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Neoadjuvant Immunotherapy Effective for Mismatch Repair–Deficient Colorectal Cancer

Mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) colorectal cancer (CRC) is an advanced form of CRC that is highly responsive to treatment with immunotherapy, especially PD-1 inhibitors. Preliminary research results demonstrate that PD-1 inhibitors are significantly effective cancer treatments, with high response rates and sustained progression-free survival. 

A new study investigated the treatment impact of neoadjuvant PD-1 inhibitors on the long-term survival of dMMR CRC patients. The study found that PD-1 inhibitor treatment before surgery was significantly effective among patients with dMMR/MSI-H CRC.

Seventy-three patients with dMMR/MSI-H CRC who had previously been treated with PD-1 inhibitors were included in a retrospective review. The most common locations of primary tumors were in the rectum (24.7%) and ascending colon (24.7%). 79.5% of patients were treated with PD-1 inhibitor alone. The study found:

  • Nearly all patients involved in the study benefited from neoadjuvant PD-1 inhibitors, with 25% experiencing complete response.
  • 84.9% of patients experienced an objective response, with 61.6% achieving a partial response. 
  • The two-year tumor-specific overall survival and disease-free survival rates for patients who underwent surgery after PD-1 blockade were both 100%.

These findings are promising for patients with nonmetastatic dMMR/MSI-H CRC, including those with locally advanced disease. Dustin A. Deming, MD, University of Wisconsin Carbone Cancer Center, stated in an NCCN newsletter, “The treatment of mismatch repair deficient locally-advanced colorectal cancer is a highly active area of research. This retrospective analysis highlights the potential for significant treatment responses with limited toxicities for these patients treated with immune checkpoint inhibitors. It will be exciting to see how these results, and other completed and ongoing studies, will be utilized to incorporate anti-PD1 treatments into the standard-of-care for locally-advanced colorectal cancers.”

To read more about types of immunotherapy drugs and their impact on cancer care, visit Understanding Cancer Immunotherapy Research. 

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Plant-Based Diets Lower Colorectal Cancer Risk in Men

Colorectal cancer (CRC), the third most common cancer and the third leading cause of cancer-related deaths in the U.S., is preventable with regular screening. In addition to routine screening, other modifiable risk factors, such as diet, play an important role in lowering the risk of CRC. For example, red and processed meats are associated with an increased risk for CRC, while diets rich in dietary fiber reduce the risk of CRC. 

A recent prospective cohort study discovered that plant-based diets rich in healthy plant foods were associated with a lower risk of CRC in men, and varied based on race, ethnicity, and tumor location. These findings signify the importance of incorporating healthy plant foods into diets and reducing meat consumption to lower the risk of CRC. 

The multiethnic cohort study included 79,952 men and 93,475 women. Three plant-based diet scores were investigated to determine the incidence of invasive CRC:

  • Overall plant-based diet index (PDI)
  • Healthful plant-based diet index (hPDI)
  • Unhealthful plant-based diet index (uPDI)

The participants completed a food frequency questionnaire with over 180 food items. PDI, hPDI, and uPDI were calculated based on scoring methods and defined food groups that included:

  • Healthy plant foods, such as whole grains, fruits, vegetables, vegetable oils, nuts, legumes, tea, and coffee.
  • Less healthy plant foods, such as refined grains, fruit juices, potatoes, and added sugars.
  • Animal foods, such as animal fat, dairy, eggs, fish and seafood, and meat. 

Each food group was associated with specific scores. 

  • High PDI scores demonstrated greater consumption of all types of plant foods. 
  • High hPDI foods showed greater consumption of healthy plant foods and lower consumption of less healthy plant foods. 
  • Higher uPDI scores demonstrated lower consumption of healthy plant foods and greater consumption of less healthy plant foods. 

The study found that a plant-based diet that includes natural, rather than processed, plant-based foods is associated with a reduced risk of CRC in men. For women, however, none of the plant-based diets were significantly associated with CRC risk. For both men and women, the average scores of PDI and hPDI were highest among Japanese Americans and lowest among Native Hawaiians. The mean uPDI was highest in Native Hawaiian men and lowest in African American men and white women. Men with higher scores for PDI and hPDI had a 24% and 21% lower risk of CRC than men with lower scores for those diets, respectively. Furthermore, no significant association was found between risk for CRC and uPDI for men.

These analyses highlight the potential significance of plant-based diets in preventing CRC and suggest that the benefits of plant-based diets can vary based on sex and race/ethnicity. The findings underscore the importance of increasing healthy and less-processed plant foods in our diet and reducing meat consumption to lower the risk of CRC.

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Masculinity May be a Barrier to Completing Colorectal Cancer Screening

Man

Colorectal cancer (CRC) mortality is preventable with regular screening. Differences in early detection screening rates lead to disparities in CRC mortality among White, Black, and American Indian/Alaska Native (AIAN) men. Complicating the issue of racial disparity observed with CRC screening rates is the psychosocial aspect of men’s health. A recent study investigated the impact of masculinity barriers on CRC screening and found that they influence CRC screening completion.  

This survey-based cross-sectional study analyzed the association between the male thought process and the successful completion of CRC screening tests. Male respondents aged 18 to 75 years from across the U.S. who self-identified as Black, AIAN, or white were surveyed. Four Masculinity Barriers to Medical Care subscale were investigated:

  • Being strong
  • Acknowledging emotions and health issues
  • Positive attitude toward medical professionals and exams
  • Negative attitude toward medical professionals and exams

The highest score, which translates into the greatest barrier for screening, was for “Being strong” and “Negative attitudes towards medical professionals and exams”

Lower scores were observed for “Acknowledging emotions and health issues” and “Positive attitudes toward medical professionals and exams”

For all men, “being strong” was associated with a 54% decreased odds of CRC screening completion. 

Reluctancy to seek and engage in preventive health services, such as CRC  screening, due to fear of presenting as weak or vulnerable is associated with men who strongly support masculine ideals. The investigation also demonstrated that Black men who scored higher on negative attitudes toward medical professionals and exams subscale had lower odds of CRC screening uptake. The sensitivity analysis of the study reflected that AIAN men had lower odds of CRC completion than Black men. 

Medical mistrust is positively correlated with masculine ideologies. Despite decreasing CRC incidence and mortality rates in adults ages 50 years and older, early-onset CRC has increased among adults younger than 50 and is predicted to increase by 90% by 2030. Considering the above masculinity barriers in future population-based and intervention research is critical for increasing men’s participation in CRC screening.

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Expanding Multigene Panel Testing Criteria for Colorectal Cancer Patients

Multigene panel testing (MGPT) is a tool to identify genetic mutations that can increase an individual’s risk of a disease such as cancer. MGPT can also be used to develop a treatment plan or to help predict whether cancer will spread to other parts of the body. A recent study examined colorectal cancer (CRC) patients and found that 14.2% of patients carried at least one pathogenic germline variant (PGV), with more than one PGV identified in 1.4% of patients. 

Identification of pathogenic or likely PGVs in hereditary cancer predisposition genes can affect a patient’s treatment plan. While there is increased support for universal MGPT for certain forms of cancer, eligibility criteria for CRC are more restrictive: germline genetic testing for CRC is recommended only for a subset of patients with CRC who meet certain “high-risk criteria,” which include:

  • Diagnosis before 50 years 
  • Lynch syndrome–related cancers 
  • Having a family history of certain Lynch syndrome-related cancers 
  • Abnormalities in mismatch repair immunohistochemistry

The above mentioned study conducted MGPT across a diverse CRC population to determine whether genetic testing criteria for patients with CRC should be broadened. The results of the study found that of the 34,244 individuals who were tested:

  • 14.2% of individuals carried at least one PGV, with more than one PGV identified in 1.4% 
  • 11.9% of individuals carried a clinically actionable variant, including 9.1% carrying a PGV in a gene associated with an increased CRC/polyposis risk 
  • 5.7% of individuals carried Lynch syndrome–related PGVs 

This research study is the largest to date examining MGPT in CRC, and demonstrated high rates of clinically actionable variants detected, independent of the age at the time of testing, the number of genes on the panel, and race/ethnicity. These findings provide evidence to support the broadening of genetic testing criteria for patients with CRC, which in turn will have a significant impact on disease management, the treatment plan, and ultimately, disease outcome.

 

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Setting it Straight: The Colonoscopy Controversy

A new study published in the New England Journal of Medicine has sparked controversy—this 10-year study involving nearly 85,000 participants in Europe highlighted that colonoscopies cut the risk of colorectal cancer (CRC) only by about a fifth, far below estimates from earlier scientific studies, and didn’t substantially reduce deaths, raising the possibility that the invasive procedure is not worth it. Doctors in the U.S. are now concerned that the study’s results could cause doubt about the effectiveness of a colonoscopy, which is a recommended CRC screening approach for those 45 and older, to be conducted once in ten years. Despite the confusion about the effectiveness of colonoscopies, national news articles and gastroenterologists in the U.S. have rebuked these conclusions. 

A major limitation that experts found with the study was that only 42% of the people who were invited to get a colonoscopy actually had one. However, researchers still reported the outcomes for the entire cohort, regardless of whether or not they underwent a colonoscopy. The study found that of those who were invited to have a colonoscopy—whether they got it or not—there was an 18% reduction in developing the disease and no statistically significant reduction in the likelihood of CRC death. Many don’t believe that this is representative of what happens in the U.S., where colonoscopy is more widely accepted as a standard screening protocol compared to European countries, and was a serious shortcoming of the study. In fact, when the individuals who did not get a colonoscopy were removed from the study, the risk of developing CRC among those who did get a colonoscopy reduced by an estimated 31% and the risk of death reduced by about 50%.

As Robin Mendelsohn, MD, co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at the Memorial Sloan Kettering Cancer Center, argues “in order for a colonoscopy to be effective, you have to have it done”.

Andrew Albert, MD, a member of the Colon Cancer Foundation (CCF)’s Interdisciplinary Medical Advisory Council (IMAC), said, “While the NordICC trial demonstrates the need for challenging the status quo related to colonoscopy, this remains an effective screening tool, particularly for individuals at average risk who may be on the fence about going in for screening. Misinformation is dangerous, especially in healthcare. If we miss catching colorectal cancer at an early stage—which is what a colonoscopy is very good at—it can have a big impact on survival. We need to remember that CRC is preventable, and treatable when caught early.”

IMAC member Matthew A. Weissman, MD, MBA, FAAP, told CCF, “I hope that the findings of this study, which have been taken out of context by many, will not discourage folks from getting screened for colon cancer by colonoscopy or other appropriate methods, which is extremely important in early detection (and prevention) of this deadly disease.”

In an accompanying editorial in the same issue, experts point to the need for a longer follow-up time for the impact of screening colonoscopy to be realized. They also point out that the skill of the endoscopist conducting the procedure has a significant impact on the detection rate—29% of endoscopists in the trial had an adenoma detection rate below the recommended 25%. 

Consequent to this study, the American Society for Gastrointestinal Endoscopy (ASGE) issued a public statement that colonoscopy remains the best and most proven way to detect and prevent CRC incidence and death. The American Cancer Society also weighed in on the study, pointing to the high number of participants who didn’t undergo the procedure. Adam Lessne, MD, a gastroenterologist at Gastro Health in Florida told VeryWell Health that “when you take away the limitations, it’s proven again that colonoscopies do save lives and they do reduce the risk of death.” 

The bottom line is that a screening test of any kind—stool-based or colonoscopy—is better than none, and CRC is preventable with regular screening. For detailed information on various CRC screening methods and current screening guidelines, visit this page on the Colon Cancer Foundation’s website. 

 

Kitty Chiu is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Distance, Region, and Insurance Coverage Associated With Increased Risk of Advanced Colon Cancer

Early-stage colon cancer is treatable and has a very promising survival rate. However, less than 40% of new colon cancer diagnoses are early-stage disease. Now, a new study has identified an association of distance, region, and insurance coverage with advanced colon cancer at initial diagnosis. Utilizing the Nation Cancer Database, patients 18 years or older diagnosed with colon cancer as a primary diagnosis between 2010 and 2017 were compared in terms of distance to their medical facility, region of residence, and insurance coverage. 

The study found that patients at an increased risk of advanced pathologic disease:

  • Traveled a greater distance to their medical facility
  • Lived in the Northeast, Mountain, or Central regions of the United States
  • Only had Medicaid or did not have insurance coverage

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Study Finds Risk-Stratified Colorectal Cancer Screening Is Feasible and Cost-Effective

Colorectal cancer (CRC) is the third most common cancer diagnosis and the second most common cause of cancer death globally. The American Cancer Society estimates that there will be 106,180 new colon cancer cases and 44,850 new rectal cancer cases in the United States in 2022. Early detection and consistent screening reduce CRC incidence and mortality. A recent randomized controlled trial that analyzed the feasibility, adherence, yield, and related costs of various screening modalities found that a risk-adapted approach is feasible and cost-favorable for population-based screening. 

Current guidelines recommend standardized screening plans for specific age groups, with colonoscopy recommended every 10 years and a fecal immunochemical test (FIT) between 1-3 years. Implementation of risk-stratified screening can potentially allow for more frequent screening and earlier detection of CRC at a population level. This would especially be beneficial for individuals who are at higher risk of CRC. Additionally, risk-stratified screening can help health practitioners detect and introduce plans for CRC treatment at earlier stages.

The National Health Service Breast Screening Programme (NHSBSP) recently investigated the potential benefits, costs, and effectiveness of risk-stratified breast cancer screening with BC-Predict, a platform that collects self-reported risk factor information for breast cancer, analyzes the self-reported information, and invites high-risk or moderate-risk women to a conversation about prevention and early detection options. BC-Predict was found to have the potential to reduce breast cancer mortality due to early screening. It also reduced screening in women who are at lower risk, minimizing the number of false positive test results in lower-risk women. The results from this analysis are pertinent to risk-stratified screening for CRC and support the implementation of a risk-adapted approach in CRC screening.

What Did the Study Find?

More than 19,000 participants in the TARGET-C trial conducted in six cities in China were placed into one of the screening arms in a 1:2:2 ratio: 

  • One-time colonoscopy (n=3,883)
  • Annual fecal immunochemical test (FIT) (n=7,793)
  • Annual risk-adapted screening (n=7,697).

The detection rate of advanced colorectal neoplasia, CRC, and advanced precancerous lesions were the main outcomes that were monitored. The follow-up to trace the rate of advanced colorectal neoplasia for all participants was conducted over a 3-year study period. 

Over three screening rounds, the participation rates for colonoscopy, FIT, and risk-adapted screening arms were 42.4%, 99.3%, and 89.2%, respectively. The costs to the for detecting one advanced neoplasm, presented as both Chinese Yuan (CNY) and US dollar, using a package payment format were:

  • CNY6,928 ($1,004) for one-time colonoscopy
  • CNY5,821 ($844) for annual fecal immunochemical test (FIT)
  • CNY6,694 ($970) for annual risk-adapted screening.

These findings underscore the value of a risk-adapted approach for CRC screening for feasibility and cost-effectiveness, as well as for allowing for more frequent screening and earlier detection of CRC for individuals with a high or moderate risk for CRC.

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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New NCCN Guidelines Recommend Genetic Testing for All CRC Patients

Colorectal cancer (CRC) is the third most diagnosed cancer and over 5 million people worldwide currently live with CRC. According to the American Cancer Society, the lifetime risk of developing CRC is 1 in 23 for men and 1 in 25 for women, and recent research indicates an increased incidence of CRC among individuals younger than 50 years of age.

Recent research has revealed that a significant number of CRC patients with heritable genetic mutations remain undiagnosed under past genetic testing guidelines, which limited testing to specific age groups and forms of cancer. Now, the National Comprehensive Cancer Network (NCCN) has announced new guidelines that recommend germline multigene panel testing for all individuals with CRC ages <50, as well as consideration for germline multigene panel testing for those with evidence of mismatch repair deficiency in their tumor or a family history of CRC. 

Robert Nussbaum, M.D., co-authored a letter to the NCCN to formally request universal germline testing for CRC patients to be added to the guidelines. He states, “As the medical community’s understanding of genetic links to cancer evolves, genetic testing guidelines must evolve with it.” Increased accessibility to multipanel genetic testing can extend the representation of medically underserved populations and reduce the exacerbation of existing disparities. Expanding guidelines for genetic testing for CRC can also help family members determine their risk for CRC, increase surveillance for early detection, discover curative treatments, and promote awareness of CRC for those at increased risk. 

Universal Versus Guideline-Directed Targeted Testing for Hereditary Cancer 

Genetic factors play a significant role in the risk of developing many forms of cancer. Identification of germline predisposition can notably determine and direct a more effective plan of care, treatment, risk-reducing interventions, cancer screening, and germline testing. A multicenter cohort study among 2,984 cancer patients compared universal genetic testing with guideline-directed targeted genetic testing based on clinical guidelines to examine the prevalence of pathogenic germline variants (PGVs) in cancer patients. One in eight patients had a pathogenic germline variant, but 48% of those cases would not have been identified with a guideline-based approach. This underscores the limitations of clinical and guideline-based risk assessment for genetic testing. The multigene panel was more efficient at identifying heritable variants compared to guideline-directed targeted genetic testing. 

Importantly, identifying PGVs in cancer patients can encourage their relatives to take earlier action for risk assessment and cancer prevention. However, financial barriers and lack of insurance coverage can limit patient participation in genetic screening. This study points to the effectiveness of multigene panel testing and its implications for cancer prevention and treatment.

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

 

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Dr. Shahnaz Sultan: Pre-Endoscopy COVID-19 Testing Led to Disparities

The Colon Cancer Foundation had the opportunity to speak with Dr. Shahnaz Sultan, MD, MHSC, AGAF, about her research team’s findings that pandemic-related pre-procedure COVID-19 testing caused higher rates of endoscopy cancellations among patients from marginalized populations. A Professor of Medicine in the Division of Gastroenterology, Hepatology, and Nutrition and the Program Director for the Gastroenterology Fellowship Training Program at the University of Minnesota, Dr. Sultan’s research interests are focused on reducing colorectal cancer morbidity and mortality by improving adherence and quality of colonoscopy.

Q: What is the main takeaway you want people to understand from your research?

One of the most important things we want to emphasize is that colorectal cancer [CRC] is a very preventable cancer and there is a lot of high-quality evidence that shows that screening for CRC actually leads to a reduction in associated mortality. We really need to think about CRC screening along a continuum—whether you are doing stool-based testing or you’re getting a colonoscopy, it’s a multi-step process, and at every step, we need to be cognizant about reducing barriers and helping patients complete their CRC screening tests. Adding another step that patients have to complete prior to colonoscopy, such as pre-procedure SARS-CoV2 testing, in addition to completing their bowel prep, following dietary guidelines, finding transportation, and coming in to get a colonoscopy, really makes it that much more challenging. Pre-procedure testing serves as one more step and one more possible barrier in terms of getting people up-to-date with their screening. 

Q: As you were conducting your research, were there any findings that surprised you?

Our objective here was to understand the impact of pre-procedure COVID-19 testing—we wanted to see the magnitude of the impact and who was specifically affected by this additional requirement. When we looked at the canceled outpatient endoscopy procedures in our cohort from March 2021 to September 2021, we were surprised that the overall cancellation rate was so high in terms of getting people to complete their colonoscopy. Among the 574 cancellations, a little under 10% were due to pre-procedure COVID-19 testing requirements, and a good proportion of the remainder, about 51%, were patient-initiated cancellations. There were a lot of additional factors that were potentially holding people back from CRC screening. Additionally, we were surprised that pre-procedure testing was disproportionately affecting certain populations. Persons who self-identified as Black, American Indian, Alaskan Native, or Hispanic were more likely to have testing-related cancellations. 

Dr. Shahnaz Sultan

Q: Of the patients who canceled their colonoscopy, do we know if they went for an alternate form of testing for colorectal cancer, such as stool-based testing?

That’s an interesting question! We do not have that health data within our health system, but you bring up a good point. During the pandemic, a lot of other health systems were shifting gears from colonoscopy to stool-based testing and using programmatic efforts to directly reach out to patients to make sure they were getting some form of CRC screening. 

Q: Healthcare challenges, such as the COVID-19 pandemic, have demonstrated to significantly disrupt CRC screening procedures and participation, especially for medically underserved communities. What steps can be taken or what policies can be implemented in the future to support CRC screening participation and prevent significant disruptions to CRC screening?                                              

There is a lot of ongoing research to understand different barriers we can address or different interventions we can take to improve screening at the population level. We really need a multifaceted or multi-pronged approach to screening. We really need to think about interventions that not only focus on patients, but we also need to target providers, health systems, and community leaders, and think about national and federal policy decisions. I think there are a lot of opportunities to decrease barriers at different levels in terms of getting people to be more up-to-date with screening at a population level.

In terms of policy, one of the things that we have been able to fix recently is this loophole that existed in the past where if a test was done for screening purposes, but polyps were removed, then it was no longer counted as a screening test, and that incurred copayments and additional burdens on patients. I think that has been a real coup for us in the gastroenterology community and overall in terms of helping to support the care of our patients. Also, I think there are a lot of opportunities at the national level to support programmatic efforts to improve screening for populations that are underinsured or don’t have access to care, and I think we need to do more outreach and find ways to include health educators and patient navigators. We need to make sure we are educating patients about the importance of screening and helping address financial or logistical barriers that might serve as additional challenges for patients to overcome.

Continued on Page 2.

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Studies at ASCO Point to Biomarker-Directed Treatment for Colorectal Cancer

CCCF Research

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, several research studies were presented that shared a targeted approach to colorectal cancer (CRC) treatment that can ensure efficacy and reduction of side effects. The infographic below highlights those studies and their key findings.

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