Recently published data in Mayo Clinic Proceedings found that the non-invasive, multitarget stool DNA “at-home” screening test developed by Exact Sciences (Cologuard®; mt-sDNA) is the most cost-effective colorectal cancer (CRC) screening option in the Alaska Native population, as compared to colonoscopy and the fecal immunochemical test (FIT), for a wide range of adherence scenarios. According to the model, Cologuard produced the highest number of Quality-adjusted Life-years (QALYs) gained and the largest reduction in CRC incidence.[1]

Despite a significant unmet need for screening, significant challenges, such as obstacles around getting people from their remote homes to healthcare facilities, which require significant time, expense, and support personnel, and a lower sensitivity for cancer and pre-cancer with other stool-based tests, have limited access to preventative screening for many Alaska Native people.  As a result, Alaska Native people have among the world’s highest reported incidence rates for colorectal cancer. Cologuard has shown to eliminates nearly all these barriers because patients can collect their samples at home.

Diana Redwood, Ph.D., MPH, Alaska Native Tribal Health Consortium | ANTHC · Alaska Native Epidemiology Center.

A Markov model was used to evaluate the effects of the three screening tests over a period of 40 years. The outcomes included the incidence and mortality, costs, QALYs, and incremental cost-effectiveness ratios (ICERs) of colorectal cancer. The study incorporated updated evidence on screening test performance and adherence and was conducted from December 15, 2016, through November 6, 2019.

The second leading cause of cancer death
Colorectal cancer is the second leading cause of cancer death for men and women in the United States, [2] in part because many cancers go undetected until later stages when treatment is less effective. [3] Alaska Native people have among the nation’s highest reported incidence rates for colorectal cancer, at 90.9 per 100,000 people compared to 45.7 per 100,000 people for the entire United States.[4]  Although screening for colorectal cancer saves lives, according to the latest available medical record data (2017), only 59% of Alaska Native people have been adequately screened.

Significant challenges
Despite the clear unmet medical need, screening Alaska Native people presents significant challenges. For example, Alaska Native people have a high prevalence of Helicobacter pylori infection–related gastrointestinal bleeding. [5][6] This, in turn, is associated with higher false-positive rates for guaiac-based fecal occult blood testing.[7] Because of the limitations of guaiac-based fecal occult blood testing, which are limited by poor patient compliance, and low sensitivity, specificity, and positive predictive value, as well as the high rates of precancerous polyps and colorectal cancer, the preferred Alaska Native screening method has been colonoscopy. However, substantial resources, including time, travel expenses, and personnel, are required to administer colonoscopy in a population residing in widely distributed and remote roadless regions.

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Another concern is that a colonoscopy is biased toward the detection of distal disease, with less effect on incidence or mortality of proximal colorectal cancer.[8][9][10]

The authors of the article in Mayo Clinic Proceedings note that this is of concern because nearly half of the diagnosed cases of colorectal cancer Alaska Native people occur in the proximal colon. They also noted that there is a well-established wide variation in colonoscopy quality metrics (eg, adenoma detection rates) across endoscopists. The authors note that this operator-dependent quality variation, which has measurable effects on screening outcomes, has not been factored into historical cost-effectiveness models.

The observed lower sensitivity for cancer and pre-cancer with other stool-based tests and obstacles around getting people from their remote homes to healthcare facilities, which requires significant time, expense, and support personnel.[12]

Best alternative
And while a colonoscopy is still considered the gold standard of colorectal cancer screening methods for its ability to view the entire colon and both detect and remove polyps during the same procedure, and it is the only test that is suitable for individuals who have risk factors such as a family history of colorectal cancer, the challenges Alaska Native people encounter may result in many people not being screened at all. Hence, to improve screening, the Cologuard test, which is not a replacement for colonoscopy in high-risk patients, provides a path to overcome some of the major barriers by offering patients a colorectal cancer screening test that allows them to collect their stool samples at home.

High sensitivity
An earlier study from lead author Diana Redwood, Ph.D. of the Alaska Native Tribal Health Consortium and Alaska Native Epidemiology Center, analyzed the performance of Cologuard, a U.S. Food & Drug Administration (FDA) approved stool DNA test for colorectal cancer, in Alaska Native people. The study showed the non-invasive Cologuard test had high sensitivity in detecting colorectal cancer and large pre-cancerous lesions making it a strong candidate for increasing the screening options available for Alaska Native people.[12]

“My earlier research showed that Cologuard is an effective screening test in Alaska Native people,” Redwood said.

“This study shows Cologuard would also be a cost-effective way to screen this unique and hard to reach population,” she added.

Each strategy reduced costs and increased QALYs in comparison without screening, with Cologuard outperforming FIT and colonoscopy screening in all adherence scenarios. With perfect adherence assumed, all screening modalities examined (colonoscopy, FIT, and mt-sDNA) decreased the incidence of colorectal cancer relative to no screening, with Cologuard decreasing incidence the most. [1][12]

“Cologuard is supported by Exact Sciences’ built-in patient navigation system, which offers round-the-clock support for patients. Data shows this support increases test completion rates, especially among people, like many Alaska Native people, who haven’t been previously screened,” said Paul Limburg, M.D., Chief Medical Officer, Screening at Exact Sciences

Perfect adherence
With perfect adherence, the incidence of colorectal cancer was reduced by 52% (95% CI, 46% to 56%) using 10-yearly colonoscopy, 61% (95% CI, 57% to 64%) using annual FIT, and 66% (95% CI, 63% to 68%) using triennial mt-sDNA screening. Compared with no screening, perfect adherence to screening added estimates of 0.19 QALYs with mt-sDNA, 0.17 QALYs with FIT, and 0.15 QALYs per person with colonoscopy. Colonoscopy was found to be the most expensive strategy: about $110 million more than mt-sDNA and $127 million more than FIT.

With best-case imperfect adherence, which represents the highest estimated adherence rate based on the author’s analysis, mt-sDNA resulted in an improvement of 0.12 QALYs/person vs. 0.05 QALYs/person by FIT and 0.06 QALYs/person by colonoscopy. Under other adherence scenarios, mt-sDNA either dominated or was cost-effective as compared with FIT and colonoscopy.

[1] 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. 2020; xx(x):1-15. doi:10.1016/j.mayocp.2020.07.035
[2] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7-33. doi:10.3322/caac/21654
[3] Zauber AG, Winawer SJ, O’Brien M, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366(8):687-696. doi:10.1056/NEJMoa110370
[4] ACS. Colorectal cancer facts and figures 2020-2022. Atlanta: American Cancer Society; 2020.
[5] Yip R, Limburg PJ, Ahlquist DA, Carpenter HA, O’Neill A, Kruse D, Stitham S, Gold BD, Gunter EW, Looker AC, Parkinson AJ, Nobmann ED, Petersen KM, Ellefson M, Schwartz S. Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency. Role of Helicobacter pylori gastritis. JAMA. 1997 Apr 9;277(14):1135-9. doi: 10.1001/jama.1997.03540380049030. PMID: 9087468.
[6] Parkinson AJ, Gold BD, Bulkow L, Wainwright RB, Swaminathan B, Khanna B, Petersen KM, Fitzgerald MA. High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults. Clin Diagn Lab Immunol. 2000 Nov;7(6):885-8. doi: 10.1128/cdli.7.6.885-888.2000. PMID: 11063492; PMCID: PMC95979.
[7] Redwood D, Provost E, Asay E, Roberts D, Haverkamp D, Perdue D, Bruce MG, Sacco F, Espey D. Comparison of fecal occult blood tests for colorectal cancer screening in an Alaska Native population with high prevalence of Helicobacter pylori infection, 2008-2012. Prev Chronic Dis. 2014 Apr 10;11:E56. doi: 10.5888/pcd11.130281. PMID: 24721216; PMCID: PMC3984942.
[8] Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, Parkin DM, Wardle J, Duffy SW, Cuzick J; UK Flexible Sigmoidoscopy Trial Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. 2010 May 8;375(9726):1624-33. doi: 10.1016/S0140-6736(10)60551-X. Epub 2010 Apr 27. PMID: 20430429.
[9] Schoen RE, Pinsky PF, Weissfeld JL, Yokochi LA, Church T, Laiyemo AO, Bresalier R, Andriole GL, Buys SS, Crawford ED, Fouad MN, Isaacs C, Johnson CC, Reding DJ, O’Brien B, Carrick DM, Wright P, Riley TL, Purdue MP, Izmirlian G, Kramer BS, Miller AB, Gohagan JK, Prorok PC, Berg CD; PLCO Project Team. Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med. 2012 Jun 21;366(25):2345-57. doi: 10.1056/NEJMoa1114635. Epub 2012 May 21. PMID: 22612596; PMCID: PMC3641846.
[10] Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L. Association of colonoscopy and death from colorectal cancer. Ann Intern Med. 2009 Jan 6;150(1):1-8. doi: 10.7326/0003-4819-150-1-200901060-00306. Epub 2008 Dec 15. PMID: 19075198.
[11] Corley DA, Jensen CD, Marks AR, Zhao WK, Lee JK, Doubeni CA, Zauber AG, de Boer J, Fireman BH, Schottinger JE, Quinn VP, Ghai NR, Levin TR, Quesenberry CP. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014 Apr 3;370(14):1298-306. doi: 10.1056/NEJMoa1309086. PMID: 24693890; PMCID: PMC4036494.
[12] Redwood DG, Asay ED, Blake ID, et al. Stool DNA testing for screening detection of colorectal neoplasia in Alaska Native people. Mayo Clin Proc. 2016;91(1):61-70. doi:10.1016/j.mayocp.2015.10.008

Featured image: Exact Sciences Laboratories, Madison, WI.

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