated that the testing reduced their anxiety about cancer recurrence. And more than 90% said they wanted to continue ctDNA testing to monitor for recurrence going forward.

“I think it’s about an informed patient having more confidence in they are getting, even if an answer that they wanted to receive,” said Dr. Kasi.

Can ctDNA testing guide treatment from the start?

Studies are now underway to test whether ctDNA measurements can be used to guide colorectal cancer treatment from the outset.

In one of these studies for people with early-stage colon cancer, which is being conducted in the NCI-funded National Clinical Trials Network, people who have a positive ctDNA test after surgery will be randomly assigned to receive a standard chemotherapy regimen or a chemotherapy regimen that is more intensive than usual. “Because it’s very likely these people’s cancer is going to recur,” explained Dr. Allegra.

In contrast, people in the trial with a negative ctDNA test will be randomly assigned to receive only surveillance after surgery or standard chemotherapy. The results from that part of the study will hopefully provide more clarity on who can safely skip adjuvant chemotherapy, Dr. Allegra added.

The BESPOKE results provide assurance that such trials are safe, Dr. Kasi explained.

“When this study was designed several years ago, at that time, to even consider using ctDNA to guide adjuvant chemotherapy was … fraught with a lot of polarized opinions. These results set the stage for ongoing clinical trials,” he said.

For now, the BESPOKE researchers will continue to follow their participants to see if doctors used ctDNA testing information to change treatment strategies in real time, and whether that impacted the risk of cancer recurrence.

Highlighting the need for better treatments

One elephant in the room, said Dr. Allegra, is that around a quarter of patients with stage II or III colorectal cancer won’t be cured even with adjuvant chemotherapy. For someone who has undergone all the standard therapies and still has ctDNA in their blood, “what do you do for that patient?” he asked.

Clinical trials are currently looking at ways to improve outcomes in this scenario, including using different chemotherapy drugs, giving second-line chemotherapy earlier, and testing immunotherapies for tumors with certain genetic characteristics, Dr. Allegra explained.

But results from the patient-reported outcomes from BESPOKE suggest that people want to know what’s happening in their bodies as soon as possible, even if the ctDNA test result is bad news, said Dr. Kasi. And they want to make shared decisions about their future care, he added.

“This test powerful insights about to consider next treatment or clinical trial options earlier,” said Dr. Kasi. “It's also picking up cancer 6 to 9 months before the scans pick it up. I would consider this an integral tool in our toolbox, and it's here to stay,” he said.

Undergoing follow-up testing for cancer recurrence more than once a year may not benefit people who have been treated for colorectal cancer, results from two new studies show.

The goal of follow-up testing, or surveillance, of people who have been treated for cancer is to improve patient survival by detecting and treating a recurrence early. But results from both studies, published May 22 in JAMA, showed that more frequent tests did not change the rate of detection of recurrence or death due to cancer.

For people who are diagnosed with colorectal cancer that has not spread to distant locations in the body, surgery can cure most patients. But in some patients, the cancer will return, usually within 3 years after surgery.

To try to detect recurrences as early as possible, people who have finished colorectal cancer treatment regularly return to their doctors for imaging tests (like CT or MRI scans) and a blood test to detect CEA, a substance that can indicate if cancer is growing. However, current medical guidelines differ on the recommended surveillance tests and how often they should be performed.

The National Comprehensive Cancer Network, for example, recommends that people who are treated for stage II or III colon or rectal cancer have CEA testing every 3 to 6 months for 2 years and then every 6 months for 3 additional years, plus CT scans every 6 to 12 months for 5 years.

“The data should definitely force us to get back together as a group and think about whether we need to revise the guidelines,” said Blase Polite, M.D., an oncologist at the University of Chicago Medical Center.

Based on the findings of these and other studies, “there is now a considerable body of evidence that imaging and CEA testing more often than every year does little to improve survival in a meaningful way,” wrote Hanna Sanoff, M.D., of the University of North Carolina at Chapel Hill, in an editorial on the two studies.

What Is the Best Surveillance Strategy for Colorectal Cancer?

Both of the new studies aimed to determine whether increased surveillance improved outcomes of colorectal cancer, but they took different approaches.

In one study, more than 2,500 people from several European countries who had had surgery to treat colorectal cancer were randomly assigned to receive either high- or low-intensity surveillance testing. Within 3 years after surgery, the high-intensity group received a CT scan and CEA assay 5 times each, while the low-intensity group received both tests twice.

The study, called COLOFUL, was led by Peer Wille-Jørgensen, D.M.Sc., of the Danish Colorectal Cancer Group.

After 5 years, the rate of detected cancer recurrence was unchanged between the high-intensity group and the low-intensity group. In addition, there was no difference in deaths overall or deaths from colorectal cancer between the two groups, the researchers found.

The findings were similar when the investigators stratified participants by cancer stage.

The other study was a retrospective cohort study, funded partly by NCI, of more than 8,500 people who had been treated for colorectal cancer in the United States and who were registered in the National Cancer Database—a collection of clinical oncology data gathered from multiple hospitals. The researchers used the database and additional information regarding surveillance testing and recurrence to track the patients’ care for a minimum of 5 years, beginning with their cancer surgery.

“We noticed that there was tremendous variation in the number of tests patients received” and that the facility where patients received their follow-up strongly influenced the number of tests, explained the lead investigator, George J. Chang, M.D., of the University of Texas MD Anderson Cancer Center.

When the researchers characterized each facility as one that performed high- or low-intensity surveillance, they found that patients who were treated at low-intensity surveillance facilities received an average of 1.6 imaging tests and 1.6 CEA tests in 3 years. At high-intensity surveillance facilities, patients received an average of 2.9 imaging tests and 4.3 CEA tests in 3 years. On average, patients who were initially treated for advanced stage colorectal cancer received more tests.

Cancer recurrence was not detected earlier in patients who were tested at high-intensity facilities, regardless of cancer stage, Dr. Chang and his colleagues found. Nor did they find a significant difference in rates of treatment for cancer recurrence between patients who were tested at high- and low-intensity facilities.

Overall survival was also unaffected by the intensity of surveillance. The 5-year overall survival rate was about 74% for participants tested at both high- and low-intensity facilities.

What the results from these two studies reveal, said Dr. Polite, is that tumor biology trumps surveillance intensity. A slow-growing colorectal cancer “probably isn’t going to change all that much between year 2 and year 3. So, you’re probably not missing that window of opportunity” by doing surveillance tests once a year, he said. And colorectal cancer that spreads quickly between yearly surveillance tests is not likely to respond to available treatments anyway, he explained.

But for people who have been treated for colorectal cancer and who have certain risk factors that increase the risk of recurrence, more intense surveillance might be appropriate, Dr. Polite added. “I think we will end up risk-adapting guidelines as we learn more,” he said.

Important, But Imperfect, Studies

Although these new studies are important, they do have limitations, Dr. Sanoff pointed out. For example, she noted, the COLOFUL trial investigators modified the design of their study to increase enrollment and aid trial completion.

And because the trial was conducted in Europe, another question is “whether the findings apply to the US population, with our diet and exercise habits,” said Dr. Polite.

Dr. Chang’s study compared the outcomes of patients who got tested at a high- or low-intensity facility, rather than comparing the outcomes of patients who received high-intensity or low-intensity testing, Dr. Sanoff noted. “Multiple factors, such as the aggressiveness of surgical resection at an individual facility, might influence these outcomes other than surveillance frequency,” she wrote.

The Bottom Line for Survivors and Their Physicians

Based on their findings, Dr. Chang and his colleagues agreed with the surveillance recommendations of the National Institute for Health and Care Excellence in the United Kingdom: In the first 3 years following initial surgery, people who have been treated for colorectal cancer should receive CEA testing every 6 months in addition to two CT scans.

Although some patients may prefer more frequent surveillance for peace of mind, the tests are not without harms, Dr. Chang pointed out. Follow-up tests can be a psychological and financial burden on patients. In addition, every test comes with the risk of false-positive results that can lead to unnecessary and invasive additional tests.

“The message for survivors is one of reassurance,” Dr. Chang said. “They don’t have to get a CT scan at every follow-up visit.”

The emphasis during follow-up should be not only on recurrence detection, but on the entire survivorship experience, he added. This encompasses monitoring people who have undergone cancer treatment for toxicities from their treatment, counseling them about leading a healthy lifestyle, and providing them with appropriate resources for psychosocial support and management of financial toxicity when needed.

That aspect of follow-up shouldn’t change, said Dr. Polite.

Colorectal cancer is a leading cause of cancer death among people of Hispanic and Latino descent in the United States. Adan Reinosa Rivera, a retired electrical engineer in Los Angeles, is doing his part to change that.

Mr. Reinosa has been living with metastatic colorectal cancer for more than a decade. The cancer was detected in his lungs a few months after a tumor was removed from his colon. He’s been managing the disease with his doctor ever since. 

Now, as the first participant in a genetic study called ENLACE, Mr. Reinosa is helping to build a body of knowledge about the molecular features of colorectal cancers in Hispanic and Latino people.

The study, supported by the Cancer Moonshot, aims to learn more about the disease in people of Hispanic and Latino descent, with the ultimate goal of improving treatments for this population group. And to achieve this aim, investigators are also testing ways to engage more people from this group in cancer research.

Mr. Reinosa, who is 65 years old and restores classic sports cars in his free time, is helping with both goals. He has provided blood and tumor samples for analysis with genomic tools such as DNA sequencers. And he is part of the study’s patient advisory panel, which is developing ideas about how to engage potential participants and improve the research experience. 

“I hope my feedback will help the study better serve other people in our community,” Mr. Reinosa said. 

Genetic counselors help participants understand their test results

ENLACE is the first study to use cutting-edge technologies to describe the molecular features of colorectal tumors in Hispanic and Latino people. Researchers plan to enroll 500 participants with all forms of colorectal cancer.

Tumor samples and blood from these participants will be analyzed for genetic changes linked to colorectal cancer, both those that arose during the development of the cancer as well as those that were inherited from a parent. 

“What’s exciting is that we are doing genetic testing in a patient population that would not have had the testing outside of this study,” said Heinz-Josef Lenz, M.D., of the USC Norris Comprehensive Cancer Center in Los Angeles, who is co-leading the research. 

Dr. Lenz said he has already identified genetic mutations in the tumors of some participants and has used that information to help guide treatment decisions. 

The ENLACE team includes bilingual genetic counselors who are trained in culturally sensitive ways of communicating genetic information. They meet with participants before testing to explain in accessible language how genetic testing for colorectal cancer works. 

The genetic counselors also help participants understand their test results. For example, if a participant were found to have an inherited genetic mutation linked to cancer, a counselor could explain how the finding would affect cancer screening and prevention for the participant and the person’s family in the future. 

“We want our patients to understand what these tests mean for themselves and their care,” said study co-leader Mariana C. Stern, Ph.D., also of the Norris Comprehensive Cancer Center. “We also want to empower patients to ask questions of their health care providers.” 

The researchers are also asking participants about aspects of their lifestyles and diets that may contribute to the risk of colorectal cancer. Other questions focus on social, economic, and physical factors that can affect a person’s health and well-being, such as where the person was born and where they are currently living. Such factors are known as social determinants of health.

Rising rates of early-onset colorectal cancer

Diagnoses of colorectal cancer in adults under age 50 have been increasing around the world, particularly in high-income countries. In the United States, the incidence of such early-onset tumors has risen more rapidly in Hispanic and Latino people than in those of any other racial and ethnic groups.

“We really do not understand why there has been a steep increase in early-onset colorectal cancer among Hispanics,” Dr. Lenz said.

To address this gap in knowledge, he teamed up with John Carpten, Ph.D., who was then chair of translational genomics at the Keck School of Medicine of USC. With Cancer Moonshot funding, they launched the Center for Optimization of Participant Engagement for Cancer Characterization, which includes ENLACE.

Their hope is that the study could also help reveal some clues about the rising incidence of early-onset colorectal cancer. “Expanding the participation of Hispanics and Latinos with colorectal cancer in genomic research is critical for making progress against the disease,” Dr. Lenz said.

A national network for improving participant engagement 

The USC participant engagement center is one of five such centers in the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Each is investigating understudied cancers or populations of patients (see sidebar).

The centers all have two main aims: to promote and support the engagement of participants in cancer research, and to learn more about the biology of understudied cancers in diverse populations.

What is the PE-CGS Network?

The PE-CGS Network was developed to address knowledge gaps in cancer genomics in diverse and underrepresented populations. The network includes a coordinating center and five PE-CGS research centers, which are studying:

• colorectal cancer in Hispanics and Latinos
• early-onset colorectal cancer, multiple myeloma, and bile duct cancer in African Americans
• low-grade gliomas
• rare sarcomas
• cancers that affect American Indian communities

The engagement aim reflects an expanded idea of what it means to participate in cancer research. Participant engagement is increasingly viewed as a mutually beneficial relationship between researchers and participants, according to an analysis led by PE-CGS researchers at The Ohio State University.

“The idea is that the research experience supports learning and sharing between participants and researchers, where the relationship is ongoing to foster continuous growth,” said study leader Anne Schuster, Ph.D., of The Ohio State University College of Medicine.

To achieve this, the research centers are exploring ways to enhance the engagement of participants throughout their studies, starting with making the recruitment phases more inviting. They're also investigating ways to address historical barriers to participation, such as poor access to research facilities or lack of trust in medical research.

“Our focus is on involving groups of people who have historically not been part of research on cancer genomics,” Dr. Schuster said. 

The PE-CGS Network was created with a goal of ensuring that underserved communities eventually benefit from the latest advances in cancer medicine, noted Leah Mechanic, Ph.D., of NCI’s Division of Cancer Control and Population Sciences and the NCI lead for the network.

“Through participant engagement,” she continued, “the network has the potential to improve the recruitment and retention of historically underserved and underrepresented populations in research.” 

Expanding awareness of recommended cancer screenings

ENLACE is an example of patient-centered care, Dr. Stern said. 

“We are providing patients with knowledge and listening to their concerns and questions so that we can optimize our study,” she said. 

Some opportunities to improve the study have begun to emerge. For instance, the questionnaires that participants answer about their health and about the study itself can take hours to complete, the researchers have learned. The time commitment can be a burden for busy participants, Dr. Lenz noted, adding that his team will explore ways to collect the information in less time.

On a positive note, many participants have made sure that family members get screened for colorectal cancer if they are eligible. Participation in the study, Dr. Lenz suggested, may start conversations about the importance of staying current on all recommended cancer screenings, including tests for breast and cervical cancer.

“We might save more lives among family members than among the patients themselves,” he said. “A few months after treating a patient, I often hear that one of the person’s relatives had a very bad polyp removed. The families are so appreciative.” 

Helping other people with colorectal cancer

Mr. Reinosa recently received the results of a genomic analysis of one of his metastatic tumors. The analysis revealed a genetic change that his doctors said could potentially play a role in the growth of the cancer and could be a potential target for treatment.

But the doctors cautioned that more research is needed to determine the finding’s significance. “It could be nothing, or it could be something,” said Mr. Reinosa. “That’s what research is for—answering these kinds of questions.” 

He remains optimistic. “I’m confident that scientists will learn something from my tumor that will help someone else with colorectal cancer, if not me.”

Radiation combined with chemotherapy, also known as chemoradiotherapy, is routinely given to people with rectal cancer whose tumors can be removed with surgery. The treatment can shrink tumors, making it easier to remove the entire tumor and helping to prevent the disease from coming back.

Now, results from a large NCI-funded clinical trial suggest that radiation may not be needed before surgery for all people with this form of rectal cancer, which is called locally advanced because it has spread within the rectum but not to other organs. A newer form of combination chemotherapy ahead of surgery appears to be just as effective as chemoradiotherapy at keeping the disease at bay, the trial showed.

“This is practice changing,” said Deborah Schrag, M.D., of Memorial Sloan Kettering Cancer Center, who led the study.

Patients with specific clinical stages of rectal cancer may be able to safely skip radiation, Dr. Schrag continued. “And if you don't get radiation, you're not going to have the long-term adverse effects of radiation, which may be very important to some people. Globally this is important because in some countries access to radiation is very scarce.”

In the trial, called PROSPECT, nearly 1,200 people with locally advanced rectal cancer were randomly assigned to receive either a chemotherapy regimen called FOLFOX or chemoradiotherapy, which uses just one chemotherapy drug, before surgery.

After a median follow-up of nearly 5 years after surgery, 81% of people in the FOLFOX group were still alive with no signs of cancer (known as disease-free survival), compared with 79% of people in the chemoradiotherapy group, Dr. Schrag reported at the American Society of Clinical Oncology (ASCO) annual meeting in June. The study results were simultaneously published in the New England Journal of Medicine.

During treatment, people in the chemoradiotherapy group reported fewer side effects than people in the FOLFOX group. However, one year after surgery, people in the FOLFOX group reported fewer side effects than those in the chemoradiotherapy group. Those results were published separately June 4 in the Journal of Clinical Oncology.

“What PROSPECT gives us is an alternative,” said Carmen Allegra, M.D., who works with NCI’s Cancer Therapy Evaluation Program and was not involved in the trial. “Patients now have an option other than chemoradiotherapy.”

Younger people who want to avoid the harmful effects of radiation on fertility might opt for FOLFOX, while someone who can’t tolerate the side effects of FOLFOX might choose chemoradiotherapy instead, Dr. Allegra said.

Questioning the need for radiation 

Globally, around 800,000 people will be diagnosed with rectal cancer in 2023, and about half with locally advanced tumors.

For more than 3 decades, chemoradiotherapy before surgery, called neoadjuvant chemoradiotherapy, has been standard treatment in the United States for people with locally advanced rectal cancer. The treatment, when combined with modern surgical techniques, is very effective. But pelvic radiation comes with many short- and long-term side effects, such as impaired bladder, bowel, and sexual function; pelvic fractures; and secondary cancers.

In recent years, multidrug chemotherapy regimens like FOLFOX have become a standard postsurgical (adjuvant) treatment for people with locally advanced rectal cancer. In addition, colorectal cancer screening rates have improved, leading to earlier diagnoses. Surgical techniques and methods for ensuring that patients’ cancers are accurately diagnosed so they get the most effective and appropriate treatment have also improved.

“All these other things got better, but we just kept doing radiation,” Dr. Schrag said. “It was time to try to capitalize on those advances.”

So she and her colleagues set out to answer some critical questions: Could neoadjuvant chemoradiotherapy be omitted for patients who respond to combination chemotherapy without increasing the risk of recurrence? And how do the two treatment options compare with respect to side effects? 

Following promising results from a pilot study of FOLFOX before surgery in people with this stage of disease, Dr. Schrag and her colleagues launched PROSPECT to compare these options head-to-head.

Similar outcomes with chemotherapy alone

In PROSPECT, which was conducted by the Alliance for Clinical Trials in Oncology, researchers randomly assigned 1,194 people with locally advanced rectal cancer (stages T2 or T3 involving lymph nodes and T3 not involving lymph nodes) to receive either pelvic chemoradiotherapy or six cycles of FOLFOX before surgery. Adjuvant chemotherapy was recommended but not required.

The study was a noninferiority trial, meaning it was designed to test whether neoadjuvant FOLFOX would be no less effective than neoadjuvant chemoradiotherapy for people with tumors that weren’t at high risk of spreading.

After almost 5 years, cancer-specific outcomes between the FOLFOX and chemoradiotherapy groups were very similar. In addition to patients in both groups having nearly identical disease-free survival, they also had nearly the same outcomes for other cancer-related findings, including their 5-year overall survival and the return of the cancer in the rectum.

For those in the FOLFOX group who had serious side effects or whose tumors shrank by less than 20%, chemoradiotherapy was given ahead of surgery. Only 9% of people in the FOLFOX group went on to receive neoadjuvant chemoradiotherapy.

When it came to side effects, there were notable differences between the groups with respect to timing. During treatment, for example, fewer people in the chemoradiotherapy group reported effects, such as appetite loss, constipation, fatigue, and neuropathy, than people in the FOLFOX group.

However, a year after surgery, the pattern had reversed, with fewer people in the FOLFOX group reporting lingering side effects than people in the chemoradiotherapy group. Participants in both groups reported similar overall quality of life during and after treatment.

Empowering people with more options 

According to Corrie Marijnen, M.D., Ph.D., of the Netherlands Cancer Institute, who commented on the study at the ASCO meeting, guidelines for treating locally advanced rectal cancers vary in different parts of the world. For example, in Europe, neoadjuvant treatment is generally only used in people with what are considered to be high-risk tumors. So PROSPECT’s findings will likely apply largely to people being treated in North America, she said.

In addition, she noted, new approaches to treating rectal cancer have emerged since the trial launched in 2012.

One approach being evaluated is total neoadjuvant therapy, which incorporates chemotherapy with chemoradiotherapy before surgery. In some cases, total neoadjuvant therapy can help some patients avoid surgery altogether.

Other studies are testing immunotherapy, particularly in people with locally advanced rectal cancer that has specific genetic changes. In one recent study of 12 people with rectal cancer whose tumors had these changes, the immune checkpoint inhibitor dostarlimab led to complete tumor shrinkage in every patient. According to updated data from the trial presented earlier this year, 30 patients have been treated and all 30 had their tumor completely disappear.

In the meantime, for many people with locally advanced rectal cancer, being able to avoid the effects of radiation can be empowering, Dr. Allegra said.

“Before PROSPECT, we didn't safe to not give radiation,” he said. “Now we know, yes, there's a safe way to skip radiation, if that's your preference. There are a lot of factors that go into that decision, but at least you have the opportunity to make that decision.”