Bernard Levin, MD, FACP

		The Cancer Intervention and Surveillance Modeling Network (CISNET) Colorectal Cancer (CRC) Working Group generated outcomes on benefits, harms, and burdens of several CRC screening strategies defined by the US Preventive Services Task Force. 

		Annual fecal occult blood testing has been shown to be effective in randomized controlled trials and all 3 CISNET models recommended annual fecal immunochemical testing over all other stool-based testing strategies. 

		Berger et al eliminated annual stool-based CRC screening strategies from consideration and re-did the analysis conducted by the CISNET CRC Working Group. With this exclusion, they found that multi-target stool DNA (mt-sDNA) every 3 years would be recommendable according to 1 of the 3 CISNET models.

Karen M. Kuntz, ScD; Ann G. Zauber, PhD; Amy B. Knudsen, PhD; Carolyn M. Rutter, PhD; and Iris Lansdorp-Vogelaar, PhD

The US Preventive Services Task Force (USPSTF) released draft recommendations for colorectal cancer (CRC) screening in October 2015.

 As part of that effort, the USPSTF requested simulation modeling to inform their recommendations. The Cancer Intervention and Surveillance Modeling Network (CISNET) CRC Working Group—a group of modelers with 3 independently developed microsimulation models of CRC&mdash;generated outcomes on benefits, harms, and burdens. They did so for a set of screening strategies defined by the Task Force in terms of age to begin screening, age to end screening, screening interval, and screening modality.

 The modeling study found that annual fecal immunochemical testing was the model-recommendable strategy among stool-based tests. In the February 2016 issue of 

, Berger et al used the output generated by the CISNET models to conduct a post hoc analysis, and they reported that their results “meet the USPSTF criteria for a recommendation for [multi-target stool DNA] mt-sDNA 3y for routine screening.”

 This letter serves to clarify several points.

In their post hoc analysis, Berger et al eliminated one set of strategies—namely, annual screening with a stool test of any kind&mdash;that are typically recommended by several organizations, including the USPSTF. The authors were able to “demonstrate that the modeling performed by CISNET supports a recommendation of mt-sDNA testing every 3 years (3y) for routine screening based on the USPSTF’s criteria, in light of data demonstrating that patients are unlikely to adhere to annual testing.” However, the original CISNET analysis was meant to inform population guidelines; therefore, in consultation with the USPSTF, the CISNET CRC Working Group assumed perfect adherence to screening regimens, including receipt of all screening, diagnostic follow-up (eg, for positive stool tests), and surveillance tests. This assumption enabled the models to predict the maximum achievable benefit for each screening strategy. Eliminating a valid screening strategy for which randomized controlled trials of its efficacy are available

 because its adherence is presumed to be lower than other strategies in the population is not rational within this context, especially when continuing to assume perfect adherence for the other strategies.

Berger et al stated that they used the same algorithm adopted by CISNET researchers, which was outlined in the report, to select the recommendable strategy among the set of stool-based strategies; however, we believe deviation from the algorithm may have occurred. Specifically, one of the criteria for deeming a strategy “recommendable” was that it had to be at least 90% as effective as the colonoscopy strategy with the same screening start and stop ages. Although the 3y mt-sDNA strategy met this criterion in 1 model, it did not in the other 2 models. Thus, on a “majority rules” basis, this criterion was not met; in other words, across the 3 models, the average life-years gained by 3y mt-sDNA was 87.3% of the life-years gained by screening with colonoscopy every 10 years (model-specific estimates were 84.0%, 87.0%, and 90.8%), which is lower than the a priori criterion of 90%.

Finally, Berger et al frame their analysis under the assumption that the USPSTF recommendations process is one that is based solely on the analysis performed by the CISNET modelers. However, we would like to emphasize that the criteria in question were used by the CISNET modeling group to present the results in a meaningful way in order to narrow down the over 200 strategies to a set of potentially recommendable strategies. The modeling results were only one consideration among many used by the USPSTF when making their draft, and now their final recommendations.

 In addition, these criteria were established by the CISNET CRC Working Group prior to doing any analysis, and they were vetted with the USPSTF. The post hoc analysis conducted by Berger et al showed that if one eliminates annual stool-based testing from consideration as a screening strategy, then a strategy of mt-sDNA 3y would be considered recommendable according to 1 of the 3 CISNET models.

Barry M. Berger, MD FCAP, and Bernard Levin, MD, FACP

Kuntz et al have detailed their objections to our elaboration of their own data in our recent article. We appreciate the fact that they do not dispute our analysis but consider it post hoc. Given that these are their data and that their rules were set a priori, we extracted the information from the Cancer Intervention and Surveillance Modeling Network (CISNET) data tables to more fully report CISNET’s own findings. We expanded their modeling conclusions to be more consistent with current clinical practice, which does not routinely achieve the “optimal” annual screening strategies they recommend.

	The CISNET group indicates that the US Preventive Services Task Force (USPSTF) defined the scope of the microsimulation modeling by specifying age to begin screening, age to end screening, screening interval, and screening modality. These strategies were then evaluated in 3 separate microsimulation models.

 In January 2014, the USPSTF provided a research framework for public comment for its review of colorectal cancer (CRC) screening. However, that public comment did not specify the type of modeling or the rules of modeling that were to be used; such specification would have facilitated appropriate comment from technical and medical experts to inform the work of modelers, thereby ensuring the most accurate and clinically useful range of modeled outcomes. Although CISNET has a concern that our analysis was post hoc, we are concerned that their a priori rulemaking was deficient given that the models do not incorporate the SSA pathway and do not accurately account for differences in stool-based test performance. The new rules consider burdens (colonoscopy volume but not fecal immunochemical test (FIT)/fecal occult blood test [FOBT] volume) rather than harms (complications) as the comparator for benefits (life-years gained). We elaborate on these concerns below.

	CISNET utilized models that were out-of-date with respect to the biology of colorectal carcinogenesis and which insufficiently distinguish the performance differences between FOBT/FIT as a single marker and multi-target stool DNA (mt-sDNA)—referred to as “FIT + DNA” in the CISNET models). These models credited FOBT/FIT-based screening with the detection of sessile serrated adenomas (SSA) 1 cm or larger with the same sensitivity as FOBT/FIT-detected conventional advanced adenomas. However, the evidence shows that FOBT/FIT is almost completely insensitive to such SSAs (5% sensitivity), while methylated stool DNA markers can identify 42% of SSAs 1 cm or larger in size even in the absence of any other advanced adenoma

; SSAs may be the precursor lesions for up to 33% of colorectal carcinomas.

 Furthermore, interval and missed cancers on colonoscopy commonly have a molecular DNA profile that indicates their frequent origin from these precursor lesions.

 Three of the 4 strategies recommended by CISNET modeling to the USPSTF cannot detect proximal colonic SSA’s directly, because they either include only annual FIT/FOBT testing or annual FIT with 10-year flexible sigmoidoscopy, which itself doesn’t reach the proximal colon. Approximately 1% (99 of 9989) of average-risk patients were found to have SSAs 1 cm or larger in size with no additional advanced adenomas.

 These lesions would only be found by random detection due to specificity failure of FIT/FOBT in 3 of the 4 strategies recommended to the USPSTF by CISNET.

	Secondly, high-grade dysplasia—the most biologically and clinically critical premalignant change&mdash;is detected significantly better by stool DNA-containing strategies (69%) than by FIT/FOBT as a single marker (46%).

 Finally, the detection of surgically curable stage CRC (stage I + II) is also significantly better with stool DNA containing strategies (94%) than FIT/FOBT as a single marker (70%).

Thus, the models did not account for the differences in detection of SSA’s, high-grade dysplasia, and CRC by stage—the 3 key distinguishing features that lead to CRC prevention and to surgical cure of CRC and that separate stool DNA performance from FIT/FOBT as a single marker. These omissions biased the model outcomes toward the FIT/FOBT strategies previously recommended by the USPSTF for stool-based testing.

	Updating models requires significant work and clinical data with which to accurately calibrate their outputs. We appreciate that CISNET was limited by the models available to them; however, they could have accounted for this deficiency by grouping the stool tests in a more relevant way that reflected differences in test biology and patient-related factors by placing multi-target stool DNA (mt-sDNA) in its own group, which then could have been examined for the effect of interval testing.

	Without consultation outside the USPSTF internal process, the USPSTF and CISNET determined that the “burden” of FOBT, FIT, and “FIT + sDNA” (mt-sDNA) were equal. They then analyzed 9 stool strategies as single group (FIT 1y, 2y, and 3y; hsFOBT 1y, 2y, and 3y; mt-sDNA 1y, 3y, and 5y). This grouping is neither justified clinically nor biologically, and takes the simplistic view that the measure of burden is simply providing a stool sample. Lessened patient burden is associated with other factors related to mt-sDNA tests, including peace of mind from superior lesion detection, longer screening interval (3y), specifically designed collection kits to minimize patient interaction with stool, and an embedded nationwide 24/7 patient navigation system to ensure the highest completion levels of successful screening. The mt-sDNA test was designed to diminish burdens on patients, providers, and health systems, which supported grouping and analyzing mt-sDNA separately from FIT/FOBT.

	Further, the mt-sDNA test was a priori designed for longer-interval testing with high sensitivity and somewhat lower point specificity. CISNET found annual stool DNA testing not as efficient as annual FIT/FOBT with respect to colonoscopies generated. This was hardly surprising as mt-sDNA was never intended to be used annually. Annual FIT/FOBT testing, in typical clinical practice, has been well documented as a failed strategy

 in all but the most highly organized health systems

 who are willing to invest in the high cost of patient navigation—recently reported as $153 per person screened for patient support.

 In contrast, every patient in the United States who uses mt-sDNA has the benefit of an embedded patient navigation system, which significantly lowers patient and system burden and raises compliance. A recent study of mt-sDNA screening in previously screening-noncompliant Medicare patients showed 88% intent to screen compliance and 90% compliance with diagnostic colonoscopy in mt-sDNA—positive patients.

 Another study showed that 42% of mt-sDNA users aged 50 to 74 years had never been previously screened with FIT/FOBT or endoscopy.

	Therefore, we do not consider our analysis “post hoc,” so much as revealing the underlying analysis provided by CISNET for the 6 member group of multi-year stool tests (FIT 2y and 3y, hsFOBT 2y and 3y, and mt-sDNA 3y and 5y). The 3 annual strategies were eliminated in our grouping because annual testing is not successfully executed in general clinical practice and does not reflect how the mt-sDNA test was designed. Biennial testing with FIT/FOBT is a widely used strategy that more accurately reflects real-life FIT/FOBT test use and is supported by 5 controlled trials showing a mortality benefit.

 Annual testing would be optimal for FOBT and FIT because they are only of modest sensitivity for curable stage cancer, poorly sensitive for advanced adenoma, and insensitive to SSAs. By contrast, mt-sDNA 3y, as designed, provides superior CRC-related incidence and mortality reduction and more life-years gained than either biennial or triennial FIT/FOBT, according to CISNET. Providing “optimal strategies alone” is not helpful when the limitation of the models precludes identifying those strategies alone as optimal.

	We did not suggest eliminating the annual FIT/FOBT strategy from the recommendation; rather, we highlighted the multi-year FIT/FOBT strategies, supported by RCTs, which CISNET did not in the recommendation. We demonstrated that when the 6 multi-year stool test strategies are more properly grouped together for evaluation, the CISNET data reveal the mt-sDNA 3y to be a strategy more beneficial than FIT/FOBT, as most commonly used in actual daily practice. When examined in light of complications rather than number of colonoscopies generated, mt-sDNA has as good or better benefits to harms ratios as other recommended strategies. Complications are more directly reflective of patient harm than colonoscopy volume itself. Although colonoscopy may be a burden according to the USPSTF, it is not a significant harm per se absent complications.

	Kuntz et al suggest we may have deviated from their a priori “rules.” We conservatively reported CISNETs own findings in the Table. There was no “majority rules” rule pre-specified by CISNET in their report.

 In addition to mt-sDNA 3y being the only multi-year modality to achieve 90% of the life-years gained by colonoscopy 10y in at least 1 of the models, the key finding is that in all 3 CISNET models, mt-sDNA 3y significantly out-performs FIT 2y and 3y and FOBT 2y and 3y, with respect to CRC incidence and mortality reduction and life-years gained. Although Kuntz et al might argue that annual FIT/FOBT is optimal for FIT/FOBT use, while we don’t disagree, we do argue that this is functionally irrelevant to the majority of individuals who use FIT/FOBT intermittently as their only CRC screening approach.

	We recognize that other factors enter into USPSTF recommendations, although the Task Force has not openly specified what all of those factors might be.

 Given the reluctance of the USPSTF to engage in transparent scientific and clinical discussion outside its own selected group of advisors, CISNET modeling takes on a principal role “to inform their recommendations.” The issues we raised with the CISNET analysis arose because CISNET established their rulemaking without significant input from outside groups. A more collegial process could have better informed CISNET or highlighted the significant questions raised here, and thus, may have led CISNET to a different a priori analytic structure and technical report discussion. We stand by our analyses and hope this exchange of opinions will enhance the CISNET modeling process.

	Kuntz and colleagues provided the data that illustrate the benefit of mt-sDNA 3y over current clinical practice of FIT and FOBT 2y, 3y. We reported out CISNET’s data in the context of multi-year testing, a strategy used in many countries outside the United States and not specific to mt-sDNA. We are committed to providing relevant data for clinicians and policy makers to use in making continued improvements in healthcare for their patients.

 University of Minnesota (KMK), Minneapolis, MN; Memorial Sloan Kettering Cancer Center (AGZ), New York, NY; Massachusetts General Hospital (ABK), Boston, MA; RAND Corporation (CMR), Santa Monica, CA; Erasmus Medical Center (IL-V), Rotterdam, The Netherlands.

 The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (KMK, AGZ, ABK, CMR, IL-V); acquisition of data (KMK, AGZ, ABK, CMR, IL-V); analysis and interpretation of data (KMK, AGZ, ABK, CMR, IL-V); drafting of the manuscript (KMK); critical revision of the manuscript for important intellectual content (KMK, AGZ, ABK, CMR, IL-V); administrative, technical, or logistic support (AGZ); and supervision (KMK).

 Karen M. Kuntz, ScD, Division of Health Policy and Management, University of Minnesota, School of Public Health, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: kmkuntz@umn.edu. 

 Exact Sciences Corporation (BMB, BL), Madison, WI.

 Barry M. Berger, MD is an employee of Exact Sciences Corporation, Bernard Levin, MD has previously served on the Exact Sciences Scientific Advisory Board.

 Concept and design (BB, BL); drafting of the manuscript (BB, BL); critical revision of the manuscript for important intellectual content (BB, BL).

	1. Draft recommendation statement: colorectal cancer—screening [table: recommended screening strategies for colorectal cancer]. US Preventive Services Task Force website. http://www. uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement38/colorectal-cancer-screening2#table-recommended-screening-strategies-for-colorectal-cancer. Published October 2015. Accessed March 15, 2016.

	2. Zauber A, Knudsen A, Rutter CM, et al; Writing Committee of the Cancer Intervention and Surveillance Modeling Network (CISNET) Colorectal Cancer Working Group. Technical report—evaluating the benefits and harms of colorectal cancer screening strategies: a collaborative modeling approach [AHRQ pub. No. 14-05203-EF-2]. US Preventive Services Task Force website. http://tinyurl.com/hw9b9zl. Published October 2015. Accessed March 15, 2016.

	3. Berger BM, Parton MA, Levin B. USPSTF colorectal cancer screening guidelines: An extended look at multi-year interval testing. 

	4. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. 

	5. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. 

 Barry M. Berger, MD FCAP, Chief Medical Officer, Exact Sciences Corporation, 441 Charmany Dr, Madison, WI 553719. E-mail: bberger@exactsciences.com.

1. Winawer SJ, Fischer SE, Levin B. Evidence-based reality-driven colorectal cancer screening guidelines: the critical relationship of adherence to effectiveness. 

. 2016;315(19):2065-2066. doi:10.1001/jama.2016.3377.

2. Zauber A, Knudsen A, Rutter CM, et al; Writing Committee of the Cancer Intervention and Surveillance Modeling Network (CISNET) Colorectal Cancer Working Group. Technical report—evaluating the benefits and harms of colorectal cancer screening strategies: a collaborative modeling approach [AHRQ pub. No. 14-05203-EF-2]. US Preventive Services Task Force website. http://tinyurl.com/hw9b9zl. Published October 2015. Accessed January 28, 2016.

3. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. 

. 2014;370(14):1287-1297. doi: 10.1056/NEJMoa1311194.

4. Rex D, Ahnen D, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. 

. 2012;107(9):1315-1329; quiz 1314, 1330. doi: 10.1038/ajg.2012.161.

5. Cyhaniuk A, Coombes ME. Longitudinal adherence to colorectal cancer screening guidelines. 

6. Gellad ZF, Stechuchak KM, Fisher DA, et al. Longitudinal adherence to fecal occult blood testing impacts colorectal cancer screening quality. 

. 2011;106(6):1125-1134. doi: 10.1038/ajg.2011.11.

Articles

This is a letter clarifying some points in an article published in the February 2016 issue of AJMC by Berger et al on colorectal cancer
screening guidelines.

A Restricted Look at CRC Screening: Not Considering Annual Stool Testing as an Option

The US Preventive Services Task Force (USPSTF) released draft recommendations regarding colorectal cancer (CRC) screening in October 2015. Despite evidence that annual fecal blood testing test use is uncommon in screen eligible adults, with only 10.4% reporting the use of such a test in 2012, and features poor adherence over time, the USPSTF recommended only 3 noninvasive screening strategy options, all including annual fecal occult blood testing: 1) annual fecal immunochemical test (FIT) alone; 2) annual FIT in combination with flexible sigmoidoscopy every 10 years; and 3) annual high-sensitivity fecal occult blood test (hsFOBT). Mt-sDNA is the only FDA-approved CRC screening test, is covered by Medicare every 3 years, and is included as an every-3-year (3y) option in the American Cancer Society guidelines. We demonstrate that USPSTF modeling includes an embedded sensitivity analysis of less frequent than annual test adherence, which provides support for the inclusion of mt-sDNA 3y as a recommended test. 

A descriptive analysis of USPSTF modeling of the clinical impact of various stool based CRC screening strategies.

We analyzed the data generated by the USPSTF CRC screening models describing the impact of noninvasive CRC screening strategies on CRC incidence, CRC related mortality, life years gained (LYG), colonoscopy volume and associated complication, test efficiency (a measure of benefits (LYG) and harms (colonoscopies generated), and identified strategies that provide 90% or more of the LYG by screening with colonoscopy every 10 years. We compared mt-sDNA at 3y intervals and FIT and hsFOBT at 2-year (2y) and 3y intervals and did not consider annual testing.

We found that only mt-sDNA 3y, FIT 2y, and FIT 3y were within 98% of the efficiency frontier. However, only mt-sDNA 3y generates more than 90% of the life-years gained with screening colonoscopy. These results meet the USPSTF criteria for a recommendation for mt-sDNA 3y for routine screening.

Given poor adherence to annual testing, any screening opportunity with a test, such as mt-sDNA, that has high sensitivity for CRC and for the most significant precancerous lesions would be an important screening option for patients for maximizing screening effectiveness in reducing CRC incidence and mortality.

	As of October 2015, US Preventive Services Task Force (USPSTF) draft recommendations for noninvasive colorectal cancer (CRC) screening depend on annual screening with fecal occult blood tests despite uncommon annual test use and poor adherence over time. 

		CRC is the second leading US cause of cancer death with, annually, 133,000 new cases, 50,000 deaths (2015 estimate), and more than $14 billion in related costs. 

		The multi-target stool DNA (mt-sDNA) test has significantly higher sensitivity for cancerous and precancerous lesions than fecal blood testing. This could be of great utility in irregularly screened patients and in allowing longer test intervals and lower health system screening-process burdens. 

		USPSTF could recommend mt-sDNA screening every 3 years based on USPSTF modeling, providing support for appropriate medical policy.

In its October 5, 2015, draft recommendation (draft statement) regarding colorectal cancer (CRC) screening, the US Preventive Services Task Force (USPSTF) assigned an “A” grade to CRC screening starting at age 50 and continuing until age 75.

 In addition to the option of screening colonoscopy every 10 years (10y), the USPSTF recommended 3 screening options that include annual fecal occult blood testing: 1) annual fecal immunochemical test (FIT) alone, 2) annual FIT in combination with flexible sigmoidoscopy 10y, and 3) annual high-sensitivity fecal occult blood test (hsFOBT). These recommendations were made despite evidence that annual CRC screening test use across the United States is the least frequent strategy used by screen-eligible adults aged 50 to 75 years (10.4%),

 and subject to poor year-over-year adherence in those patients that use it in routine clinical practice. Higher rates can be obtained in highly resourced screening environments focused on annual screening, although reported initial uptake remains less than 50%.

 demonstrate significantly inferior single application sensitivity (point sensitivity) to multi-target stool DNA testing (mt-sDNA).

 Mt-sDNA—specifically, the Cologuard test&mdash;can be performed at 3-year (3y) intervals.

 and access are key considerations for ensuring screening effectiveness and adherence. In view of the poor adherence to regular repeat testing, it is critical that the first opportunity we have in screening a patient should be with a test that has a high sensitivity for both CRC and significant precancerous lesions. This would maximize screening effectiveness in reducing CRC incidence and mortality.

Given the lack of adherence to annual testing and patient preference for longer intervals, a comparison of mt-sDNA 3y with biennial or triennial FIT/hsFOBT would be more clinically relevant than comparison with annual testing by the same methods. However, with minimal clinical rationale and no expressed scientific rationale, and without accounting for patient preference factors, the Cancer Intervention and Surveillance Modeling Network (CISNET), which provided the model data to inform USPSTF recommendations, grouped “stool tests” together and ruled that only a single strategy could be “recommended” from that group.

 By considering only annual strategies, the USPSTF recommended both annual FIT and hsFOBT for routine screening, but not mt-sDNA. Mt-sDNA was included in the draft statement as an “alternative test” that “may be useful in select clinical circumstances.” Mt-sDNA is currently recommended for use at 3-year intervals, not annually.

Mt-sDNA uses a single random stool sample to identify 11 biomarkers associated with CRC and precancerous lesions: 9 for altered DNA, 1 for the reference gene beta-actin, and 1 for hemoglobin. Biomarker results are algorithmically combined, provide a composite score, and generate a single “negative” or “positive” patient result. A prospective, cross-sectional, 90-site, 10,000-patient screening study demonstrated that mt-sDNA was significantly superior to FIT for detecting any class of colorectal neoplasia, including 92% versus 74% and 69% versus 46% sensitivity for CRC and high-grade dysplasia, respectively. Specificity (no lesions found during colonoscopy) was 90% for mt-sDNA versus 96% for FIT.

Poor screening adherence can have grave consequences for patients. Although preventable and treatable, CRC is the second leading cause of cancer death in the United States, with an estimated 133,000 new cases and 50,000 deaths estimated for 2015.

 indicate that screening rates plateaued in 2010, with an estimated 23 million Americans eligible for, but not participating in, CRC screening.

The aim of this analysis was to demonstrate that the modeling performed by CISNET supports a recommendation of mt-sDNA 3y for routine screening based on the USPSTF’s criteria, in light of data demonstrating that patients are unlikely to adhere to annual testing.

We reviewed the CISNET consortium modeling data in the technical report accompanying the draft statement

 and identified an embedded sensitivity analysis of nonannual adherence by considering mt-sDNA 3y, FIT every 2 years (2y), FIT 3y, hsFOBT 2y, and hsFOBT 3y all as a group, and not considering data from annual testing. CISNET used 3 well-characterized CRC disease state models—Simulation Model of Colorectal Cancer (SimCRC), Microsimulation Screening Analysis (MISCAN) for Colorectal Cancer, and Colorectal Cancer Simulated Population Model for Incidence and Natural history (CRC-SPIN)&mdash;to provide screening outcomes under various stool-screening scenarios. These scenarios involved different modalities (hsFOBT, FIT, and mt-sDNA), intervals (2y, 3y, and every 5 years), and screening age groups (50-75, 50-80, 50-85, 55-75, 55-80, and 55-85 years). All scenarios assumed 100% adherence to the screening modality and interval.

Model screening outcomes included CRC incidence reduction, CRC mortality reduction, life-years gained (LYG), total colonoscopies performed, and screening complications, including adverse events related to follow-up colonoscopy. Screening scenarios were plotted against LYG and colonoscopies performed to create an “efficiency frontier,” a line connecting the most efficient screening scenarios based on the trade-off between LYG and colonoscopies. By excluding annual stool tests, we recreated CISNET’s analysis of the “efficiency frontier” and compared these screening scenarios with each other and with 10y colonoscopy screening. Per CISNET, tests were recommended if they were within 98% of the LYG at the equivalent point on the efficiency frontier and generated at least 90% of the LYG generated by 10y screening colonoscopy.

CISNET modeling showed that mt-sDNA 3y, FIT 2y, and FIT 3y were within 98% of the efficiency frontier, whereas hsFOBT 2y and hsFOBT 3y were not (

). In comparison with FIT 2y and 3y and hsFOBT 2y and 3y, only mt-sDNA 3y generated greater than 90% of the LYG by screening colonoscopy 10y in at least 1 of the 3 models (SimCRC only) (

By considering only annual strategies, the USPSTF recommended both annual FIT and hsFOBT for routine screening, but not mt-sDNA. Mt-sDNA was included in the draft statement as an “alternative test” that “may be useful in select clinical circumstances” and is currently recommended for use at 3-year intervals, not annually. Screening test adherence is an important determinant of clinical effectiveness, but annual strategies are difficult to execute and are burdensome on patients, clinicians, and health systems. Biennial or triennial adherence more accurately reflect clinical experience with stool testing and provide a more realistic base for projecting outcomes using modeling. This critical issue was not reflected in the USPSTF’s draft statement; however, the USPSTF modeling data itself provide a basis for the evaluation and recommendation of noninvasive screening strategies performed at intervals of more than 1 year.

Combining modeling data, empirically derived data, and clinical experience allows for reasonable clinical decisions on test strategies. We found that the CISNET modeling data support the use of mt-sDNA 3y for routine CRC screening using USPSTF criteria: mt-sDNA 3y lies within 98% of the efficiency frontier and provides greater than 90% of the LYG by screening colonoscopy (SimCRC). Further, the models show that hsFOBT 2y and hsFOBT 3y are not within 98% of the efficiency frontier and do not provide greater than 90% of the LYG by screening colonoscopy. Therefore, logically, the superior performance of mt-sDNA 3y over hsFOBT 2y allows the clinical utility inferred for hsFOBT 2y (from previous randomized controlled trials that showed CRC-related mortality reduction with biennial FOBT screening)

 to be inferred as well for mt-sDNA 3y. Finally, clinical experience supports the use of high-sensitivity nonannual testing, and patient preference for high-sensitivity long-interval testing is known.

Patient-level cost concerns are mitigated by coverage. The USPSTF-recommended screening tests are free of co-pays and deductibles under the Affordable Care Act, which will help increase access to more effective screening options by eliminating patient out-of-pocket expense. Medicare already covers mt-sDNA every 3 years for traditional Medicare beneficiaries without co-payments or deductible (Medicare cost $509). At a list price of $649, which includes a nationwide 24 hour, 7 day a week patient navigation/compliance system, mt-sDNA is less expensive than colonoscopy and more expensive than FIT/FOBT; at an average cost of $600, it has a cost effectiveness ratio of $11,313 per quality-adjusted life-year compared with not screening, which is well within an acceptable range.

The first opportunity we have to screen a patient for CRC may be the last opportunity. Screening tests should have minimal opportunity for complications and high sensitivity for CRC and significant precancerous lesions to maximize screening effectiveness in reducing CRC incidence and mortality.

Three factors—CISNET modeling, relied on by the USPSTF in its draft statement; inferential clinical utility data supporting CRC mortality reduction; and clinical experience with lack of adherence to annual testing&mdash;all support a recommendation by the USPSTF for mt-sDNA 3y as a routine colorectal cancer screening test.

 Exact Sciences Laboratories, LLC (BMB, MP) and Exact Sciences Scientific Advisory Board (BL), Madison, WI.

 Exact Sciences Corporation (Madison, WI).

 Dr Berger and Mr Parton are employees and stockholders of Exact Sciences Corporation, which is the developer and manufacturer of Cologuard, the only mt-sDNA available on the market; USPSTF guideline recommendations could have an impact on the commercial success of Cologuard and on Exact Sciences’ financial performance. Dr Levin is a member of Exact Sciences Scientific Advisory Board and has received consulting fees, though not for this publication.

 Concept and design (BB, MP); acquisition of data (MP); analysis and interpretation of data (BB, MP); drafting of the manuscript (BB, BL); critical revision of the manuscript for important intellectual content (BB, MP, BL); statistical analysis (MP); provision of patients or study materials (MP); administrative, technical, or logistic support (MP); and supervision (BB).

 Barry M. Berger, MD, FCAP, Chief Medical Officer, Exact Sciences Corporation, 441 Charmany Dr, Madison, WI 553719. E-mail: bberger@exactsciences.com.

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Re-analysis of US Preventive Services Task Force colorectal cancer screening guidelines shows that every-3-year screening with multi-target sDNA could address poor performance of recommended annual testing.

Bernard Levin, MD, FACP

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