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.^{1-4, a}  Learn more at the mt-sDNA Overview.

Footnotes
^aACS: CRC screening starting at age 45 is a qualified recommendation. Individualized decision for screening at ages 76–85 years, consideration based on patient preference, life expectancy, overall health, and prior screening history (qualified recommendation). USPSTF: The USPSTF concludes with moderate certainty that there is a moderate net benefit of starting screening for colorectal cancer in adults aged 45 to 49 years (Grade B recommendation).

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. 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.

4. 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.^1-4  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. 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. Shaukat A, Kahl CJ, Burke CA, et al. ACG clinical guidelines: colorectal cancer screening 2021. Am J Gastroenterol. 2021;116:458-479.  

4. 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, USPSTF, MSTF, 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.^3,5-8 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.

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

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.  

8.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.

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 

Possible study limitations include the use of self-reported NHIS survey data in which respondents may have incorrectly reported use and/or timing of CRC tests. Also, the 2018 NHIS adult response rate was relatively low (53%) as compared to data from earlier years. While survey results were weighted to account for non-response bias, some bias may still exist.¹

In Limburg, et al. 2021, trends in utilization of CRC screening tests were examined using Medicare claims data from 2014-2018.2 As shown in the figure below, the use of colonoscopy and FIT remained relatively constant over time. There was a significant increase in the use of mt-sDNA (P<0.001) and a significant decrease in the use of FOBT (P<0.001).²

Fisher, et al. 2021 queried administrative claims databases to examine CRC screening and test use between 8/1/2011 and 7/31/2019.³ Participants included individuals aged 45-75 years at average risk of CRC. The primary outcome was the proportion of patients who were up to date or not due for CRC screening during each measurement year and the type of screening test used. The sample included 97,776 individuals and data were determined for 2 age groups – 45 to 49 years (n=37,006) and ≥50 years (n=60,770).

Trends showed an increase in participants up to date with CRC screening from 50.4% in 2011 to 69.7% in 2019. The use of FOBT decreased between 2011 (17.4%) and 2019 (6.6%), mt-sDNA increased between 2016 (1.9%) and 2019 (14.2%), and there was no change for FIT or screening colonoscopy. The increase in mt-sDNA use occurred after the CPT code became available in 2016.

Barthold, et al. 2022 conduced a cohort study to examine CRC screening rates in 2 states (Oregon and Kentucky) that have implemented policies to eliminate consumer cost-sharing of CRC screening compared to neighboring states that did not using data from administrative claims databases from January 1, 2012, to December 31, 2019.⁴ Oregon was compared to Idaho and Washington and Kentucky was compared to Indiana, Tennessee, and West Virginia. Participants included individuals aged 45-64 years with 12 months of continuous enrollment in self-funded plans. Oregon was further restricted to ages 50-64 years and excluded enrollees with high-deductible plans. The sample included 2,327,935 person-years among 1,215,580 individuals.

After policy implementation in 2017 in Oregon, individuals had 6% higher odds of receiving any CRC screening and 35% higher odds of undergoing an initial noninvasive test after policy implementation. There was no statistically significant difference for the odds of receiving a colonoscopy conditional on undergoing noninvasive CRC screening in Oregon. For Kentucky, there was no significant difference for any outcome. The authors concluded that access to full coverage resulted in significant increases in overall CRC screening and the use of noninvasive testing in Oregon but not Kentucky. 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.

3. Fisher DA, Princic N, Miller-Wilson LA, et al. Utilization of a colorectal cancer screening test amount individuals with average risk. JAMA Netw Open. 2021;4(9):e2122269.

4. Barthold D, Yeung K, Lieberman D, et al. Comparison of screening colonoscopy rates after positive noninvasive testing for colorectal cancer in states with and without cost-sharing. JAMA Netw Open. 2022;5(6):e2216910.

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

Jensen, et al. 2016
In a retrospective, longitudinal study in an integrated delivery healthcare system using an organized screening program, the first-round adherence rate for FIT was 48.2%. For those who completed screening in the first round, repeat adherence rates ranged from 75.3% to 86.1% in rounds 2 through 4.²

Murphy, et al. 2020
A second retrospective study in a safety-net health system reported rates ranging from 15.8% to 28.8% in rounds 2 through 4 in patients with a normal FIT in round 1.³ Of those who completed the first FIT, only 15.8% completed two FIT tests, 3.1% completed three FIT tests, and 0.8% completed four FIT tests over the 4-year period.

Fisher, et al. 2022
More recently, a study that analyzed data from diverse health plans for participants who completed an index FIT showed that 23.4% completed a repeat FIT at period 2 and 10.6% of participants completed a repeat test at both period 2 and 3.⁴

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. Jensen CD, Corley DA, Quinn VP, et al. Fecal immunochemical test program performance over 4 rounds of annual screening: a retrospective cohort study. Ann Intern Med. 2016;164(7):456–463.

3. Murphy CC, Halm EA, Skinner CS, et al. Challenges and approaches to measuring repeat fecal immunochemical test for colorectal cancer screening. Cancer Epidemiol Biomarkers Prev. 2020;29(8):1557–1563.

4. Fisher DA, Princic N, Miller-Wilson LA. et al. Adherence to fecal immunochemical test screening among adults at
average risk for colorectal cancer. Int J Colorectal Dis. 2022;37:719–721.

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.^3,4 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 

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].

To help address these concerning trends, CRC screening guidelines from the American Cancer Society, ACG, MSTF, 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.^2,7-9 Learn more at Guidelines and Young Onset Disease. 

References

1. Siegel RL, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254.  

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.Montminy EM, Zhou M, Maniscalco L, et al. Shifts in the proportion of distant stage early-onset colorectal adenocarcinoma in the United States. CA Epidemiol Biomarkers Prev. 2022;31(2):334-341.

5. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2022;73(1):17-48.  

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.  

9. 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.

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 was 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 was 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,  depending on the specific strategy used
• Translates to an estimated 104-123 days of life gained per person screened

Additionally, per 1000 adults, it was calculated that lowering the starting age of screening from 50 to 45:⁶

•  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, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254

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. 

Imperiale, et al. 2021 (Act Now Study) performed a blinded prospective study of 983 average-risk patients, aged 45-49 years. The primary outcome measure determined the specificity of mt-sDNA in this group using colonoscopy as the reference method.¹ 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.¹

mt-sDNA has a specificity of 95.2% (CI, 93.4-96.6) in this study (n=767 participants with no CRC or advanced precancer on colonoscopy).¹ This showed that the majority of participants with no CRC or advanced precancer had a negative mt-sDNA result, as intended. The corresponding false positive rate
was 4.8%.¹

CRC sensitivity data in the 45–49-year-old group was less robust due to study size and other limitations. No CRC was found in >800 evaluable participants by mt-sDNA or colonoscopy; thus, CRC sensitivity could not be calculated.
1 The mt-sDNA sensitivity for advanced precancerous lesions (APLs) was 32.7% (95% CI,19.9%–47.5%), ¹ which was comparable to the nearest age group findings (50–59- year-old participants) in the DeeP-C study where mt-sDNA detected 38.0% (65 of 171) of APLs. ^2,3a

As a condition of FDA approval for label expansion, Exact Sciences Corporation is sponsoring a postapproval study in the 45 to 49-year-old cohort.⁴ It will be a multicenter study with over 50,000 participants. Three or more CRC cases will be included. Patients with mt-sDNA results will be followed by record review. The aim is to study mt-sDNA positivity rate, adherence to follow-up with a colonoscopy, observed sensitivity and specificity, and subsequent colonoscopy findings^.4

Learn more at ACT NOW.

Footnotes

^a The FDA considered data from this adjacent age group when approving mt-sDNA age expansion to 45 years.³

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, 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.

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

4. FDA. A post-marketing real world study. Post-approval studies (PAS) database. Page last updated November 14, 2022. Accessed April 14, 2023.
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?t_id=664987&c_id=5693

The false positive rate for mt-sDNA is 13%.¹ Many average-risk colorectal cancer (CRC) screening patients have no CRC or advanced adenomas.^2a The mt-sDNA screening test was developed to distinguish such individuals from those with CRC and advanced adenoma.³ In the 2014 pivotal study by Imperiale et al., mt-sDNA accurately identified 87% of individuals (80 out of 92) with no CRC or advanced adenomas (true negative rate, specificity).¹ Conversely, 13% (12 out of 92) received a positive mt-sDNA result despite having no CRC or advanced adenomas on colonoscopy (false positive rate, 1- specificity).¹

The 45% represents the proportion of individuals with a positive mt-sDNA result and negative colonoscopy findings (no CRC, advanced precancerous lesions or nonadvanced adenomas). This is calculated from results of the pivotal study extrapolated to 10,000 individuals: 1611 would have had a positive mt-sDNA result. Of those 1611, 732 individuals (45.4%) would have had negative colonoscopy results (732/1611).¹

Learn more at mt-sDNA Overview.

Footnotes

^a Advanced adenoma was defined in the pivotal mt-sDNA study as high-grade dysplasia, adenomas with ≥25% villous features, or adenomas or sessile serrated lesions ≥1 cm.

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

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

 A positive mt-sDNA test distinguishes those with a high likelihood of CRC or advanced adenomas from those with a low likelihood of CRC or advanced adenomas.  Out of the 10,000 individuals tested in the pivotal study, 1611 (16%) would have received a positive mt-sDNA test result. After colonoscopy of the 1611 who tested positive:¹

• 60 individuals (3.7%) would have had colorectal cancer
• 321 individuals (19.9%) would have had advanced adenomas
• 498 individuals (30.9%) would have had non-advanced adenomas
• 732 individuals (45.4%) would have had non-neoplastic or negative findings

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.  

A negative mt-sDNA test distinguishes individuals with a lower chance of CRC or advanced adenomas from those with a higher chance of CRC or advanced adenomas.  Out 10,000 individuals tested in the pivotal study, 8389 (84%)
would have received a negative mt-sDNA result. After colonoscopy of the 8389 who tested negative:¹

• 5549 individuals (66.1%) would have had non-neoplastic or negative findings
• 2398 individuals (28.6%) would have had non-advanced adenomas
• 437 individuals (5.2%) would have had advanced adenomas
• 5 individuals (0.06%) would have had colorectal cancer

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.  

Patients should not provide a sample for Cologuard if they have diarrhea or blood in their urine or stool from bleeding hemorrhoids, bleeding cuts or wounds on their hands, rectal bleeding, or menstruation.

If a patient notices visible blood in the stool, urine, collection container or on the toilet tissue, the patient should discard the entire sample, rinse the collection container with warm water only, let the container air dry, and recollect at another time. Learn more at Indications/Contraindications.

Reference

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

A negative result means that Cologuard did not detect abnormal DNA and/or blood in the sample.¹ The chance for CRC after a negative Cologuard test goes down to 0.06%, and the chance for advanced pre-cancerous lesions decreases to 5.2%.² 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.³

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 A positive Cologuard result is associated with an increased chance of colorectal cancer (3.7% after a positive result) and for advanced precancer (19.9% after a positive result).² Therefore, if a patient has a positive Cologuard result, they should get a colonoscopy.1 Per guidelines, patients with a high-quality negative colonoscopy after a positive mt-sDNA result do not require additional clinical evaluation.⁴  Learn more at mt-sDNA Overview.

References

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

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. 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.

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.

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.  

mt-sDNA is indicated to screen adults of either sex, 45 years or older, who are at average-risk for CRC.¹ Patients with  non-neoplastic lesions are not considered to be at high-risk for CRC and are indicated for the mt-sDNA test.¹ However, the science behind hyperplastic polyps and associated CRC risk is currently evolving. Several guideline societies have recently issued recommendations that indicate a conservative approach to screening for individuals with large or numerous hyperplastic polyps.  

Recently updated recommendations by the US Multi-Society Task Force suggest that individuals with more than 20 hyperplastic polyps distributed throughout the colon, with at least 5 being proximal to the rectum, or those with 5 serrated polyps proximal to the rectum >5 mm, with at least two ≥10 mm (serrated polyposis syndrome) may require specialized management.² Clinicians should exercise their own discretion to determine further screening intervals for patients with large or numerous hyperplastic polyps.  Learn more at Indications/Contraindications.

References

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

2. 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;91(3):463-485.e5.  

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.² It also includes the salivary glands, liver, gallbladder, and pancreas.³ Learn more at Indications/Contraindications.

References

1. National Institutes of Heath. NCI Dictionary of Cancer Terms. Bethesda, MD. Accessed April 14, 2023. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/aerodigestive-tract

2. National Institutes of Health. NCI Dictionary of Cancer Terms. Bethesda, MD. Accessed April 14, 2023. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/gastrointestinal-tract

3. National Institutes of Health. NCI Dictionary of Cancer Terms. Bethesda, MD. Accessed April 14, 2023. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/digestive-system

mt-sDNA is contraindicated for individuals with a family history of CRC.¹ In the clinical study evaluating the performance of mt-sDNA, family history of CRC was defined as one first-degree relative diagnosed with CRC before the age of 60 or ≥2 first-degree relatives diagnosed with CRC at any age.² Learn more at Indications/Contraindications.

References

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

2. Multi-Target Colorectal Cancer Screening Test for the Detection of Colorectal Advanced Adenomatous Polyps and Cancer (DeeP-C). ClinicalTrials.gov Identifier NCT01397747. Last Updated posted December 3, 2015. Accessed April 14, 2023. https://clinicaltrials.gov/ct2/results?cond=&term=DeeP-C&cntry=&state=&city=&dist=  

No dietary or medication modifications need to be made prior to a patient using Cologuard.¹

Patients were enrolled in the pivotal clinical study validating Cologuard performance regardless of their medication or dietary history.² In addition, no common substances potentially present in stool specimens interfered with the molecular or hemoglobin assay components of mt-sDNA.³

The mt-sDNA molecular assay was evaluated with potential interfering substances in the following categories:³

• 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.

Similarly, the mt-sDNA hemoglobin assay was evaluated with potential interfering substances in the following categories:³

• 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)
• Animal hemoglobin and myoglobin 

References

1.Cologuard Clinician Brochure. Exact Sciences Corporation. Madison, WI.
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. FDA. Cologuard summary of safety and effectiveness data. August 11, 2014