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Issued by

National Cancer Institute (NCI)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to solicit applications directed toward identifying, characterizing, and mitigating risk factors, identifying biomarkers for early detection, best screening modalities, and preventive interventions for early-onset colorectal cancer (EOCRC), defined as occurring before 50 years of age.

Background

While the incidence and mortality of CRC have significantly declined in the US since the mid-1980s, an age-adjusted analysis shows that this favorable trend was limited to screening-aged individuals. Between 2008 and 2017 CRC death rates declined by 0.6% annually in individuals aged 50 to 64 years and an even larger annual decline (3%) occurred in the population ?65 years of age. During this same period, the incidence of CRC in subjects <50 years of age increased 2% annually, and related deaths in this age group increased 1.3% annually. There were approximately 18,000 new cases of EOCRC diagnosed in 2020. 12% of the newly diagnosed CRCs occurred in people younger than 50 and 7% of the CRC mortality occurred in this younger population. These trends are concerning, and research focused on the etiology, early detection, screening, and prevention of EOCRC are urgently needed.

The biomedical research community currently has little guidance on how to find the at-risk younger population, which is necessary to disrupt this concerning trend. Both patients and healthcare providers often do not recognize and act on what would be red-flag symptoms in an older population. This leads to the younger population being diagnosed at more advanced stages, with poorly differentiated tumors. Several clinical and biological features of EOCRC also differ from those of late-onset disease. Early-onset tumors typically occur in the distal colon and rectum, compared with late-onset disease, where proximal tumors predominate. The EOCRC anatomical location may provide important insight into the underlying pathogenesis since there is increasing evidence that ascending colon cancers differ biologically from descending colon and rectal cancers and there is a disparate increase in the incidence of rectal versus colon cancer.

Regional, racial, and socioeconomic disparities have been well documented but are also not well understood. Understanding the molecular/genetic, environmental, and regional drivers that account for these disparities is critical for characterizing risk factors and establishing evidence-based, cost-effective early detection, prevention, and screening modalities for people younger than 45. Further, through a better understanding of clinical and biological EOCRC features, potential biomarkers for early cancer detection, screening modalities, and interception strategies can be identified to ultimately reverse the upward trend of EOCRC incidence and mortality.

Feasibility

Given the likelihood that the rising incidence of early-onset cancers is multifactorial, successful applications may include investigation of genomic/epigenomic effects of environmental exposures or novel screening approaches that use currently available, non-invasive screening procedures (FIT, Cologuard, mSEPT9) or multi-cancer early detection using liquid biopsy tests. Validating existing screening procedures for this younger population or developing new approaches based on either epidemiology or basic biology methods would help disrupt the EOCRC alarming rise.

Although increasing at a concerning rate, the incidence of early-onset cancers is relatively uncommon; therefore, when appropriate, applicants may consider making use of existing cohorts and data repositories. Preclinical studies establishing new models to test critical gene–environment interactions would help define mechanisms of pathogenesis. Studies that identify biomarkers for early detection focused on how changes in screening practices and healthcare provider education could reduce mortality in this population are also encouraged. Studies investigating the role of risk factors in the context of differences in racial/ethnic distribution would also be responsive to this NOSI.

Research Objectives

Approaches may include epidemiological and/or clinical cohort studies (retrospective or prospective) to characterize risk factors, identify biomarkers that correlate with risk, or preclinical studies focusing on the etiologic factors that affect the development and progression to early-onset cancer. Studies may include examining how dietary, environmental, infectious, and pharmaceutical exposures in childhood alter immune function, metabolism, and/or microbial interactions with the host that contribute to the initiation or progression of EOCRC. Clinical studies that help in planning/feasibility of randomized clinical trials that help to identify best screening modalities, and preventive interventions are encouraged. All research proposals are encouraged to evaluate factors of race, ethnicity, and socioeconomics on EOCRC.

Responsiveness

Eligible applications should focus on areas related to:

• The mechanisms and biology of early and preinvasive stages of EOCRC carcinogenesis
• Molecular/genetic drivers that account for racial/ethnic and regional disparities in EOCRC
• Mechanistic insight to account for the high prevalence of rectal and distal tumors in EOCRC
• Molecular signatures of early-life influences/exposures and social determinants of health that explain the increasing occurrences since the mid-1980s
• Establish evidence that can contribute to EOCRC screening guidelines

Applications considered not responsive to this NOSI will include research focused on:

• Late-onset CRC—defined as onset ? 50 years
• Solely on hereditary cancer syndromes and/or established familial components of CRC (early or late onset)
• Irritable bowel syndrome (IBS)

Research areas of interest for this NOSI include but are not limited to:

1. Evaluate/validate existing FDA-approved CRC screening modalities for the detection and screening of EOCRC
2. Develop grading criteria for EOCRC risk stratification to support evidence-based, cost-effective screening guidelines
3. Feasibility/planning studies to identify the appropriate control or comparison group to use in subsequent EOCRC clinical trials for precision prevention
4. Develop training opportunities for research staff that improve recruitment of younger patients to clinical trials.
5. Develop educational/training opportunities that improve physician and patient engagement in EOCRC screening.
6. Identify potential pathways for cancer interception in this younger population and develop promising interventions based on functional drivers of preneoplasia progression
7. Delineation of causative genetic and epigenetic changes and immune regulators that determine specific preneoplasia stages and their subsequent progression or regression
8. Gain mechanistic insight to account for the higher prevalence of rectal and distal tumors
9. Development of preclinical models that could assist in understanding the underlying mechanisms of EOCRC
10. Understanding the underlying mechanisms for birth cohort effects
11. Developing comprehensive molecular profiles for EOCRC
12. Identification and characterization of behavioral and environmental factors that correlate with the risk of EOCRC, including early-life influences, diet, weight, physical activity, and antibiotic use that could explain increasing trends since the mid-1980s
13. Characterize the molecular/genetic drivers that account for racial disparities in EOCRC
14. Identify behavioral and sociocultural determinants of health that contribute to EOCRC prevalence and outcome disparities among regional and diverse populations
15. Identify/characterize underlying mechanisms contributing to racial disparities in EOCRC prevalence and outcomes.
16. Characterize the effects of age on molecular/genetic drivers in EOCRC

Application and Submission Information

This notice applies to due dates on or after January 5, 2023, and subsequent receipt dates through July 02, 2025.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcements through the expiration date of this notice.

Disparity-Focused Research Funding Opportunities

Early Stage Investigators Funding Opportunities

Planning and Exploratory Research Funding Opportunities

Research and Program Project Funding Opportunities

Trainees' Funding Opportunities

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-CA-23-018” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
• All applicants are strongly encouraged to contact the NCI program contacts, listed below, to discuss the specific aims of the application before submission.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

(For applications related to cancer screening and prevention translational clinical studies)

Gary Della’Zanna
National Cancer Institute (NCI)
Telephone: 240-276-7042
Email: Gary.DellaZanna@nih.gov

(For applications related to cancer biology)

Phillip J. Daschner
National Cancer Institute (NCI)
Telephone: 240-276-6227
Email: Phillip.Daschner@nih.gov

(For applications related to training and early investigator development)

Nastaran Zahir
National Cancer Institute (NCI)
Telephone: 240-276-6333
Email: Nas.Zahir@nih.gov

(For applications related to Reduce Cancer Health Disparities)

Anil Wali
National Cancer Institute (NCI)
Telephone: 240-276-6183
Email: Walia@mail.nih.gov

Financial/Grants Management Contact(s)

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
E-mail: hines@mail.nih.gov