Advances in Colorectal Cancer Research

Prevention and Early Detection

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.

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 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. 

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.

• The NCI-supported genetic study, ENLACE, aims to learn more about colorectal cancer in people of Hispanic and Latino descent, with the ultimate goal of improving treatments for this population group. To achieve this, scientists are also testing ways to engage more people from this group in cancer research.
• 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 for Cancer Health Equity, 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.
• 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.

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:

• Colorectal Cancer Screening: Where Does the Shield Liquid Biopsy Fit In?
• ctDNA May Guide Who Needs Chemo After Colorectal Cancer Surgery
• ENLACE Study Explores Colorectal Cancer in Hispanic and Latino People
• Is AI Ready to Play a Leading Role in Colorectal Cancer Screening?
• Some People with Rectal Cancer Can Skip Radiation Before Surgery
• How Fatty Liver Disease Helps Cancer Thrive in the Liver

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