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Increased Risk of CRC in Patients with Slow-Transit Constipation

Slow-transit constipation (STC) is reported to occur in 15-30% of people in the U.S. The most widely accepted definition of STC is two or fewer bowel movements per week or straining at stool more than 25% of the time. Research continues to point to STC as a risk factor for colorectal cancer (CRC).

A study published in 2020 that looked at 2,165 patients (median age 54 years), found that the cumulative probability of CRC was 0.2% 5 years after STC diagnosis and 0.4% 10 years after STC diagnosis. This was not significantly different (p=0.575) than among those without STC diagnosis. However, this may be due to the small number of patients (5) who were diagnosed with CRC.

Although the authors of the 2020 study did not find a significant difference among those with and without STC diagnosis, it is well established that STC increases CRC risk. Gurérin et al. in their 2014 study of over 100,000 patients identified a statistically significant risk of CRC among those with STC:

  • 56% higher for CRC
  • 260% higher for benign neoplasm
  • 256% higher for benign neoplasm in colon
  • 262% higher for anal and rectal polyps

Current management options for STC range from dietary counseling, pharmacological therapy, and surgery. 

While the etiology of STC remains unclear, there is increasing evidence that it is caused by an imbalance in the gut microbiome. Zhang et al. in their 2021 review published in Gastroenterology Report found that gut microbiota may play a major role in modulating colonic motility, secretion, and absorption. However, there is still much research needed to understand how the gut microbiome modulates movement of fecal matter through the small intestine and colon.

Conversations about the role of the gut microbiome in CRC development were a part of the Early-Age Onset Colorectal Cancer Summit held by the Colon Cancer Foundation in May 2022.

 

Gargi Patel is a Colon Cancer Prevention Intern with the Colon Cancer Foundation.

 

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New Blood Test for CRC Coming Soon, Guardant Health’s LUNAR-2

Recently at the American College of Gastroenterology’s 2021 Annual Scientific Meeting, Dr. Hee Cheol Kim, Professor of Surgery at Samsung Medical Center in  Seoul, South Korea, presented an abstract detailing results from a study on Guardant Health’s LUNAR-2 blood test for colorectal cancer (CRC). It was found that the test had a sensitivity (percent of CRC patients identified as having CRC) of 96%  and a specificity (percent of patients without CRC as not having CRC) of 94%.

LUNAR-2 is a multimodal circulating tumor DNA (ctDNA) blood test. ctDNA is the tiny amount of DNA from cancer cells that moves freely in the bloodstream and can be used as a biomarker for cancer diagnosis. Tests for ctDNA are often very sensitive to the smallest amount of tumor DNA and can catch cancer much earlier than physical screening tests such as a colonoscopy.

The efficacy of LUNAR-2 as a CRC screening test was evaluated retrospectively in a cohort of 699 patients with stage 1, 2, or 3 disease. Furthermore, LUNAR-2 was able to identify 90% of asymptomatic patients. This is significant because early detection is strongly associated with improved survival. 

Currently, a larger trial with more than 10,000 patients is underway (ECLIPSE study) to further test whether LUNAR-2 is able to diagnose early-stage CRC. Enrollment is expected to be completed later this year.

It is important to have a less invasive and simpler test for CRC screening because of the challenges in adherence to timely screening. Colonoscopy, which is recommended once in 10 years, requires general anesthesia and is considered a medical procedure. Additionally, colonoscopy can be expensive. Stool-based screening tests, such as a FIT test or a FIT-DNA test, have to be done frequently and many people feel uncomfortable getting them done.

Guardant Health Co-CEO AmirAli Talasaz explains in the company press release why a blood test is critical right now, in a post-COVID world. “During the COVID-19 pandemic, screening rates have dropped, wellness visits have declined, and postponements of non-emergency medical procedures have made it harder for people to complete life-saving CRC screening. The study results show that the LUNAR-2 test could provide both patients and physicians with an easy-to-use and highly accurate CRC screening alternative in the form of a blood test.”

 

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Clinical Alert: Preventing the Rise in Early-age Onset Colorectal Cancer

Did you know that the incidence and mortality rates of early-age onset colorectal cancer (EAO-CRC) have skyrocketed in recent years? Many of these patients may not have been screened yet for CRC, and may be misdiagnosed with another gastrointestinal condition. A lack of awareness of EAO-CRC combined with the potential for misdiagnosis and myriad other factors has contributed to patients under the age of 55 being 58% more likely to be diagnosed with advanced CRC than their older counterparts. While individuals with a known family health history of CRC may be more likely to get screened at a younger age, 70% of EAO-CRC cases occur in individuals with no known risk factors, who, therefore, may not have any knowledge of CRC symptoms and may not be inclined to consult a doctor if symptoms arise. 

The rapid rise in EAO-CRC cases makes it vital for primary care physicians to be acutely aware of CRC symptoms (e.g. rectal bleeding and abdominal pain), and not hesitate to refer patients to get screened even if they do not have a family history of the disease or are young. CRC is largely treatable if diagnosed at a localized stage, so it is imperative that patients are made aware of the symptoms and that physicians respond to their concerns appropriately. To learn more about what you can do to combat the rise of EAO-CRC, please take a look at the infographic below.

Final Clinical Alert Infographic Download

 

 

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USPSTF: Screening for Colorectal Cancer Should Start At 45

It is finally here! The U.S. Preventive Services Task Force (USPSTF)’s final recommendation has lowered the colorectal cancer (CRC) screening age for average-risk adults from 50 to 45 years. This long-awaited final recommendation came a little over six months after the draft recommendation was released in October last year.

This is a B grade recommendation, meaning that there is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Screening for 50–75-year-old adults remains an A grade recommendation, meaning USPSTF believes there is high certainty of substantial net benefit with screening that age group. The recommendations have also been published in JAMA.

Lowering the screening age from 50 to 45 years is great news for the CRC community because it will significantly influence the earlier diagnosis of CRC among the younger age group. To bring this into perspective, a recent paper in JAMA Network Openprojected that by 2040, CRC will be the second most common cancer in the 20-49 age group and it will be the leading cause of cancer-related deaths in that age group.

Ana Acuna-Villaorduna, MD, Department of Medical Oncology at Montefiore Health System, believes that the lowering of screening age could halt the alarming rise in early-age onset CRC, particularly among racial and ethnic minority populations. “Considering US-based population projections that foresee a continuous increase in racial/ethnic minorities and have higher frequencies and worse clinical courses of colorectal cancer among young patients, it is necessary to adopt a screening strategy aimed to halt this alarming trend,” Dr. Acuna-Villaorduna wrote in an email.

She believes that general practitioners and family physicians will be strategic players in implementing the new measures by educating patients in the community, along with gastroenterologists and medical oncologists. However, uptake of these recommendations by the primary care clinical community may be slow, depending on the messaging strategies that are utilized.

“As usual, it will take a while to get the message out,” Zuri A. Murrell, MD, FASCRS, Chair, Cancer Committee, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, told the Colon Cancer Foundation. “Having a media blitz will be helpful. Organizations like the American Cancer Society and the Colon Cancer Foundation will be the main people who will not only get the word out to providers, but to the community as well,” he added.

Dr. Acuna-Villaorduna thinks that the USPSTF recommendation will finally build a consensus across the various medical societies that have disparate CRC screening recommendations. She believes that some physicians may already have been screening average-risk adults at 45 years, so guideline uptake may be faster.

What Else Will Influence Uptake of the Guidance?

Another important question is whether our health care system has the capacity to onboard the 20-21 million adults in the 45-49 age group who are now eligible to get screened. While colonoscopy remains the gold standard, other screening options, including stool-based testing, could be used to conduct the initial screen. Whitney Jones, MD, Founder, Colon Cancer Prevention project, agrees. “While we cannot conduct colonoscopy in all the new population, we can definitely send them stool-based testing kits. That’s what health systems should focus on,” he said while speaking with the Colon Cancer Foundation.

The other issue is insurance coverage for CRC screening as a preventive care service for the 45-49 age group and making sure payers—both government and private—are aware of the updated guidelines and are integrating these within their policy.

Currently, most insurers will cover the cost of a preventive screening test for those 50 years or older, but the enrollee may have to share the cost of a diagnostic screening test if a polyp or tumor is found.

If historical trends are any indication, insurance coverage of colonoscopy will significantly influence increased screening in the younger age group. Evidence for this is stark in the Medicare population: colonoscopy rates jumped from 20% in 2000 to 61% in 2018 among those 50 and older after Medicare started covering colonoscopy screening for all beneficiaries in 2001.

Once the updated recommendations of CRC screening age are implemented, Dr. Murrell is hopeful that insurance companies will listen and hopefully start covering the cost of the simple preventive procedure. He also raised an important point about eliminating fear from the mind of the younger community. “I have coined a slogan that I always share with my patients: ‘You shouldn’t die from fear you shouldn’t die from embarrassment.’ This will be the first step in helping and encouraging people to get a colonoscopy,” he added.

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Comparing the Outcomes From Real-World Observational Studies and Targeted Clinical Trials

The titular study published on March 30, 2021 was a comparative effectiveness study, a study that compares two or more health interventions to evaluate which poses the greatest benefit and harm, and was inspired by and relied on the International Duration Evaluation of Adjuvant (IDEA) trial. The IDEA trial was a pooled analysis of six randomized clinical trials that studied patients with stage III colon cancer and compared the effects of three months of adjuvant chemotherapy to the standard duration of six months. 

Adjuvant chemotherapy refers to the additional therapy given to cancer patients after their primary therapy; in this case, the primary therapy was surgery. Adjuvant chemotherapy is administered to maximize the benefits of the primary therapy and to decrease the risk of cancer recurrence.

In the IDEA trial, the adjuvant therapy was either adjuvant 5-flourouracil/leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Both FOLFOX and CAPOX are chemotherapy regimens used for advanced colorectal cancer, and, as stated, both contain oxaliplatin, a known neurotoxic agent. Therefore, the implications of reducing the duration of adjuvant therapy are immense, as it could potentially decrease the neuropathic effects of the drug, as well as reduce treatment cost and increase treatment adherence.

The IDEA trial in particular was chosen as a benchmark due to the many controversies that surrounded the study’s findings. The IDEA trial found that “a shortened duration of adjuvant chemotherapy was noninferior among patients with T1 to T3 and N1 stage disease and among patients prescribed CAPOX.” In this case, noninferior means that the experimental treatment, i.e. the shortened adjuvant chemotherapy, is not substantially worse than the control treatment, i.e. the standard six month duration of adjuvant chemotherapy. 

This was controversial, as a worldwide survey of 145 oncologists showed that 1 in 3 supported the six months duration of adjuvant chemotherapy. Additionally, there were concerns as to how these findings could be generalizable to a real-world population of cancer patients.

This current study aimed to remedy these controversies by conducting a target trial emulation, a method used by investigators to mimic a clinical trial using observational techniques. Though randomized clinical trials continue to provide the strongest evidence for comparing the effectiveness of two or more interventions, they can be slow, costly, and at times impossible to conduct due to ethical considerations. Therefore, target trial emulations, in which an ideal clinical trial is imitated using already-existing, real-world data, can prove useful.

This study utilized the data of patients who were diagnosed with stage III colon cancer between January 2004 and December 2015 in Alberta, Canada, and the eligibility criteria mimicked that of the IDEA trial. Overall, 485 patients were included in the trial emulation, with 230 being women and the median age being 59 years.

Both a target trial emulation and a naive observational analysis were conducted, a naive observational analysis being one that did not take into account any of the factors of the target trial emulation. More specifically, the naive observational analysis did not factor in allowable reasons for therapy cessation, values that change over time like treatment dosage, or immortal time bias. 

In this study, the findings of the target trial emulation and the naive observational analysis differed. The findings of the target trial emulation mirrored that of the original IDEA trial; a shortened duration of adjuvant therapy, specifically CAPOX, was found to be noninferior to the standard six month duration. However, the naive observational analysis found that a shortened duration of CAPOX therapy was associated with a decreased overall survival for patients. 

According to the authors, these disparate findings show “the importance of explicitly emulating a target trial when conducting comparative efficacy research using real-world data.”

 

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Artificial Intelligence Could Be the Key to Improving the Accuracy of Colonoscopies

Earlier this month, the U.S. Food and Drug Administration (FDA) authorized Medtronic and Cosmo Pharmaceuticals to start marketing its novel artificial intelligence (AI) device, the GI Genius, that improves the quality of colonoscopies by detecting precancerous polyps that clinicians may otherwise overlook if they are flat or are located in areas of the colon that are difficult to see with an endoscope.

 

According to a systematic review and meta-analysis of 43 international publications, 13 of which were conducted in the United States, many cases of colorectal cancer can be attributed to polyps and adenomas that are not detected during routine screenings. The study found that 26%  (95% CI: 23%-30%) of adenomas are missed during colonoscopies as well as 27% of serrated polyps (95% CI: 16%-40%). GI Genius is one of a few devices cleared by the FDA to aid in colonoscopies and is the first computer-aided detection (CADe) system that uses AI to recognize polyps. The tool was reviewed through the FDA’s De Novo premarket review pathway for low-to-moderate risk novel devices.

 

The GI Genius works by emitting a sound and displaying green markers that are superimposed over the endoscope video when it recognizes a potential lesion; it is compatible with many video endoscopy systems. GI Genius utilizes an algorithm to recognize polyps that was developed by reviewing over 13 million colonoscopy videos. Gastroenterologists labeled tissues as being either healthy or unhealthy to help “teach” the GI Genius how to distinguish the two. While the GI Genius can recognize unhealthy tissue, it does not characterize lesions and is not a substitute for lab sampling to diagnose the tissue in question.

 

The safety and effectiveness of the GI Genius were assessed through a large randomized controlled trial in Italy. Out of a subpopulation of 263 subjects who required screening or surveillance at least every three years, 136 patients had a colonoscopy with the assistance of the GI Genius, while 127 patients served as controls and underwent a standard colonoscopy. In the experimental group, adenomas or carcinomas were detected in 55.1% of patients, while they were only identified in 42% of patients in the control group. No adverse events related to the use of GI Genius were reported, although its use led to a small increase in the amount of healthy tissue that was biopsied.

 

Overall, GI Genius shows great promise as a way to enhance the quality and reliability of colonoscopies by aiding physicians who may otherwise miss polyps that are hard to see.

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Phase III BEACON Trial Results Promising for Patients With Metastatic Colorectal Cancer

Updated phase III results from the BEACON study have found that encorafenib with cetuximab can lead to promising survival outcomes among patients with advanced colorectal cancer (CRC) who had received previous lines of treatment.

The third most common cancer and the third most common cause of cancer-related deaths in the U.S., CRC occurs when there is development of mutations in oncogenes, tumor suppressor genes, and genes that aid in DNA repair. Depending on the site of the mutation, CRC can be classified as familial, inherited, or sporadic. Chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) are pathogenic mechanisms through which CRC can develop. These mutations, changes in the chromosomes, and translocations can affect various signaling pathways (Wnt, TP53, TGF-β, and MAPK/PI3K) and genes such as c-MYC, KRAS, BRAF, SMAD2, and SMAD4. Oftentimes, mutations in these genes can serve as important predictive markers in the context of patient outcomes.

In addition to CRC, mutations in BRAF have been found to be responsible for various other cancers such as melanoma, thyroid, small-cell lung, and hairy cell leukemia. BRAF encodes for  the B-RAF serine/threonine kinase protein, which is a part of the RAS/RAF/MEK/ERK pathway. Most of the mutations that take place in the BRAF gene lead to a V600E substitution, which often leads to a poor prognosis in patients. The BRAFV600E mutation initiates activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which causes the tumor cells to rapidly divide. It has been estimated that approximately 10% of patients with metastatic CRC have a mutation in BRAF.

In the past, treating metastatic CRC with BRAFV600E mutations has led to low response rates, partly due to incomplete inhibition of the MAPK signaling. Recently, the combination of a BRAF (encorafenib) and EGFR (cetuximab) inhibitor has shown promising results compared to BRAF inhibitor monotherapy. The BEACON CRC study is a randomized, open-label, phase III trial that enrolled 665 patients and compared triple combination therapy; encorafenib (300 mg x1 a day) plus binimetinib (45 mg 2x a day) plus cetuximab (400 mg/m2 x1 a week) versus double combination therapy; encorafenib plus cetuximab versus cetuximab plus irinotecan or FOLFIRI. Of the total 665 patients, 224 received triple therapy, 220 received double therapy, and 221 received the control therapy.

The objective of the BEACON trial was to detect the overall survival in relation to the triple combination therapy/double combination therapy as compared to the control. It was determined that triple/double therapy led to a median overall survival of 9.3 months, while the control group showed an overall survival of 5.9 months. This indicates that both triple/double therapy improved the overall survival rate and can therefore be used as the new standard of care in patients with metastatic CRC with BRFV600E mutations.

 

 

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Brett Walker, M.D., Awarded the 2021 Thomas K. Weber Colorectal Cancer Research Scholar Award

In February 2021, Brett Walker, M.D., became the 10th awardee of the Thomas K. Weber Colorectal Cancer Research Scholar Award, awarded by the Colon Cancer Foundation in partnership with the Society of Surgical Oncology.

The award was renamed in 2020 after Thomas K. Weber, M.D. (1954-2019), founder and former president of the Colon Cancer Foundation. Dr. Weber devoted his life to increasing colorectal cancer awareness, detection, and prevention, and his dedication to “a world without colon cancer” lies at the heart of the Colon Cancer Foundation. Thus, the award was renamed to keep his legacy alive while celebrating members of the community that display excellence in translational research pertaining to the molecular biology of colorectal cancer.

This year, Dr. Walker received the award for his abstract submission on circulating hybrid cells (CHCs) as a potential biomarker for treatment response in gastrointestinal cancers. CHCs are a type of hybrid cell created by the fusion of an immune cell and a tumor cell. Research pertaining to CHCs is novel as the primary focus of previous studies on cancer cell biomarkers has been on circulating tumor cells (CTCs), cells that bud off from a primary tumor and circulate in the bloodstream. 

Though CHCs also disseminate outward from a primary tumor and circulate in the peripheral blood, the difference between the two lies in their names. Whereas CTCs only express cytokeratin, a tumor protein, CHCs express both cytokeratin and CD45, an immune cell marker. It is postulated that CHCs have both immune and tumor cell markers in order to successfully evade the immune system to form new tumors. 

“CHCs have this opportunity to escape out of the primary tumor and migrate to different areas and potentially seed new metastatic tumors,” said Dr. Walker in an email correspondence with the Colon Cancer Foundation. 

According to Dr. Walker, CHCs have the potential to be a better evaluative marker of treatment response and disease progression compared to CTCs because there are more of them circulating in the bloodstream. 

Dr. Walker’s research itself indicates the effectiveness of CHCs as biomarkers. According to The ASCO’s Post description of his research, CHCs “successfully discriminated pathologic complete response from non–pathologic complete response in both rectal and esophageal cancers.”

Additionally, Dr. Walker mentioned that CHCs can provide information on the actual tumor itself. 

“By collecting CHCs, we can actually gain information on the tumor, specifically what proteins they express and their genetic makeup including mutations, which could potentially help guide targetable treatments for patients,” said Dr. Walker.  

Though more studies need to be conducted into CHCs, the implications of the research conducted by Dr. Walker’s laboratory are immense. If indeed CHC levels can be used as an effective biomarker, then patients with colorectal cancer can opt for non-invasive blood tests to track disease and treatment progression, as opposed to undergoing traditionally invasive imaging techniques and endoscopies. This in turn improves patients’ quality of life by avoiding intensive procedures that can cause stress and fear. 

 

Dr. Walker expressed excitement over CHCs as a biomarker and hopes that his research will inspire others in the field to conduct their own studies. 

 

“I think that there’s a huge opportunity here for us to really affect how we both detect and manage colon cancer. And so I really think this is an awesome opportunity to bring attention to hybrid cells and hopefully expand the number of researchers in this field.”

 

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Fight CRC Urges Congress to Provide Funding for CRC Research

The American Cancer Society’s 2021 Cancer Facts and Figures includes staggering statistics about colorectal cancer (CRC) in the United States:

  • It is the third most common type of cancer diagnosed in men and women
  • It is the third leading cause of cancer-related deaths in men and women
  • CRC incidence rates are increasing in adults younger than 50
  • CRC mortality rates are increasing in adults younger than 55
  • Black people have the highest CRC incidence and mortality rates among all ethnic groups

These shocking figures are why Fight CRC, a patient advocacy group with a mission to “cure colorectal cancer,” is working with members of Congress to provide funding for CRC research.

Fight CRC calls for the allocation of $20 million for a CRC research program within the Department of Defense (DoD). Congressional champions of the group are leading a letter to the House Appropriations Committee in support of this effort. According to the letter, CRC is the only cancer among the top five cancer killers without its own program within the DoD’s Congressionally Directed Medical Research Program (CDMRP). 

Fight CRC wants to change that. They believe it is past time for CRC to be spotlighted, and they have “no plans of slowing down or stopping until they reach their goal: a cure.” At the Colon Cancer Foundation, we wholeheartedly stand by this mission and we will continue to work towards, in the words of founder Dr. Thomas K. Weber, “a world without colon cancer.”  

Imagine a world in which CRC is not one of the most common types of cancers. Imagine a world in which CRC does not cause deaths anymore. Now, imagine that you don’t have to imagine any of this: you can make this world a reality by clicking on Fight CRC’s action alert and urging your members of Congress to sign the letter to create a distinct program for CRC research. Share it with your friends, family, and colleagues so that together, we can all create a world without CRC.

 

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Awareness Activities During National Colorectal Cancer Awareness Month 2021

In 1999, the Prevent Cancer Foundation designated March as the National Colorectal Cancer Awareness Month. The foundation partnered with the American Digestive Health Foundation and the National Colorectal Cancer Roundtable to raise awareness and advocate for policy change for the third most common type of cancer in the United States. On November 19, 1999, an official declaration came through from the United States Senate and the House of Representatives. 

With approximately 100,000 new cases of colorectal cancer (CRC) every year, March is an important month to cast a spotlight on the value of preventative measures such as screening. The American Cancer Society estimates there will be 149,500 new cases of CRC and 52,980 deaths in 2021. In December 1995, the United States Preventive Services Task Force (USPSTF) recommended that adults with an average risk of CRC should be screened between the ages of 50-75 years. Due to increasing evidence over the last few decades, in December 2020 the USPSTF released draft recommendations saying screening should start at the age of 45 years.

The COVID-19 pandemic led to a drastic reduction in the number of colonoscopies in 2020: about a 90% drop compared to previous years. Approximately 1.7 million Americans missed their annual screening test in 2020, and 18,800 CRC diagnoses were either delayed or missed altogether. 

In recognition of the month of March, the Colon Cancer Foundation (CCF) had several activities planned, including the #GiveACrap Challenge. The Challenge encouraged individuals to sign up to receive a free Fecal Immunochemical Test (FIT), and the chance to receive a special limited-edition beer. People also had the option of making a donation to the foundation to receive the test kit and the beer. Other activities included the CCF Challenge which is a 45-mile walk-run and a concert celebrating the culmination of a week full of activities.

In his proclamation for National Colorectal Cancer Awareness Month, President Joseph Biden urged Americans to call attention to CRC risk factors and increase annual screening practices. He emphasized that March is the perfect opportunity to improve public understanding of CRC and to educate individuals about the age for proper screening. He reiterated that if caught early, CRC is highly treatable and curable. “Because of the Affordable Care Act, most health insurance plans must cover a set of preventive services with no out-of-pocket cost. This includes colorectal cancer screening in adults aged 50 and older,” President Biden said.

Fight Colorectal Cancer and the Colon Cancer Coalition urged business leaders and landmarks to go blue to spread CRC awareness. As of March 9, 2021, businesses, healthcare systems, and landmarks in 21 states had confirmed their status to “Go Blue” in honor of CRC Awareness Month. Moreover, the Colon Cancer Coalition hosted a ‘Get Your Rear in Gear’ event on March 21, 2021, in-person and virtually, as a 5K untimed run/walk-in Charlotte, North Carolina. 

Every year in March, various events take place all throughout the U.S. with the hope of spreading awareness and advocating for CRC. It is essential to spread the word about CRC and emphasize the importance of regular screening to prevent, manage, and treat CRC.

 

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