Advances in Colorectal Cancer Research

Prevention and Early Detection

Screening can reduce the risk of CRC through detection of precancerous growths, or polyps, before they become cancerous. It can also allow cancers to be detected early, before they cause symptoms and when treatment may be more effective.

CRC screening tests. These include colonoscopy, sigmoidoscopy, stool-based tests, and virtual colonoscopy. Also, the screening test Cologuard, approved by the FDA, is a home test that checks for changes in DNA and blood in the stool. Either change could mean that a polyp or colon cancer is present.

Despite the availability of effective CRC 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.

A Positive FIT? Get that Follow-Up Colonoscopy

Dying from colorectal cancer twice as likely in those who didn’t get follow-up.

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 screen patients for CRC
• developing blood tests that can be used to detect the presence of specific cancers

Repeat screening or follow-up. The guideline for getting a screening colonoscopy is every 10 years. However, if one or two small noncancerous polyps are found, people usually get a repeat screening 5 years later.

NCI’s FORTE Colorectal Cancer Prevention Trial, is now looking at whether some people with 1 or 2 small polyps can wait 10 years before returning for another colonoscopy. By comparing two study groups, one with repeat screenings after 5 years, and one with screenings 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. 

Another concern about CRC screening is that some people don’t repeat screenings or follow up on abnormal test results. NCI is funding research to better understand how to increase the acceptance of repeat and follow-up screenings. Scientists are also studying the many levels of the healthcare delivery system and their effect on the decision to get screened.

Treatment for Colorectal Cancer

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 is the most common treatment for local and locally advanced rectal cancer, advanced stages may also be treated with radiation, chemotherapy, and targeted therapy.

In addition to these standard treatments, researchers are continuing to study new colorectal cancer treatments, such as immunotherapies, as well as new combinations of existing treatments, in clinical trials.

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

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

A genetic feature known as microsatellite instability-high (MSI-H) makes up about 15 percent of patients with stages II and III colorectal cancer and about 5 percent 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.

Indeed, the immune checkpoint inhibitors nivolumab (Opdivo), ipilimumab (Yervoy), and pembrolizumab (Keytruda) have been approved for the treatment of metastatic CRC in patients with Lynch syndrome. They also have been approved for metastatic CRC in patients with MSI-H cancers . 

The COMMIT study is combining chemotherapy, bevacizumab (Avastin), and/or atezolizumab (Tecentriq) in treating patients with deficient DNA mismatch repair metastatic colorectal cancer. The hope is that combining the different ways they work will improve the treatment results in patients with colorectal cancer.

Another NCI-sponsored trial is studying the combination of chemotherapy with or without atezolizumab in treating patients with stage III colon cancer and deficient DNA mismatch repair. The goal is to see how well the combination works compared with chemotherapy alone.

Combining immunotherapy with other treatments for patients without Lynch syndrome

Immune checkpoint inhibitors have been less effective in the 80% of CRC patients without Lynch syndrome, and those 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 CRC. The goal is to find agents that can block the activity of the abnormal proteins produced by these mutations. For example the:

• NCI-supported trial showed that colorectal cancer that contains mutations in the BRAF gene responds to treatment with the drug vemurafenib (Zelboraf). This drug targets mutant B-Raf proteins when combined with cetuximab (Erbitux) and irinotecan (Camptosar) (a chemotherapy drug).
• FDA approved the drug encorafenib (Braftovi) 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.
• NCI-sponsored SOLARIS trial is testing how well vitamin D3 given with the already approved combination of chemotherapy and bevacizumab works in treating patients with metastatic colorectal cancer. The goal is to see if adding high dose vitamin D3 to the combination may help shrink or stabilize the cancer more than chemotherapy and bevacizumab alone.
• 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 CRC have tumors that express 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 CRC early, measure treatment responses, identify treatment resistance, and monitor for disease recurrence.

One example is the COBRA trial which studies how well circulating tumor DNA (ctDNA) testing in the blood works to identify patients with stage IIA colon cancer who might benefit from additional treatment with chemotherapy after surgery. ctDNA are small pieces of genetic materials (DNA) that are shed by tumors into the blood. Finding ctDNA in the blood may help identify patients with colon cancer who would benefit from receiving chemotherapy after surgery.

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and world, are seeking ways to address colorectal cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts for colorectal cancer.

• NCI's Gastrointestinal (GI) SPOREs focus on translational research in the gastrointestinal system. Currently, GI SPOREs focus on cancers of the colon, rectum, esophagus, liver, gastrointestinal stromal tumors (GIST), and pancreas, which account for the majority of new diagnoses.
• The Population-based Research to Optimize the Screening PRocess (PROSPR) is an NCI-supported network conducting research to better understand how to improve the entire cancer screening process (recruitment, screening, diagnosis, referral for treatment) for lung, colorectal, and cervical cancer in community healthcare settings.
• Accelerating Colorectal Cancer Screening and Follow-Up Through Implementation Science (ACCIS) is intended to promote research in colorectal cancer screening, follow-up, referral-to-care and best practices for how multilevel interventions can be scaled-up in regions of the United States where screening rates are below national standards.
• Approaches to Identify and Care for Individuals with Inherited Cancer Syndromes are studies designed to increase screening, prevention, and early treatment of people at high risk of cancer due to an inherited genetic susceptibility.
• The NCI-funded Colon Cancer Family Registry (CCFR) has established an international cohort of thousands of colorectal cancer patients, their relatives, and individuals at increased risk of colorectal and other cancers. Over 10,000 families from the United States, Canada, Australia, and New Zealand have been registered. The database includes more than 2,000 individuals with Lynch syndrome, from 781 families. 
• The goal of the Screen to Save Initiative, funded by NCI’s Center to Reduce Cancer Health Disparities, is to increase colorectal cancer screening in areas that need it most. Through community health educators, the program provides education and outreach to increase access to resources for those who may be affected by colorectal cancer.
• Dissemination of a Colorectal Cancer Screening Program Across American Indian Communities in the Southern Plains and Southwest United States is an effort to increase the use of colorectal cancer screening tests in American Indians. This project supports research on system-level changes and culturally appropriate media to promote screening, with the goal of closing the gap in colorectal cancer outcomes between the American Indian population and the general US population.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for colorectal cancer screening, to prevent colon and rectal cancer, and treatment for colon cancer and rectal cancer. 

Colorectal Cancer Research Results

The following are some of our latest news articles on colorectal cancer research:

• Tucatinib and Trastuzumab Combination Approved for Advanced Colorectal Cancer
• Keto Molecule Offers Clue for Preventing Colorectal Cancer
• Colonoscopy after Positive FIT Test Cuts Risk of Colorectal Cancer Death
• Does Too Much Fructose Help Colorectal Cancers Grow?
• Pattern of DNA Damage Links Colorectal Cancer and Diet High in Red Meat
• Should People Over Age 75 Be Screened for Colorectal Cancer?

View the full list of Colorectal Cancer Research Results and Study Updates.