Fight CRC Working Group Members Lead Early-Age Onset CRC Research: Five-Part Series

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In February 2019, Fight Colorectal Cancer (Fight CRC) convened researchers from around the world to identify and prioritize what is causing the dangerous rise in cases of early-age onset colorectal cancer (EAO CRC). 

Since that meeting, the EAO CRC working group has published a meeting summary and a commentary in Gastro, reconvened in smaller groups at conferences such as Digestive Disease Week (DDW), and is currently planning a symposium in Madrid, Spain with working group member, Dr. Jose Perea. Working group members are also leading research in their respective fields. 

This is a five-part series highlighting different areas of research being conducted by Fight CRC working group members to understand where the science is headed, and what it means for our community of patients.

Part 1: Featuring Dr. Jordan Karlitz

Summary of the Research: EAO CRC

To better understand the increase in the incidence of colorectal cancer from ages 49 to 50 years old (when screening begins for average risk populations), researchers conducted a cross-sectional study between 2000 and 2015 looking at colorectal cancer incidence rates.

In contrast to prior studies in which wide age group blocks were analyzed (for example age 30-39, 40-49, etc.) this study was more of a "high-definition" analysis in which incidence rates were examined in one-year-age increments. They stratified by regions in the U.S. (South, West, Northeast and Midwest), sex, race, disease stage, and location of tumor (rectum vs. colon). 

In total, there were 170,434 colorectal cancer cases and 165,160 patients analyzed. Researchers found a steep increase in incidence rates between the ages of 49 to 50 across all regions, sexes, and white and black populations in rectal and colon cancers and in localized and regional stage cancers.

To better understand what these findings mean, we reached out to lead author Dr. Jordan Karlitz to gain insight on the significance of this work. 

Why is This Paper Impactful?

Given debate and differing guidelines over when average-risk colorectal cancer screening should begin (age 45 vs age 50), we felt that performing a detailed incidence rate analysis in one year age increments (as opposed to age range blocks as has been done in the past)  would be revealing. In particular, we were interested in the transition from age 49 to 50, as this is when average-risk screening has historically been recommended. 

What Does This Mean for the Debate About the Screening Guideline? What Do You Recommend for Patients and Advocates?

Our analysis revealed a 46% spike in colorectal cancer incidence rates from age 49 to 50.  Stage stratification revealed that 93% of the cases were invasive (beyond in situ stage), which may require more aggressive treatment, including surgery and possibly chemotherapy and radiation. Given that cancers may take several years to grow, these lesions were likely present and developing for several years prior while patients were in their 40s, but ultimately detected with screening initiation at age 50.

These findings support a significant undetected preclinical colorectal cancer burden in those under age 50, which is not reflected in observed incidence rates. Hence, relying on observed incidence rates of those 45-49 years of age alone to assess potential impacts of earlier screening may underestimate cancer prevention benefits. 

It is important to highlight that an undetected, preclinical-cancer-case burden may be present in patients of any age, including those over age 50, which may be compounded by non-optimized CRC screening rates. But a key aspect of our study is that we assessed this preclinical burden in those approaching screening age, which is important given ongoing debates on when screening should be initiated.  We are hoping this data can contribute to the earlier screening debates and can be taken into consideration by those developing screening guidelines.

Another key message is that despite debates over screening age initiation, screening rates are not optimal in general, particularly in younger patients (28-47% in those aged 50-54 from 2000-2015 according to prior studies). So it is really important that patients discuss getting screened with their healthcare providers. In addition, given rising rates of early-onset colorectal cancer, concerning symptoms should prompt thorough evaluations and cancer family histories must be known as a family history may require much earlier screening.

Comparing observed incidence rates between those under age 50 and those 50 and older with regard to estimating the potential impact of earlier screening initiation can be misleading. This is because in general, observed incidence rates in those age 50 and older reflect both average-risk screening detected cases in addition to diagnostically detected cases (due to symptoms), whereas in those under age 50, incidence rates would be expected to primarily reflect diagnostically detected cases or higher-risk screened groups (cancer family history) because average-risk screening has historically not been performed. 

Observed incidence rates of those in their mid to late 40s would be expected to be significantly lower than those in their early 50s, not because the underlying case burden is substantially lower, but because many CRCs may be present yet undetected until diagnosed at 50 years when screening is ultimately initiated.

Part 2: Featuring Dr. Josh Demb

Summary of the Research: Risk Factors for Early-Age Onset Colorectal Cancer

This case-control study of veterans aged 18-49 in the United States compared veterans with and without diagnosis of colorectal cancer. Researchers identified early-age onset colorectal cancer cases between 1999 and 2014 through a national cancer registry and collected data on age, weight, sex, race/ethnicity, body mass index (BMI), diabetes, smoking status, and aspirin use. These cases were compared to a group who had usual care colonoscopy without colorectal cancer diagnosis within the same time period.

Researchers identified 651 EAO CRC cases, and 67,416 controls. The average age of all individuals was 45 years old, and 82% were male. Of those who were diagnosed with CRC, a higher proportion were males, current smokers, non-aspirin users, and had lower BMIs.

Aspirin use and being overweight/obese were associated with decreased odds of early-age onest CRC. Weight loss of five kilograms within five years before a colonoscopy increased the odds of developing CRC. 

This finding highlights how unexplained weight loss should be a clinical sign that triggers a diagnostic assessment of early-age-onset CRC.

In order to better understand what this research means for EAO CRC, we interviewed Dr. Josh Demb, a postdoctoral fellow at the University of California San Diego (UCSD), who led part of this work.

Why is This Work Impactful?

The paper is impactful primarily because of the lack of prior research on risk factors in early-age-onset CRC. Our goal was to better contextualize the association between traditional CRC risk factors and early-onset CRC odds, which could help us identify similarities and differences between early-age-onset CRC and later-onset CRC.  

As prior studies dealt with sample size issues or a lack of risk-factor data, particularly for modifiable risk factors such as diabetes and body weight, we felt that our cohort within the VA system was well-positioned to address this knowledge gap.

What Does This Mean for the Debate About the Screening Guideline?

Relevant to the ACS guidelines that advocated for screening starting at 45, our study found that 75% of the cases in our study population were diagnosed between the ages of 40-49.  This could imply that screening earlier might detect a substantial proportion of early-age-onset CRC cases. However, more research is needed to determine the best strategy for identifying individuals under 50 who might benefit from screening.

What Do You Advise Patients and Advocates to Learn/Know About the Work, and What is Their Role in Considering the Impact of this Paper?

In addition to our main findings showing some similarities in risk factors between early-age-onset CRC and later-onset CRC (persons with increasing age and men have higher odds of EAO CRC), we also think it is important that patients and advocates be aware of possible warning signs. 

Notably, our study found that weight loss of 5kg or more within five years before a baseline colonoscopy was associated with increased early-age-onset CRC odds. This finding highlights how unexplained weight loss should be a clinical sign that triggers a diagnostic assessment of early age onset CRC. While the primary aim of our project was to look at possible risk factors that could be modified to lower risk of early-age-onset CRC, knowing possible signs and symptoms can also help ensure people are staying vigilant about their health. 

As patients and advocates learn about this work, their impact can be best felt by identifying where they still see information gaps. While this study provides key information, there is still a lot of work to be done to more comprehensively understand early-age-onset CRC risk factors. Patients and advocates can help identify particular areas that can be addressed, which can further guide where research might go.

Part 3: Featuring Dr. Jose Perea and Dr. Caitlin Murphy

Summary of the Research: Deciphering the Increasing Incidence

Dr. Jose Perea and colleagues in Spain published an editorial in the journal United European Gastroenterology in January 2020 discussing the issue of early-age onset colorectal cancer and identifying steps to address the rise in incidence. We chatted with Dr. Perea to understand why this work is critical to advancing our understanding of EAO CRC.

Why is This Paper Impactful?

The main objective of the article is to draw attention to the international dimension of the problem and underlining geographical differences in the increasing incidence. Europe is a good example, with a significant proportion of countries having increases, but with some having decreases..

What Does it Mean for the Debate About the Screening Guidelines?

One of the important aspects to take into account about EAO CRC is its geographical differences, as well as certain differential features that, until now, have been identified from the molecular point of view. Another important issue is the development of collaborative multi-center studies with a worldwide-international dimension, in order to define the future guidelines. 

What Do You Advise Patients and Advocates to Learn/Know About the Work and What is Their Role in Considering the Impact of this Paper?

Patients and advocates play an essential role both in supporting the development and dissemination of knowledge about EAO CRC, as well as being spokespersons for concerns, problems, or aspects that in other circumstances could be complicated to recognize by clinicians and researchers.

The bottom line? The increasing incidence of EOCRC appears to be a worldwide problem.

We also spoke to working group member, Caitlin Murphy, PhD who recently had a significant grant accepted by the National Institute of Health (NIH). 

Dr. Murphy’s grant will utilize data on 19,044 children previously enrolled in the Child Health and Development Studies (CHDS), along with cancer registry data to:

  • Estimate the association of antibiotics (prenatal, perinatal, childhood), cesarean delivery, birth weight, and childhood obesity with EAO CRC.
  • Explore whether the association between these exposures in early life and EAO CRC differs among those with and without a family history and/or germline mutations.
  • Estimate the population impact of early-life exposures on the risk of EAO CRC.

The ultimate goal of Dr. Murphy’s research is to use data on early-life exposures to inform CRC prevention and risk-reduction strategies. 

“Although increasing rates of early-age-onset colorectal cancer have attracted substantial research attention, we still know so little about the causes of this disease. Our study will generate much-needed evidence concerning environmental and genetic causes of early-age-onset colorectal cancer. This evidence can ultimately be applied to cancer prevention and risk-reduction strategies, such as personalized screening. For example, results may provide patients and clinicians with information on additional factors to consider when weighing decisions of when to initiate screening and with what type of test.”

-Caitlin Murphy, PhD

Part 4: Featuring Rebecca Siegel, MPH from the American Cancer Society

Summary: 

Rebecca Siegel, MPH, from the American Cancer Society and colleagues recently published research updating data on the number of new cases of early-age onset colorectal (EAO CRC). According to the research, “In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years.” 

We chatted with Rebecca to understand the impact of the updated ACS report and how it will influence research in this area.

Why is This Paper Impactful?

This report is impactful because it provides a snapshot of the current colorectal cancer burden. The shift to a younger patient population highlights the need for clinicians to be aware of the unique challenges faced by this population, such as the need for conversations about fertility preservation and sexual health before treatment begins. Doctors and patients also need to be aware of the risk of long-term treatment effects, including increased risk for new cancers, because of the extended life expectancy compared to older patients. In addition, this should be a wake-up call for clinicians to immediately follow-up patients who present with symptoms of CRC, regardless of their age – two out of three people younger than 50 are diagnosed with advanced disease and 26% are diagnosed with metastatic disease.

What Does it Mean for the Debate About the Screening Guidelines?

This report may help build more consensus for beginning to screen before age 50. In 2018, the American Cancer Society lowered their recommended age to begin screening from 50 to 45, but there has been substantial debate about this change. The fact that the burden is rapidly shifting younger and incidence is now increasing in ages 50-64 years provides additional support for screening to begin at 45. Doubling down on screening for all appropriate age groups is essential right now; fewer than half of people 50-54 years have been screened.

What Do You Advise Patients and Advocates to Learn/Know About the Work and What is Their Role in Considering the Impact of this Paper?

Everyone needs to help increase awareness about rising early-onset disease, the symptoms of CRC, and the importance of insisting on timely follow-up to reduce delays in diagnosis. We also need to work to de-stigmatize CRC. No one should die because they were too embarrassed to go to the doctor with rectal bleeding until it was too late. Advocacy organizations do a great job with this, but we need more efforts targeted at young adults.

Part 5: Featuring Dr. Dr. Whitney Jones

Summary: 

Dr. Whitney Jones, founder of the Colon Cancer Prevention project and gastroenterologist in Louisville, Kentucky recently published a commentary on Improving on-time colorectal cancer screening through lead time messaging along with Fight CRC Medical Advisory board member, Dr. Dennis Ahnen, and EAO WG member, Dr. Paul Schroy. Dr. Jones spent some time unpacking this commentary, elucidating what this research means for the patient community.

A Screening Paradigm

The communication impact in our recently published paper was to link both our current successes and failures in the current CRC screening paradigm which shared common themes. The rise of EAO CRC low screening rates among our highest at risk population, and low compliance rates with screening in the first 5 years after age 50 all share the common theme that we are too late in delivering an impactful message designed for today's CRC fight. And while the search for the causes of EAO CRC progresses, we can still do something now. Our current national and societal messaging focus, age 50 (or 45 in some states), on the average risk population falls short given our current understanding of the changing face of CRC. Screening only those aged 50/45 leaves out the 20 -25% of persons who are at high risk requiring screening at age 40 or sooner. It leaves out the 5% with family cancer risk profiles calling for screening and when appropriate, genetic testing. Is it ok that we only ID 10% of Lynch persons prior to their first cancer diagnosis? It leaves out those patients and providers with sporadic EAO CRC who BOTH lack information about their increasing risk shown to contribute to unacceptable delays in presentation to providers and aggressive diagnostic testing once in the healthcare system.

Finally, for those ages 50-55, either the message intensity or frequency of message delivery is inadequate to achieve 80% compliance with current guidelines on time with increasing incidence of CRC in the 50-55 age group as of today. The paper is a call-to-action that in order to put into effect the great information we already know, and we must transform our current CRC message into an earlier messaging package that not only addresses lifestyle risks factors - smoking, diet, and obesity – but critically, family history of CRC and advanced adenomas/polyps, symptoms, and on-time screening dates determined by a person’s individual risk. Most importantly, the messages should be delivered much earlier and with enough frequency to achieve the goal of getting a person screened/tested on time for their individual risk profile.

What Does it Mean for the Debate About the Screening Guidelines?

I suspect all states will soon recognize testing should begin at 45 instead of 50 given the overwhelming data. The authors concur with the current guidelines across organizations in which there is great consensus. So, in fact, outside of the soon to be resolved 45/50 issue, the debate should be how we set and achieve goals for those in the high risk family history and sporadic EAO CRC groups.

Although it’s hard to digest, we must reconfigure (not replace) our national communication strategy to reach all persons 20 and older and convey messages through their adult life around their own symptoms, their family’s hereditary cancer risks, and their family CRC and polyp history specifically. Just as we don’t know in advance who will have a polyp found in a colonoscopy until we look, we do not know who is at familial risk or who may develop symptoms until we ask. Sporadic, by its nature, means anyone. In order to execute recommendations on time - when they will have their optimal effect - they must be delivered years, if not decades, earlier and with enough frequency to achieve >80% compliance. More clinical and behavioral research around this is critical.

What Can We Do Now?

The guidelines don’t have to change, we must change our communication strategy.

Organizations should not rest on our laurels. With new data we must acknowledge our current messaging package’s shortcomings and push for clear statements of goals to ensure ALL persons receive and follow evidence-based guidelines when they have the greatest impact, not just focus on those at normal risk. Member organizations should be advocating NOW to our top national organizations ( NCCRT, ACS, USPSTF, Multi-Society Task force, ACG, etc.) to an earlier and expanded messaging package, allowing ample lead time for personal action.

Organizations, including the NCCRT, should go about setting a national goal for identification of persons at higher risk who should be screened by or before age 40 WITH colonoscopy as the preferred method of screening. Given that the risks are higher with these people, we should be setting higher goals for adherence. Ninety percent sounds right to me. Currently we are well under 40% by many accounts. We need to identify 90% of Lynch Syndrome patients in the pre-cancer state. We need to talk about family history again and use the powerful tools of multi-gene panel testing on those meeting criteria > 90% of the time. And yes, multiple messages now and over an adult lifetime will inevitably lead to improvement in the on-time and up-to-date CRC screenings, the 80% who are asymptomatic normal risk individuals.

It’s common sense and this approach supports our values to be more proactive. Surely we can all agree on this now.

The takeaway: To be more successful, the CRC community message must reach, in a meaningful way, all persons some time in their 20s with a compelling and continuous message to know and act on both symptoms and individual risks, especially in regards to family history of CRC (or other cancers in the genetic realm). The best-in-class message profile will result in: a) behavioral change to seek earliest possible evaluation/diagnosis for new symptoms, b) accurate determination and completion of high risk screenings with colonoscopy based or genetic panel testing if indicated, and c) greater 45/50 on-time compliance for normal risk, asymptomatic individuals, with the entire menu of on-time screening choices.


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