FAQ

Patients who are not at “high risk” for CRC are considered “average risk” for colorectal cancer. Multiple national organizations recommend routine CRC screening for asymptomatic patients at “average risk” beginning at the age of 45-50 through 75 years of age.^1-6,a  Learn more at the mt-sDNA Overview.

Footnote

^a All recommendations are category 2A unless otherwise indicated. The National Comprehensive Cancer Network (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. 

References 

1. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. 

2. Wolf A, Fontham E, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68:250-281.

3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colorectal Cancer Screening V.2.2021. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed February 23, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

4. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2017:112(7):1016-1030.

5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/familial high-risk assessment: colorectal. Version 1.2021. May 11, 2021. Accessed January 26, 2022. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

6. Gupta S, Lieberman D, Anderson JC, et al. Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterol. 2020;158(4):1131-1153.e5.

CRC screening guidelines vary in not only the start of screening age, but also the level of recommendation and quality evidence supporting the recommendation.^1-5,a  Learn more at Guidelines.

Footnote

^a All recommendations are category 2A unless otherwise indicated. The National Comprehensive Cancer Network (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. 

References

1. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. 

2. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guidelines update from the American Cancer Society. CA Cancer J Clin. 2018;68:250-281.  

3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colorectal Cancer Screening V.2.2021. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed February 23, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

4. Shaukat A, Kahl CJ, Burke CA, et al. ACG clinical guidelines: colorectal cancer screening 2021. Am J Gastroenterol. 2021;116:458-479.  

5. Patel SG, May FP, Anderson JC, et al. Updates on age to start and stop colorectal cancer screening: recommendations from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterol. 2022;162(1):285-299.

While studies^1,2 have shown declines in CRC incidence and mortality rates^a in adults aged ≥55 years, the incidence of CRC in adults <50 years increased by about 51% between 1994 and 2014.³

CRC incidence rates in adults aged <50 increased by 2.2% annually in years 2012-2016 and mortality rates increased by 1.3% annually in years 2008-2017.² Along with an increasing incidence, patients younger than 50 years are more likely to be diagnosed with a later-stage of CRC.⁴ Among adults aged <50 years, increases in CRC incidence rates are driven by tumors in the distal colon and rectum, with the exception of adults age 40-49 years, among whom rates are also increasing for proximal tumors.²

In 2020, an estimated 12% (17,930/147,950) of cases of CRC are predicted to be diagnosed in adults <50 in addition to 3640 (out of 53,200) CRC deaths in that age group.²

To significantly reduce CRC incidence and mortality, the detection and subsequent removal of precursor lesions at an earlier, more favorable stage is critical.³ Per ACS modeling estimations, more than 10% of premature mortality from CRC was due to diagnosis of patients aged 45 to 49, as measured in person-years of life lost (YLL).³

To help address these concerning trends, CRC screening guidelines from the ACS, National Comprehensive Cancer Network^® (NCCN^®)^b, USPSTF and American College of Gastroenterology (ACG) all recommend that adults ages 45 and older with an average risk undergo regular CRC screening with a high-sensitivity stool-based or structural exam, depending on patient preference and test availability.^3,5-7 Learn more at Incidence and Mortality.

Footnotes

^a Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics.

^b All recommendations are category 2A unless otherwise indicated. The National Comprehensive Cancer Network (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References

1. Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109(8):djw322.  

2. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.  

3. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guidelines update from the American Cancer Society. CA Cancer J Clin. 2018;68:250-281.  

4. Abdelsattar ZM, Wong SL, Regenbogen SE, et al. Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening. Cancer. 2016;122:929-934.

5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colorectal Cancer Screening V.2.2021. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed February 23, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

6. Shaukat A, Kahl CJ, Burke CA, et al. ACG clinical guidelines: colorectal cancer screening 2021. Am J Gastroenterol. 2021;116:458-479. 

7. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977.  

It is estimated that 10.5% of new colorectal cancer cases occur in persons younger than 50 years.¹ Incidence of colorectal cancer (specifically adenocarcinoma) in adults aged 40-49 years has increased by almost 15% from 2000-2002 to 2014-2016.¹ Because there is limited evidence to support starting screening in this younger population, the USPSTF recommendations are based on predictive modeling strategies. CISNET modeling analyses were performed and the majority of the 49 strategies modeled were efficient options with all 3 models. Forty-one of these specified screening beginning at age 45. This resulted in 22-27 LYG with fewer colonoscopies per additional LYG relative to other strategies.² Learn more at Guidelines.

References

1. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. 

2. Knudsen AB, Rutter CM, Peterse EFP, et al. Colorectal cancer screening: a collaborative modeling study for the US Preventive Services Task Force. JAMA. Published May 18, 2021; doi:10.1001/jama.2021.5746

Shapiro et al. 2021 analyzed CRC screening test utilization rates using self-reported data from participants in the 2018 National Health Interview Survey (NHIS).¹ Specifically, the use of CRC screening tests overall and the use of specific tests (colonoscopy, stool-based tests, sigmoidoscopy, and CT colonography) were examined.¹ Time trends in use for the specific tests were also examined to understand how the use of different tests contributed to overall changes in CRC screening prevalence between 2010-2018. The sample included 10,595 adults in 2018 aged 50-75 years without a personal history of CRC and with complete information for at least one CRC screening test. Overall, 66.9% were up to date with CRC screening in 2018.¹

The most commonly used tests were colonoscopy (61.1% within the past 10 years), FOBT/FIT (8.8% within the past year), mt-sDNA or FIT-DNA (2.7% within the past 3 years), sigmoidoscopy (2.4% within the past 5 years), and CT colonography (1.0% within the past 5 years).¹

After the CRC screening rates were age-standardized to the 2010 census population, the percentage of participants up to date with screening increased between 2015 (61.2%) and 2018 (65.3%). This increase was primarily due to the increased use of stool-based tests, including mt-sDNA (or FIT-DNA).¹

Use of any CRC screening test was lower for adults who were younger, had less education or lower family income, were born outside of the US, without a usual source of healthcare, and/or had fewer doctor visits. Use was also lower for non-Hispanic Black, non-Hispanic Asian, and Hispanic adults, for those who were never married, and for those who lived in the South and West. Specifically for stool-based tests, the use of any stool-based test was higher for adults who were Hispanic and non-Hispanic Asian, not born in the US, having fair/poor health status, living in the West, aged 50-64 years with Medicaid or other (not private) insurance, and aged 65-74 with dual-eligible health coverage or Medicare Advantage.¹ Learn more at Modalities.

References

1. Shapiro JA, Soman AV, Berkowitz Z, et al. Screening for colorectal cancer in the United States: correlates and time trends by type of test. Cancer Epidemiol Biomarkers Prev. 2021; doi:10.1158/1055-9965.EPI-20-1809  

2. Limburg PJ, Finney Rutten JL, Ozbay AB, et al. Recent trends in colorectal cancer screening methods based on Medicare claims data. Curr Med Res Opin. 2021;37(4):605-607.

Miller-Wilson et al. 2021 investigated mt-sDNA cross-sectional adherence in a national sample of insured patients.¹ Of 1,420,460 participants ≥50 years who were covered by commercial insurance or Medicare, those with a valid mt-sDNA test order placed between January 1 and December 31, 2018, showed an overall cross-sectional adherence of 66.8%. Mt-sDNA test adherence varied by age, location, insurance type and provider:¹

Redwood et al. 2021 used a range of initial, follow-up, and repeat test adherence rates derived from clinical publications in their cost/benefit modeling of CRC screening in an Alaskan Native population.²

Piscitello et al. 2020 used a first-round screening participation rate of 40% for FIT in their modeling study examining the impact of differential adherence rates on the comparative effectiveness of stool-based CRC screening modalities.³ The FIT participation rate was derived from a meta-analysis where values from individual studies ranged from 26% to 62%.^3,4 First-round participation for HSgFOBT was approximately 16% lower than FIT in the same meta-analysis;⁴ thus, a value of 34% was used (40% FIT / 1.16 = 34%).³ An initial test cross-sectional adherence value of 70%^a was used for mt-sDNA, which was based on a retrospective cohort analysis by Weiser et al. 2020.^3,5

Footnote

^a Weiser et al. 2020 cites 71.1% in their publication.⁵

References

1. Miller-Wilson LA, Finney Rutten LJ, Van Thomme J, et al. Cross-sectional adherence with the multitarget stool DNA test for colorectal cancer screening in a large, national study of insured patients. J Clin Oncol. 2021;39(3) suppl, 27-27.

2. Redwood DG, Dinh TA, Kisiel JB, et al. Cost-effectiveness of multitarget stool DNA testing vs colonoscopy or fecal immunochemical testing for colorectal cancer screening in Alaska Native People. Mayo Clin Proc. 2021;96(5):1203-1217.  

3. Piscitello A, Saoud L, Fendrick AM, et al. Estimating the impact of differential adherence on comparative effectiveness of stool-based colorectal cancer screening using the CRC-AIM microsimulation model. PLoS ONE. 2020;15(12):e0244431.  

4. Hassan C, Giorgi Rossi P, Camilloni L, et al. Meta-analysis: adherence to colorectal cancer screening and the detection rate for advanced neoplasia, according to the type of screening test. Aliment Pharmacol Ther. 2012; 36(10):929–40.  

5. Weiser E, Parks P, Swartz RK, et al. Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening: Real-world data from a large cohort of older adults. J Med Screen. 2021;28(1):18-24.  

CRC trends overall reflect most cases that occur in older age groups, while not addressing trends in young adults. CRC incidence rates have been increasing since the mid-1980s in adults ages 20-39 years and since the mid-1990s in adults ages 40-54 years, with younger age groups experiencing the steepest increase. This pattern is called a birth cohort effect because generations of individuals with higher incidence carry the elevated risk with them as they age. After decades of decline, incidence rates have also begun to increase in younger ages.

The most recent data years of 2012-2016 shows CRC incidence rates in adults aged <50 increased by 2.2% annually and by 1% annually in those ages 50-64, which is a sharp contrast to declines of 3.3% per year in adults ages 65 and older.¹ In addition, CRC incidence has slowed or decreased among adults 55 years and older.² Along with increasing incidence, younger adults are more likely to present with a more advanced stage of CRC.³ Among adults aged <50 years, increases in CRC incidence rates are driven by tumors in the distal colon and rectum.¹ 

CRC mortality rates have increased in adults aged <50 by 1.3% annually in years 2008-2017, further highlighting the importance of early diagnosis.¹

In 2020, an estimated 12% (17,930/147,950) cases of CRC are predicted to be diagnosed in adults <50, in addition to 3,640 (out of 53,200) CRC deaths in that age group.¹

To significantly reduce CRC incidence and mortality, the detection and subsequent removal of precursor lesions at an earlier, more favorable stage is critical.³ Per ACS modeling estimations, more than 10% of premature mortality from CRC was due to diagnosis of patients aged 45 to 49, as measured in person-years of life lost (YLL).³

The National Comprehensive Cancer Network^® (NCCN^®)^a notes that between 1992 and 2015, there was a relative increase of 30% in the incidence of CRC in 40-year-olds. However, this translates to an absolute difference in incidence of 8.2 cases per 100,000.^5,a

While recent data shows CRC incidence rates increasing in adults aged <50 years, analyses of CRC histologic subtypes - adenocarcinoma and carcinoid tumors - have not been previously reported.⁶ Carcinoid tumors have a distinct pathogenesis and are managed differently from adenocarcinomas,⁶ and their contribution to overall CRC incidence rates (IRs) may be underappreciated. [Note: the biomarkers comprising mt-sDNA do not detect carcinoid tumors of the colorectum].

Montminy et al. 2020⁶ conducted a retrospective analysis (2000-2016) of the SEER 18 database to assess early-onset CRC IRs and changes in IRs over time. Results from 119,624 patients with CRC were stratified by histologic subtype and age. Colorectal carcinoid tumor IRs increased more steeply than adenocarcinoma in all age groups, which affected the contribution of carcinoid tumors to overall cancer cases over time. These changes were predominantly driven by rectal carcinoid tumors. 

To help address these concerning trends, CRC screening guidelines from the American Cancer Society, NCCN^®,a, ACG, and USPSTF all recommend that adults ages 45 and older with an average risk undergo regular CRC screening with a high-sensitivity stool-based or structural exam, depending on patient preference and test availability.^2,5,7,8 Learn more at Guidelines and Young Onset Disease. 

Footnote

^a All recommendations are category 2A unless otherwise indicated. The National Comprehensive Cancer Network (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References

1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.  

2. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250-281.  

3. Virostko J, Capasso A, Yankeelov TE, Goodgame B. Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004-2015. Cancer. 2019;125(21):3828-3835.  

4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7-33. 

5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colorectal Cancer Screening V.2.2021. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed February 23, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

6. Montminy EM, Zhou M, Maniscalco L, et al. Contributions of Adenocarcinoma and Carcinoid Tumors to Early-Onset Colorectal Cancer Incidence Rates in the United States. Ann Intern Med. 2021;174(2):157-166. 

7. Shaukat A, Kahl CJ, Burke CA, et al. ACG clinical guidelines: colorectal cancer screening 2021. Am J Gastroenterol. 2021;116:458-479.  

8. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977.  

Expansion of the screening age for CRC is expected to have substantial impacts on the utilization of screening resources.^1,2 As of 2018, there are an estimated ~19 million average-risk adults eligible for screening in the U.S. between the ages of 45 and 49 years.³ This estimate is based on the US population aged 45-49 as of 2018, adjusted for the reported rates of high-risk conditions and prior screening history for CRC.

Although the absolute risk of developing colorectal cancer is much lower in adults younger than age 50 years, age-period-cohort analysis indicates a recent trend for increasing risk of CRC in adults younger than age 50 years.⁴ Modeling performed by CISNET (2021 USPSTF recommendations) suggests that starting CRC screening at age 45 years may potentially moderately increase life-years gained and decrease CRC cases and deaths compared to beginning screening at age 50 years.⁵

Per 2021 USPSTF recommendations based on averaging estimates across the 3 CISNET models, if screening were performed from ages 45- 75 years with one of the USPSTF recommended strategies:⁶

• An estimated 286 to 337 life-years would be gained

• An estimated 42- 61 cases of colorectal cancer would be averted

• An estimated 24- 28 colorectal cancer deaths would be averted, per 1000 adults screened, depending on the specific strategy used

• Translates to an estimated 104-123 days of life gained per person screened

• Results in an estimated additional 2-3 cases of colorectal cancer being averted,

• An estimated 1 additional colorectal cancer death averted, and

• An estimated 22-27 additional life-years gained per 1000 adults (i.e., 8-10 additional days of life gained per person screened)

• No studies reported on harms of stool-based tests

• Potential harms of over-detection of adenomas not destined to become cancer; no studies directly assessing health effects from such harms identified

Learn more at Guidelines, Modeling, and Young Onset Disease. 

References

1. Ladabaum U, Mannalithara A, Meester RGS, et al. Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years. Gastroenterol. 2019;157(1):137-148.  

2. Anderson JC, Samadder NJ. To screen or not to screen adults 45-49 years of age: that is the question. Am J Gastroenterol. 2018;113:1750-1753.  

3. Piscitello A, Edwards DK. Estimating the screening-eligible population size, aged 45 to 74, at average risk to develop colorectal cancer in the United States. Cancer Prev Res. 2020;13(5):443-448.  

4. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.  

5. Knudsen AB, Rutter CM, Peterse EF, et al. Colorectal cancer screening: a decision analysis for the US Preventive Services Task Force. AHRQ Publication No. 20-05271-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; 2021.

6. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer - US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. 

The clinical validation study was conducted in patients 50 years of age and older.¹  Cologuard performance in patients ages 45-49 was estimated by sub-group analysis of near-age groups. Included in the Cologuard Clinician Brochure is a description of a retrospective study of Exact Sciences Laboratories results, among average-risk patients ages 45 to 49, 92.6% were negative mt-sDNA results indicating that the specificity in this age group is ≥92.6%. These analyses support the expansion of the indication to ages 45 and older.²

Exact Sciences has recently conducted the ACT-NOW study (NCT03728348) with the primary outcome measure of evaluating the specificity of the mt-sDNA test in average-risk individuals aged 45-49 using colonoscopy as the reference method.³ Secondary outcome measures included sensitivity for CRC and advanced adenoma, positive and negative predictive values, positive and negative likelihood ratios, distribution of colorectal epithelial lesions among positive mt-sDNA test, and the rate of no mt-sDNA result.

In this prospective, cross-sectional study of 983 participants aged 45-49 years at average risk for CRC, the specificity of mt-sDNA was 95.2% [95% CI, (93.4-96.6)] among those with nonadvanced adenoma or negative results on colonoscopy.³  Learn more at ACT NOW.

References

1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.  

2. Cologuard Clinician Brochure. Exact Sciences Corporation. Madison, WI.

3. Imperiale TF, Kisiel JB, Itzkowitz SH, et al. Specificity of the multi-target stool DNA test for colorectal cancer screening in average-risk 45-49 year olds: a cross-sectional study. Cancer Prev Res. 2021;14:489-496. 

Most screen-eligible patients at average-risk for colorectal cancer (CRC) will have no CRC or advanced adenoma (AA).¹ In the pivotal study, the true negative rate - defined as the proportion of patients without disease and with a negative mt-sDNA test result (specificity) - was 87%. The false positive rate (1-specificity) included the 13% who did not have disease but had a positive mt-sDNA test result.² Overall, 16% (1611) of the 10,000 population mt-sDNA results were positive.^2,3 False positive rates cannot exceed the total number of positive test results.

A negative colonoscopy included all non-advanced, non-neoplastic findings and negative results on colonoscopy.²

The false positive rate of mt-sDNA was 10% when a negative colonoscopy only (N=4457) included those subjects who had no biopsy or tissue excision or had findings that were negative upon histopathological review (N=455).² These positive results are a subgroup of the overall positive 16% (1611/10,000);* therefore, this is 45% of the 16% of positive test results which does not meet the definition of the false positive rate (1-specificity). Learn more at mt-sDNA Overview.

References

1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164.  

2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.  

3. Cologuard Physician Brochure. Exact Sciences Corporation. Madison, WI.

Of the patients with positive mt-sDNA results, 3.7% (60/1612) had CRC, 19.9% (321/1612) had advanced precancerous lesions, 30.9% (498/1612) had nonadvanced adenomas, and 45.4% (733/1612) had non-neoplastic findings or negative results on diagnostic colonoscopy.¹

When the data were extrapolated to a hypothetical reference population of 10,000 individuals at average risk for CRC who would be undergoing screening, the results were similar. Positive predictive value (PPV) is defined as the proportion of persons with disease among those with a positive test. In this population, the PPV for CRC was 3.7% and for APL was 19.9%.^1,2  Learn more at mt-sDNA Overview.

References

1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.  

2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening supplement. N Engl J Med. 2014;370(suppl1):1-10,s2-s3.

Of the patients with negative mt-sDNA results, 0.06% (5/8377) had CRC, 5.2% (436/8377) had advanced precancerous lesions, 28.6% (2395/8377) had nonadvanced adenomas, and 66.1% (5541/8377) had non-neoplastic findings or negative results on diagnostic colonoscopy.¹

When the data were extrapolated to a hypothetical reference population of 10,000 individuals at average risk for CRC the results were similar. Negative predictive value (NPV) is defined as the proportion of persons without disease among those with a negative test. In this population, the NPV for CRC was 99.94%. and the NPV for APL was 94.7%.^1,2 Learn more at mt-sDNA Overview.

References

1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.  

2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening supplement. N Engl J Med. 2014;370(suppl1):1-10,s2-s3.  

Patients should not provide a sample for Cologuard if they have observable blood in their stool (e.g., from bleeding hemorrhoids, bleeding cuts or wounds on their hands, rectal bleeding, or menstruation).¹

If the sample has visible blood on the stool or toilet tissue, the patient should dispose of the entire sample, rinse the collection container with warm water only, let the container air dry, and recollect at another time.

If the blood in the stool is the result of a temporary condition that resolves, the patient may proceed with Cologuard testing. Learn more at Indications/Contraindications.

Reference

1. Cologuard Physician Brochure. Exact Sciences Corporation. Madison, WI.

A negative result means that mt-sDNA did not detect abnormal DNA and/or blood in the sample.¹ Patients with a negative result should continue in an appropriate screening program which, according to some guidelines, can include rescreening with mt-sDNA in three years.²

A positive Cologuard test means that the test detected abnormal DNA and/or blood that could be caused by precancer or cancer in the colon or rectum.¹ Patients with a high-quality negative follow-up colonoscopy after a positive mt-sDNA result do not require additional clinical evaluation.³ Learn more at mt-sDNA Overview.

References

1. Cologuard Physician Brochure. Exact Sciences Corporation. Madison, WI.

2. Wolf AMD, Fontham E, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250-281. 

3. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2017:112(7):1016-1030.  

The mt-sDNA test result is determined by comparing a composite score calculated from the patient’s individual methylation, mutation and hemoglobin assay results, according to an established threshold from an algorithm.¹ Positive results and negative results are defined as above and below the threshold, respectively. The numerical values generated from the component assays of the mt-sDNA test are excluded from the scope of the approval and are not clinically validated as individual test results. These numerical values are only constituents of the validated test algorithm that generates the qualitative mt-sDNA composite result (positive/negative). The mt-sDNA composite score is not a continuous variable and is therefore also not reported.

A description of the algorithm, as well as sample biomarker analytic data, composite score, and clinical findings from participants in the pivotal study, is available in the supplementary appendix to Imperiale et al.² As shown below, the algorithm has three components:

Step One: The Logistic Score is calculated from a logistic regression formula that allows the biomarkers, as a group, to be used to discriminate between patients with colorectal cancer and/or advanced precancerous lesions from negative cases.

Step Two: The Sum of Scores calculation incorporates the Logistic Score and individual marker scores for the DNA markers. These DNA biomarker scores are entered as either “0” or “10” depending on whether the DNA marker is below (“0”) or above (“10”) the 99.5 percentile of normal. The Sum of Scores calculation ensures that if any one DNA marker is above the 99.5 percentile of normal (boundary condition), the test will have a “positive” result.

Step Three: The final Composite Score is generated when the Sum of Scores is subjected to an exponential equation. This creates a range from 0-1000 for the mt-sDNA test Composite Score. If the Composite Score is ≥183, the mt-sDNA result is “positive.” If the Composite Score is <183, the result is “negative.”

Learn more at Biomarkers/Algorithm.

References

1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.  

2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening supplement. N Engl J Med. 2014;370(suppl1):1-10,s2-s3.  

Yes, hyperplastic polyps are not currently considered malignant or associated with a significantly increased risk for CRC and are not a contraindication to using mt-sDNA.^1,2,a Learn more at Indications/Contraindications.

Footnote

^a All recommendations are category 2A unless otherwise indicated. The National Comprehensive Cancer Network (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. 

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colorectal Cancer Screening V.2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed January 26, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

2. Shussman N, Wexner SD. Colorectal polyps and polyposis syndromes. Gastroenterol Rep. 2014;2(1):1-15.

For mt-sDNA screening purposes, a “related cancer” is a cancer in the airway or gastrointestinal system that includes the lips, mouth, tongue, nose, throat, vocal cords, trachea, lungs and esophagus, as well as the stomach, small intestine, large intestine, rectum, and anus. It also includes the salivary glands, liver, gallbladder, and pancreas.¹ Learn more at Indications/Contraindications.

References

1. National Institutes of Heath. National Cancer Institute. NCI Dictionary of Cancer Terms. Bethesda, MD. Search terms: Aerodigestive; gastrointestinal tract. Accessed January 26, 2022. https://www.cancer.gov/publications/dictionaries/cancer-terms/

A family history of CRC includes one first-degree relative (parent, sibling, or offspring) with CRC <60 years or ≥2 first-degree relatives of any age with these findings.^1,2 Mt-sDNA is contraindicated for individuals with a family history of CRC.³ Learn more at Indications/Contraindications.

References

1. Smith RA, von Eschenbach AC, Wender R, et al. American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. CA Cancer J Clin. 2001;51(1):38-75.

2. Rex DK, Boland CR, Dominitz JA, et al. Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterol. 2017;153(1):307-323.

3. Cologuard Physician Brochure. Exact Sciences Corporation. Madison, WI.

When there is no visible bleeding during sample collection, study findings have indicated that hemorrhoids are unlikely causes of positive mt-sDNA results.^1,2 Rather, a positive result is more likely to be caused by a neoplasm such as cancer or advanced precancer.^1,2 Learn more at Indications/Contraindications.

References

1. Johnson D, Kisiel J, Burger K, et al. Multitarget stool DNA test: Clinical performance and impact on yield and quality of colonoscopy for colorectal cancer screening. Gastrointest Endosc. 2017;85(3):657-665.

2. Talabiska N, Bergenstock M, Pedroso C, et al. Abstract P0726 A single center review of patients with a positive multi-target stool DNA test and negative colonoscopy. Am J Gastroenterol. 2020;115:S137-S138.

The Cologuard molecular assay was evaluated with potential interfering substances in the following categories:¹

• Common lotions, creams, and feminine over-the-counter products
• Stool softeners, anti-diarrhea, and laxative products
• Anti-acids and upset stomach relief products
• Animal genomic DNA of commonly edible animals (both high and low levels)
• Urine and alcohol
• A mixture of common vegetables and fruits
• Fecal fats (fatty acids and cholesterol)

No interference with the molecular assay component of Cologuard was observed for any of the tested substances.

In addition, the Cologuard hemoglobin assay was evaluated with potential interfering substances in the following categories:¹

• Common lotions, creams, and feminine over-the-counter products
• Urine
• Stool softeners, anti-diarrhea, and laxative products
• Anti-acids and upset stomach relief products
• Antibiotics, anti-inflammatories, anti-fungal drugs, pain relievers, and decongestants
• A mixture of common vegetables and fruits
• Fats and lipids
• Alcohol
• Iron sulfate (as found in oral supplements)
• Vitamin C
• DNA Stabilization Buffer (preservative solution provided in the Cologuard Collection Kit for the whole stool sample used in the molecular assay)

None of the substances tested interfered with the Cologuard hemoglobin assay. Participants in the pivotal study were not excluded due to the use of any medications or dietary restrictions, and no medication log was collected from participants.² Accordingly, there are no dietary or medication restrictions with the use of Cologuard.³

References

1.  FDA. Cologuard summary of safety and effectiveness data. Published August 11, 2014.
2.  Imperiale TF, Ransohoff DF, Itzkowitz MD, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.
3.  Cologuard Physician Brochure. Exact Sciences Corporation. Madison, WI.