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 Identifying New Biomarkers in Fecal Samples to Detect Colorectal Cancer

Biomarkers allow scientists to identify certain diseases from a simple biological sample like urine, breath, or even feces. Volatile organic compounds (VOCs) are the byproducts of metabolic processes associated with cancer, necrosis, or other metabolic changes. Scientists have now identified a new biomarker associated with both colorectal cancer (CRC) and adenoma (noncancerous tumor) that can be used for detection.

The cross-sectional study included 24 newly diagnosed CRC patients, 24 patients with adenomas, and 32 individuals who had a normal colonoscopy between July 2017 and July 2020. Individuals with normal colonoscopies and those with adenomas had fecal samples collected before and after their colonoscopy. Samples were requested from CRC patients 3-4 weeks after diagnosis and before treatment.

Of the 60 VOCs identified, only 3 showed different peaks between CRC and the control groups: p-cresol, 1H-indole, and 3(4H)-DBZ. There was a statistically significant difference between p-cresol peak values in each group with the greatest difference between CRC and the control group. This was also the same for 3(4H)-DBZ. However, 1H-indole did not have a significant difference between the study groups.

After adjusting for sex, age, and body-mass index (BMI), the researchers found that only CRC was associated with increased p-cresol and 3(4H)-DBZ, and p-cresol seemed to be the best possible predictor of CRC. A combination of p-cresol and 3(4H)-DBZ “is also optimistic as a combined biomarker” according to the study authors.

p-cresol was also abundant among patients with adenomas compared to healthy controls. This was also the case after adjusting for age, sex, and BMI.

Although more work needs to be done to determine what processes produce these VOCs, these associations can launch a new set of studies to confirm its use in a clinical setting. Other biomarkers have been identified that can  predict CRC occurrence and mortality. Overall, the ability to better detect CRC and precancerous adenomas play an important role in global prevention efforts. A better understanding of the biological processes involved in these diseases is crucial for those efforts to be successful.

 

Kaylinn Escobar is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

Photo credit: National Cancer Institute on Unsplash

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Can Circulating Tumor DNA Predict Who Will Benefit from Colorectal Cancer Chemotherapy?

Over 30% of patients with stage II or stage III colorectal cancer (CRC) and 60-70% of patients who undergo oligometastatic resection experience cancer recurrence. Stage II or III CRC is usually treated with surgery followed by adjuvant chemotherapy (ACT). However, patients with clinical and pathological risk factors only see a 10-15% decrease in cancer recurrence with standard ACT. 

Now, a new study proposes using circulating tumor DNA (ctDNA) as a predictive biomarker to guide chemotherapy treatment decisions in CRC patients. 

ctDNA is a minimally invasive biomarker that can help oncologists measure disease status and progression during cancer therapy, including the detection of molecular residual disease (MRD). In this study, researchers evaluated whether ctDNA following surgery could predict disease recurrence in early-stage CRC. 

The study enrolled 1,563 patients with:

  • Stage II or III CRC 
  • Surgically resectable stage IV CRC 
  • Recurrent CRC were prospectively enrolled in the study 

Blood samples were collected before and at predetermined time intervals after surgery (up to 18 months), and imaging was performed every six months until 18 months after surgery. MRD, defined as ctDNA positivity after surgery or therapy, is strongly associated with poor prognosis in patients with surgically resectable CRC. Of the 1,039 patients included in the ctDNA analysis, 18.0% were ctDNA positive four weeks after surgery.

Researchers discovered that patients with high-risk stage II, stage III, and stage IV CRC, who were ctDNA-positive four weeks after surgery, benefited from ACT. ctDNA was identified as the most significant risk factor for CRC recurrence in these patients, and ctDNA positivity is an important predictor of ACT benefit. 

Regardless of the pathological stage of CRC, patients with a higher risk of recurrence based on ctDNA status may benefit from ACT, while those with negative ctDNA status may be able to avoid unnecessary ACT. These findings can guide clinicians in making evidence-based treatment decisions for CRC patients.

 

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

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CDC Report: Why Do Certain Populations Never Screen for Colorectal Cancer?

Cancer screening remains a powerful tool. Even limited screening has long-term benefits compared to no screening  and can lower the risk of cancer and related deaths. A recent study by researchers at the CDC compared data on adults who reported they had not received a colorectal cancer (CRC) screening test between 2012 and 2020 using information from the Behavioral Risk Factor Surveillance System (BRFSS). The study identified various trends, most notably that 22 states did not meet the CDC’s Healthy People 2020 goal of 70.5% adults screened for CRC.

The sample was limited to adults aged 50 to 75 years, with up to date screenings defined as one of the following:

  • Home stool-blood test within the past year
  • Sigmoidoscopy within five years with fecal occult blood test or within one year with fecal immunochemical test
  • Colonoscopy within ten years

The ‘never screened’ numbers were a composite of those who answered no to being screened or those who were not up to date. Those who declined to answer or reported uncertainty were excluded. Overall, the study identified:

  • A 5.8% decrease in unscreened adults between 2012 and 2020 
  • States with the largest improvements were also those with the largest unscreened population in 2012 

 

Despite these improvements, CRC screening goals have yet to be met and may be difficult to meet with the new Healthy People 2030 standards. The target of 74.4% screened may have been a challenge to meet, possibly further exacerbated by the COVID-19 pandemic.

Researchers noted that including just two more questions on the BRFSS in 2020, the percentage of up to date screenings increased to 71.6%. These two questions enquired about:

  • Stool DNA testing
  • Computerized tomographic colonography

It is important to note that the National Colorectal Cancer Roundtable—a membership organization established by the CDC and the American Cancer Society—has set its goal to 80% screening rates across the country.

Study authors recognized recall bias and an inability to distinguish between screening versus diagnostic tests as major study limitations. Additionally, social desirability bias and a low response rate may have also affected the results. However, financial factors and health disparities may also describe the differences between states.

Following implementation of the Affordable Care Act, researchers at the American Cancer Society found that CRC screening among low-income adults across the U.S. increased by up to 8%, with the greatest increases observed in early Medicaid expansion states. They also noted that a majority of those who were never screened also lived in a state without expansion (South Dakota). 

Nonfinancial factors such as health disparities were studied in a mixed-methods analysis conducted at the Virginia Commonwealth University’s School of Medicine. Here, researchers noted that participants of gender-specific and race-specific focus groups brought forth nuanced concerns regarding screening. This included lack of awareness of both the disease and the screening, lack of physician recommendation that is clear and rational, and fear of being diagnosed and complications associated with testing. These concerns, if unaddressed, may limit others from seeking out CRC screening.

To read more about the Healthy People 2030 CRC screening standards and the current progress, visit Healthy People 2030.

 

Kaylinn Escobar is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation. 

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Fecal Immunochemical Tests Affordable and Effective for Colorectal Cancer Screening

As we emerge from the initial waves of COVID-19, patients may have been reluctant to take more time out of their life for a colonoscopy prep, procedure, and recovery. Fortunately, non-invasive stool-based screening tools, such as fecal immunochemical tests (FIT) and multi-target stool DNA (mt-sDNA or Cologuard), are practical options that allow patients to provide a sample in the comfort of their home and could address access and care gap issues as they are less expensive. 

According to a new study presented during the Scientific Forum at the American College of Surgeons Clinical Congress 2022, these non-invasive stool-based screening methods are equally effective for screening for early-stage colorectal cancer (CRC). Pavan K. Rao, MD, a general surgery resident at Allegheny Health Network in Pittsburgh, Pennsylvania, presented study results that evaluated 117,519 enrollees within the Highmark claims database who underwent CRC screening in 2019. The researchers found:

  • About 60% of patients taking either the fecal immunochemical test or the DNA test at home instead of having a routine colonoscopy had early-stage cancer, but a FIT detected it at one-fifth the cost. 
  • The total annual costs for the tests were $6.47 million—$1.1 million for a FIT (about $24 per test) and $5.6 million for mt-sDNA (about $121 per test). Costs were calculated using Medicare reimbursement rates.
  • Transitioning all non-invasive CRC screening to FIT would result in $3.9 million in savings annually in the study population. 

Similarly, these results support previous studies out of Japan and the Netherlands that found FIT was more cost-effective than other types of non-invasive CRC screening tests. This provides our healthcare system with an efficient alternative at a reduced cost that maintains patient outcomes without compromising the quality of care. 

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Patient Preference Key to Success of Colorectal Cancer Screening Programs

Colorectal cancer (CRC) screening is a vital preventative method to detect and remove a polyp and to diagnose cancer before it advances to an incurable stage. CRC screening options include endoscopy and stool-based testing. Now a new study that surveyed unscreened individuals at average risk for CRC has found that people have a preference for the stool-based screening option. 

The third most diagnosed cancer in the U.S., over 5 million people worldwide currently live with CRC. One method of CRC screening is a colonoscopy, which detects swollen, abnormal tissues, polyps, or cancer in the large intestine (colon) and rectum. Another form of CRC screening is the fecal immunochemical test (FIT). FIT is one of the most widely used CRC screening methods globally and is an affordable screening tool for studying large populations. FIT detects hidden blood in stool, a potential early sign of cancer, and it has an overall 95% diagnostic accuracy for CRC. 

It is estimated that 106,180 new colon cancer cases and 44,850 new rectal cancer cases will be diagnosed in the U.S. in 2022. With the screening age for CRC for average-risk adults lowered to 45 years, we need a better understanding of what the various age groups may prefer as a screening option to improve compliance and screening rates. 

The new study that was published has found that individuals in the 40-49 age group and those ≥50 years prioritized test modality above effectiveness when choosing their screening test. The findings of this study demonstrate that:

  • Both 40-49-years-old and ≥50-year-old age groups preferred FIT-fecal DNA every three years
  • The second preferred test for both age groups was a colon video capsule, or capsule endoscopy, every five years 
  • Regarding only the USPSTF tier 1 tests, both age groups preferred an annual FIT over a colonoscopy every ten years
    • 68.9% of 40-49-year-olds and 77.4% of ≥50-year-old participants preferred an annual FIT

These results conflict with current CRC screening approaches in the U.S., where colonoscopy is the screening test customarily used. Furthermore, these findings prompt the modification of current CRC screening guidelines and suggest that healthcare providers consider sequential-based screening procedures where FIT is offered before colonoscopy. The results, however, are consistent with a 2007 study, which supports the effectiveness of providing FIT before colonoscopy—the percentage of patients that were up-to-date with screening increased by almost 50% between 2000 and 2015 when they were offered direct-to-patient annual FIT outreach with colonoscopy. 

Scheduling delays and longer waiting times for colonoscopies have increased as millions of newly eligible individuals need a colonoscopy, all of which can strain resources and delay access and early screening for patients, especially for those at greater risk for CRC. Sequential approaches for CRC screening, such as those that offer FIT before colonoscopy, can help acknowledge and adjust to the increased need for screening and the lack of resources and help prioritize access to colonoscopy for those at greater risk for CRC.

 

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

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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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ASCO 2022: Access, Education, and Adherence Important for Colorectal Cancer Screening

A series of abstracts presented at the 2022 Annual Meeting of the American Society of Clinical Oncology identified ways to improve access to colorectal cancer (CRC) screening, including for minority and underserved populations; compared different screening modalities for efficiency; and highlighted ways to improve the impact of screening programs at health centers. The infographic below provides a snapshot of these research findings.

Abstracts presented at the 2022 Annual Meeting of the American Society of Clinical Oncology.

 

Details on the studies and their findings can be found below:

  1. https://meetings.asco.org/abstracts-presentations/208933
  2. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.11020
  3. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.10529
  4. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.3526
  5. https://meetings.asco.org/abstracts-presentations/206470
  6. https://meetings.asco.org/abstracts-presentations/206684

 

Juhi Patel was a Colon 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.

Left column:
Right column:
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Disparities and Multilevel Barriers for Colorectal Cancer Screening May Extend to Younger Populations

In May 2021, the US Preventive Services Task Force (USPSTF) revised the colorectal cancer (CRC) screening age for average-risk adults to 45 years. However, stakeholders are concerned about the lack of awareness, access, and motivation among the younger age group to get screened. Now, a new research study has found that the prevalence of CRC screening remained lowest for individuals ages 50 to 54 years old and young adults (age<50) experienced smaller increases in screening prevalence over time, regardless of race, ethnicity, education, income, and insurance coverage. 

An investigation using population-based data from the National Health Interview Survey (NHIS), an annual, cross-sectional survey of the U.S. population conducted by the National Center for Health Statistics at the U.S. Centers for Disease Control and Prevention, studied CRC screening participation using surveys from multiple years. A sample of 80,220 participants ages 50 to 75 years old was analyzed for CRC screening participation. For each survey year, the prevalence of CRC screening was estimated for age, race, ethnicity, educational attainment, family income, and health insurance.

Racial, ethnic, and socioeconomic disparities influence screening rates. Despite the prevalence of CRC screening increasing from 36.7% in 2000 to 66.1% in 2018, screening prevalence was observed to be the lowest for:

  • Participants ages 50 to 54 years old
  • Hispanic populations (56.5%)
  • Asian populations (57.1%)
  • Participants with less than a high school degree (53.6%)
  • Participants from low-income families (56.6%)
  • Participants without insurance (39.7%) 

This may be the result of a lack of concern for cancer and cancer screening among younger adults and their healthcare providers, limited access to healthcare, absence of or limited insurance coverage, and other priorities for young adults, such as work and family. Disparities in screening rates can potentially extend to adults ages 45 to 49 as the new USPSTF recommendations are implemented. Multilevel barriers, such as patient-, provider-, and system-level factors, impact the completion of CRC screening for young adults (age<50), creating disparities and inequities in CRC screening. The administration of new CRC screening guidelines must acknowledge and account for multilevel disparities in screening programs to ensure all populations have equal access to CRC screening and benefit from CRC screening, especially newly eligible adults ages 45 to 49 years old. 

The benefits and outcomes of the updated USPSTF guidelines to extend CRC screening to ages 45 to 49 years old have been debated by clinicians and researchers. Concerns about the updated guidelines include redirecting endoscopic resources away from higher-risk and older patients, resulting in a more significant exacerbation of health disparities. Another criticism is that adults ages 45 to 49 years old who participate in screening may be less likely to belong to groups at higher CRC risk. 

One benefit of expanding CRC screening to the 45-49 age group is to increase the screening participation rate among older populations. Awareness of CRC screening may also increase, resulting in newly eligible adults having more time to schedule their first screening test. However, the impact of screening among those in the 45-49 age group on disparities, benefits, and participation of older adults may take several years to be fully recognized and understood, as the USPSTF’s effect on insurance coverage only occur in mid-2022.

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

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