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Fecal DNA Analysis for Colorectal Cancer Screening
EXECUTIVE SUMMARY
Background
Various screening methods for colorectal cancer in persons at average risk are available, including
1
several types of fecal DNA tests. Imperiale et al (2014) published results of a fecal DNA test study in a
large screening population. Their results supported the U.S. Food and Drug Administration approval of a
specific test (Cologuard) in August 2014. This study is the only large scale study of a current fecal DNA
test.
Objectives
To evaluate fecal DNA testing as a strategy for colorectal cancer screening. It should be noted that the
specific test reviewed in this Special Report combines both fecal DNA markers and an immunochemical
1
hemoglobin assay. This Report specifically addresses the test assessed by Imperiale et al and
discusses:




the current context of colorectal cancer screening, including current published recommendations,
and other emerging screening tests;
the molecular basis for fecal DNA screening;
1
the results of the study by Imperiale et al, with an evaluation of study quality;
decision modeling techniques for evaluating different methods of colorectal cancer screening, as
they relate to translating study results into possible conclusions about the efficacy of reducing
colorectal cancer mortality.
Search Strategy
We searched MEDLINE (via PubMed) through July 2014, updated in September 2014, using the following
search terms: “fecal DNA” and screening. The search was intended to identify whether there were any
studies evaluating fecal DNA testing for colorectal cancer in a large screening population. Besides the
1
2
Imperiale et al (2014) study, the only other study found was also by Imperiale et al (2004), who
1
evaluated a fecal DNA test that is no longer on the market. Thus Imperiale et al (2014) represents the
sole study of a currently marketed or investigated test subjected to a rigorous evaluation of diagnostic
performance.
For other aspects of this Report, we drew from the 2008 U.S. Preventive Services Task Force (USPSTF)
3
guidelines for screening for colorectal cancer. In addition to guidelines, USPSTF has published
4,5
systematic reviews and commissioned a decision analysis. The decision analysis compares different
screening methods and predicts which methods might be most effective.
Main Results
1
Imperiale et al (2014) enrolled over 12,000 asymptomatic subjects at average risk of colorectal cancer,
all of whom had fecal DNA testing, fecal immunochemical testing (FIT), and screening colonoscopy.
Screening colonoscopy results provided the reference standard for evaluation of fecal DNA testing and
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Special Reports should not be construed to suggest that Blue Cross Blue Shield Association or the TEC Program recommends, advocates, requires,
encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment
or nonpayment of the technology or technologies evaluated.
Blue Cross Blue Shield Association is an association of independent Blue Cross and Blue Shield companies.
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TEC SPECIAL REPORT
Fecal DNA Analysis for Colorectal Cancer Screening
FIT. The study was of good quality. In 9989 evaluable subjects, fecal DNA test sensitivity for cancer was
92.3% and 73.8% for FIT. For advanced precancerous lesion, fecal DNA test sensitivity was 42.4% and
23.8% for FIT. Specificity of fecal DNA testing was lower than that for FIT. When used to identify patients
with negative colonoscopy, specificity of the fecal DNA test was 89.8% and 96.4% for FIT.
Although fecal DNA testing had higher sensitivity than FIT for various types of colorectal lesions, these
results represent the diagnostic characteristics of the fecal DNA test in a one-time cross-sectional study.
To understand how these study results may translate to reduced colorectal mortality in a screening
program, we considered modeling studies of colorectal cancer screening and how effective fecal DNA
testing might be in these models. A modeling study produced for USPSTF estimated that 4 screening
5
methods were most effective cancer screening strategies with reasonable resource use. Annual FIT was
among the recommended strategies. Because the diagnostic characteristics of the fecal DNA test show
better sensitivity but worse specificity than FIT, it is likely that annual fecal DNA testing would
demonstrate equal or better efficacy for reducing colorectal cancer mortality than FIT, but with greater
resource use due to the higher false-positive rate. Calculating the effectiveness and resource use of less
frequent fecal DNA testing would require formal modeling using its diagnostic characteristics. It is likely
that a less frequent than annual screening interval could be estimated that reduces colorectal mortality in
the range of other recommended strategies.
Author Conclusions and Comment
The recent study evaluating a fecal DNA test showed higher sensitivity but lower specificity than FIT. The
diagnostic characteristics of the test are consistent with reduced colorectal cancer mortality if used in a
longitudinal screening program. However, it remains to be determined how effective the test would be
when used at a particular frequency within a screening program, and thus its efficacy and impact on
resource use compared with established methods are unknown.
References
1.
Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N
Engl J Med. Apr 3 2014;370(14):1287-1297. PMID 24645800
2.
Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Fecal DNA versus fecal occult blood for colorectal-cancer
screening in an average-risk population. N Engl J Med. Dec 23 2004;351(26):2704-2714. PMID 15616205
3.
Force USPST. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation
statement. Ann Intern Med. Nov 4 2008;149(9):627-637. PMID 18838716
4.
Whitlock EP, Lin JS, Liles E, et al. Screening for colorectal cancer: a targeted, updated systematic review for the
U.S. Preventive Services Task Force. Ann Intern Med. Nov 4 2008;149(9):638-658. PMID 18838718
5.
Zauber AG, Lansdorp-Vogelaar I, Knudsen AB, et al. Evaluating test strategies for colorectal cancer screening: a
decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med. Nov 4 2008;149(9):659-669.
PMID 18838717
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TEC SPECIAL REPORT
Fecal DNA Analysis for Colorectal Cancer Screening
AUTHORS, STAFF, AND MEDICAL ADVISORY PANEL
TEC Staff Contributors
Lead Author: David H. Mark, M.D., M.P.H.
Executive Director, Center for Clinical Effectiveness: Suzanne E. Belinson, Ph.D., M.P.H.
Executive Director, Clinical Evaluation, Innovation, and Policy: Naomi Aronson, Ph.D.
Director, Technology Assessment: Mark D. Grant, M.D., Ph.D.
Research/Editorial Staff: Claudia Bonnell, R.N., M.L.S., Kimberly Hines, M.S., Michael Vasko, M.A.
Blue Cross Blue Shield Association Medical Advisory Panel
Chair
Trent T. Haywood, M.D., J.D., Senior Vice President, Clinical Affairs/Medical Director, Blue Cross Blue Shield Association
Vice Chair
Suzanne E. Belinson, Ph.D., M.P.H., Executive Director, Center for Clinical Effectiveness, Blue Cross Blue Shield Association
Scientific Advisors
Steven N. Goodman, M.D., M.H.S., Ph.D., Dean for Clinical and Translational Research, Stanford University School of Medicine, and
Professor, Departments of Medicine, Health Research and Policy
Mark A. Hlatky, M.D., Professor of Health Research and Policy and of Medicine (Cardiovascular Medicine), Stanford University School of
Medicine; American College of Cardiology Appointee
Panel Members
Peter C. Albertsen, M.D., Professor, Chief of Urology, and Residency Program Director, University of Connecticut Health Center
Ann Boynton, Deputy Executive Officer, Benefits Programs Policy and Planning, CalPERS
Virginia Calega, M.D., M.B.A., F.A.C.P., Vice President, Medical Management and Policy, Highmark Inc.
Sarah T. Corley, M.D., F.A.C.P., Chief Medical Officer, NextGen Healthcare Information Systems Inc.; American College of Physicians
Appointee
Helen Darling, M.A., Strategic Advisor, National Business Group on Health
Josef E. Fischer, M.D., F.A.C.S., William V. McDermott Professor of Surgery, Harvard Medical School; American College of Surgeons
Appointee
Lee A. Fleisher, M.D., Professor and Chair, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of
Medicine, Senior Fellow, Leonard Davis Institute of Health Economics
I. Craig Henderson, M.D., Adjunct Professor of Medicine, University of California, San Francisco
Jo Carol Hiatt, M.D., M.B.A., F.A.C.S., Chair, Inter-Regional New Technology Committee, Kaiser Permanente
Saira A. Jan, M.S., Pharm.D., Associate Clinical Professor, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,
Residency Director and Director of Clinical Programs Pharmacy Management, Horizon Blue Cross and Blue Shield of New Jersey
Lawrence Hong Lee, M.D., M.B.A., F.A.C.P., Vice President and Executive Medical Director for Quality and Provider relations, Blue Cross
and Blue Shield of Minnesota
Bernard Lo, M.D., President, The Greenwall Foundation
Randall E. Marcus, M.D., Charles H. Herndon Professor and Chairman, Department of Orthopaedics, Case Western Reserve University
School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio
Barbara J. McNeil, M.D., Ph.D., Ridley Watts Professor and Head, Department of Health Care Policy, Harvard Medical School; Professor of
Radiology, Brigham and Women's Hospital
William R. Phillips, M.D., M.P.H., T.J. Phillips Endowed Professor in Family Medicine, University of Washington; American Academy of
Family Physicians Appointee
Rita F. Redberg, M.D., M.Sc., F.A.C.C., Professor of Medicine and Director, Women's Cardiovascular Services, University of California San
Francisco
Maren T. Scheuner, M.D., M.P.H., F.A.C.M.G., Chief, Medical Genetics, VA Greater Los Angeles Healthcare System; Professor,
Department of Medicine, David Geffen School of Medicine at UCLA, Affiliate Natural Scientist, RAND Corporation; American College of
Medical Genetics and Genomics Appointee
Leslie Robert Schlaegel, M.S., Associate Vice President of Human Resources, Stanford University
J. Sanford Schwartz, M.D., F.A.C.P., Leon Hess Professor of Medicine and Health Management & Economics, School of Medicine and The
Wharton School, University of Pennsylvania
John B. Watkins, Pharm.D., M.P.H., B.C.P.S., Pharmacy Manager, Formulary Development, Premera Blue Cross
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Fecal DNA Analysis for Colorectal Cancer Screening
Fecal DNA Analysis for Colorectal Cancer Screening
ASSESSMENT OBJECTIVE
Various screening methods for colorectal cancer in persons at average risk are available, including
several fecal DNA tests. However, in the 2008 version of the U.S. Preventive Services Task Force
(USPSTF) guidelines on colorectal cancer, evidence was considered insufficient to assess the benefits
1
and harms of fecal DNA testing. At that time, only 1 fecal DNA test had been evaluated in a large
screening population. Although some aspects of the evaluation were promising, the manufacturer
removed the test from the market after the U.S. Food and Drug Administration (FDA) informed them that
the test would need approval. Until now, no fecal DNA test has been evaluated in a large screening
population.
2
Imperiale et al (2014) published a study of a fecal DNA test (Cologuard; Exact Sciences Corp.) in a large
screening population; results supported FDA approval of the test in August 2014. Our review of the
current literature on fecal DNA tests revealed no other studies evaluating tests in large screening
populations. Such studies in screening populations are necessary to establish test performance in the
appropriate population of interest, and must be large enough to accumulate enough cancer cases to
calculate sufficiently precise estimates of diagnostic performance.
The objective of this Special Report is to evaluate the specific fecal DNA test reviewed by FDA in August
2014. Although we use the term fecal DNA test, the actual test combines both fecal DNA markers and an
immunochemical hemoglobin assay to arrive at a test result. This Report specifically addresses the test
2
assessed by Imperiale et al and discusses:




the current context of colorectal cancer screening, including current published recommendations,
and other emerging screening tests;
the molecular basis for fecal DNA screening;
2
the results of Imperiale et al, with an evaluation of the quality of the study;
decision modeling techniques for evaluating colorectal cancer screening, as they relate to
translating study results into possible conclusions about the efficacy of reducing colorectal cancer
mortality.
This Special Report does not address adherence to different methods of colorectal cancer screening.
Although high uptake of screening in a population is critical to reducing colorectal cancer mortality, there
is no definitive research demonstrating that certain screening methods are associated with higher
adherence to screening programs than others. Although noninvasive methods of screening such as the
fecal occult blood test (FOBT) and fecal DNA test may be easier to administer, less time consuming, and
more widely available without delay or additional medical visits, they require repeat screening tests at
regularly prescribed intervals to be as effective as invasive methods.
BACKGROUND
Disease
Colorectal cancer is the third most common type of cancer in terms of incidence and mortality in both men
and women in the United States. The American Cancer Society estimated in 2011 that about 141,200
3
persons were diagnosed with colorectal cancer and that about 49,400 died of the disease.
Various patient demographic, ethnic, and other characteristics are associated with increased risk of
colorectal cancer. The incidence of colorectal cancer increases with age. Overall, 90% of new cases and
CT
FDA
FIT
computed tomography
Food and Drug Administration
fecal immunochemical testing
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Abbreviations and Acronyms
FOBT
RCT
USPSTF
fecal occult blood test
randomized controlled trial
U.S. Preventive Services Task Force
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94% of deaths occur in individuals 50 years of age and older. Colorectal cancer incidence is
approximately 35% to 40% higher in men than in women. Among different ethnic groups, incidence and
mortality rates are highest in African American men and women; incidence rates are 20% higher and
mortality rates are about 45% higher than among whites. Incidence and mortality rates among major
racial/ethnic groups other than African American are lower than those among whites. Other risk factors for
colorectal cancer include family history, physical inactivity, obesity, dietary factors, and smoking.
Colorectal cancer usually develops slowly over several years. The cancer typically begins as a
noncancerous polyp (most polyps never become cancerous). Certain kinds of polyps, called
adenomatous polyps or adenomas, are the most likely to become cancerous. Adenomas are common; an
estimated one-third to one-half of all individuals will eventually develop 1 or more adenomas.
Cancer screening tests can reduce colorectal cancer mortality and morbidity by leading to detection of
either cancer or adenomas. Direct detection of the cancer at an earlier stage can result in improved cure
rates. Detection and removal of adenomas prevent the occurrence of cancer. Although early detection of
cancer should result in better outcomes, due to potential biases in evaluation of health outcomes (eg,
lead time bias, length bias), proof that a particular method of cancer screening is effective has often
required randomized controlled trials (RCTs). Among the current common methods of colorectal cancer
screening, FOBT and flexible sigmoidoscopy have demonstrated reductions in colorectal cancer mortality
in large RCTs.
Studies have also shown that colorectal cancer screening is not optimally utilized in the United States,
with both under- and overutilization of all cancer screening methods, including more frequent colonoscopy
4,5
screening than is recommended.
Current Recommendations for Colorectal Cancer Screening
USPSTF currently gives a grade A recommendation to 3 methods for colorectal cancer screening for
1
adults age 50 to 75 years of age. USPSTF recommends (1) annual screening with high-sensitivity FOBT,
(2) sigmoidoscopy every 5 years, with high-sensitivity FOBT every 3 years, or (3) colonoscopy every 10
years. High-sensitivity FOBT is not specifically defined but appears to include fecal immunochemical
testing (FIT) and Hemoccult SENSA, but not Hemoccult II. For adults ages 76 to 85 years, USPSTF gives
a grade C recommendation: do not screen routinely. For adults older than 85 years, USPSFT gives a
grade D recommendation: do not screen. According to USPSTF analysis, the likelihood that screening will
yield a mortality benefit declines after age 75 because of the long average time between adenoma
development and cancer diagnosis.
At the time these recommendations were issued, USPSTF also conducted a systematic review of other
colorectal cancer screening tests such as computed tomographic (CT) colonography and fecal DNA
6
testing. USPSTF concluded that the evidence was insufficient to assess the benefits and harms of fecal
DNA testing and CT colonography. The only fecal DNA test reviewed was the PreGen Plus, version 1,
7
test (the study reviewed in this Special Report by Imperiale et al [2004] ). Although the fecal DNA test had
higher sensitivity for detecting colorectal cancer than the specific FOBT (Hemoccult II) with whose
performance it was compared, both had low sensitivity (51% and 12.9%, respectively). Regarding CT
colonography, USPSTF concluded that it was as sensitive as colonoscopy for detecting large adenomas
and colorectal cancer, but had variable diagnostic characteristics for smaller polyps. Additional areas of
uncertainty included potential harms from radiation exposure, and detection of extracolonic findings.
Extracolonic findings (eg, chest nodules, kidney nodules) detected by CT colonography are common,
occurring in 27% to 69% of screened persons.
Rationale and Background of Fecal DNA Testing
The rationale for fecal DNA testing is based on the presence of different types of genetic alterations
present in colon cancer cells. Cancer-associated gene mutations and epigenetic markers can be detected
in exfoliated intestinal cells found in stool specimens. Because malignant cells are continuously
exfoliated, fecal DNA testing offers the potential for greater sensitivity for detecting cancer than FOBT,
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which relies on detecting intermittently released occult blood. Colorectal neoplasms are heterogeneous in
the mutations they express; no single mutation is expressed by all colorectal cancers. Thus fecal DNA
tests have largely evaluated multiple types of cancer markers.
2
Prior to the current study by Imperiale et al (2014), only 1 large-scale evaluation of a fecal DNA test in a
7
screening population was published. Imperiale et al (2004) reported the results of an evaluation of the
PreGen-Plus, version 1, test in which this test and FOBT were both administered to patients undergoing
screening colonoscopy. Of 5486 subjects enrolled, 4404 completed all aspects of the study. A subgroup
of 2507 subjects was analyzed, including all those with a diagnosis of cancer or advanced adenoma plus
a random sample of subjects with no polyps or minor polyps.
There were 31 colorectal cancer cases in the study population. The PreGen-Plus test had a sensitivity of
51.6% versus 12.9% for FOBT. For all advanced adenomas, the PreGen-Plus test had a sensitivity of
15.1% versus 10.7% for FOBT. The specificity for detecting absence of any polyps on colonoscopy was
94.4% for PreGen-Plus and 95.2% for FOBT.
Although the PreGen-Plus test had a much greater sensitivity than FOBT in this study, several problems
were noted. In particular, the trialists noted that the sensitivity of FOBT for colorectal cancer found in the
7
study was unusually low compared with other studies.
At that time, the PreGen-Plus test was marketed without the need for FDA approval because the test was
performed only in a central laboratory regulated under the Clinical Laboratory Improvement Amendment
of 1988. However, in 2007, FDA decided the test was subject to FDA regulation as a medical device; the
8
test was thereon withdrawn from the market.
Development of Current Fecal DNA Test
The Cologuard fecal DNA test was developed by Exact Sciences Corp., the same company that
developed the PreGen-Plus test. Cologuard consists of molecular assays for aberrantly methylated BMP3
and NDRG4 promoter regions, mutant KRAS, -actin (as a reference gene for human DNA quantity), and
an immunochemical assay for hemoglobin. The incorporation of what in essence is an FIT into the test
means that its sensitivity is likely to be no worse than FIT, and its specificity can be no better than FIT.
Any additional cancers or other lesions detected by the other molecular assays will improve sensitivity
relative to FIT, but any additional false positives will lower specificity relative to FIT.
9
10
Early development and evaluation of the test was published by Ahlquist et al and Lidgard et al. In
9
Ahlquist et al, a logistic regression model was developed from the values of the molecular assays from
previously defined samples of patients with colorectal cancer, patients with large adenomas, and patients
with normal colonoscopy results. This approach is typical of studies done early in the development of a
test, and it is subject to numerous potential biases. The fitting and testing of the model in the same
patients in whom it was developed tend to produce overly optimistic estimates of diagnostic performance.
The predefined samples of cancer subjects and healthy subjects potentially cause spectrum bias, in that
either sample may not be representative of typical cancer and cancer-free subjects in a screening
population. In this study, the fecal DNA test had a sensitivity of 85% for detecting colorectal cancer, using
a test cutoff value that fixed specificity at 90%.
10
9
The study by Lidgard et al used an approach similar to that of Ahlquist et al, but automated processing
of stool samples. The study also enrolled predefined samples of subjects with colorectal cancer, subjects
with adenomas, and control patients. Data from the enrolled patients were used to generate a logistic
regression model, which was then used to determine test results in the same patients. The researchers
assigned a cutoff value to the test, which resulted in a specificity of 90%. The test had a sensitivity of 98%
for detecting colorectal cancer at its fixed specificity of 90%. For detection of noncancerous advanced
lesions, sensitivity increased from 57% to 83% as adenoma size increased from 1 cm or greater to
greater than 3 cm.
These studies of the fecal DNA test showed high sensitivity (85%-98%) for detecting colorectal cancer at
cut points corresponding to 90% specificity, but should not be viewed as accurate estimates of test
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performance in the screening setting. The study sample selection process potentially causes a spectrum
bias. The logistic regression model used was generated from the study sample itself, and is not a true
validation of test performance. The cutoff point used for test positivity was not predetermined before the
study, but set at a value to achieve a certain desired specificity.
FDA Status
In August 2014, Cologuard (Exact Sciences) was approved by FDA through the premarket approval
process for use in colorectal screening. Cologuard is intended for the qualitative detection of colorectal
neoplasia‒associated DNA markers and for the presence of occult hemoglobin in human stool. A positive
result may indicate the presence of colorectal cancer or advanced adenoma and should be followed by
diagnostic colonoscopy. Cologuard is indicated to screen adults of either sex, 50 years or older, who are
at average risk for colorectal cancer. Cologuard is not a replacement for diagnostic colonoscopy or
surveillance colonoscopy in high-risk individuals.
METHODS
Search Strategy
We searched MEDLINE (via PubMed) using the following search terms: “fecal DNA” and screening. The
search was performed through July 2014, and updated September 2014, limited to English-language
articles on human subjects. The search was intended to identify if there were any studies that evaluated
fecal DNA testing for colorectal cancer in a large screening population. We found 1 study by Imperiale et
2
7
al (2014) that met these criteria. The only other study was also by Imperiale et al (2004), who evaluated
a fecal DNA test that was withdrawn from marketing and is no longer available.
Study Selection
2
The study by Imperiale et al (2014) represents the sole study of a currently marketed or investigated test
(Cologuard; Exact Sciences Corp.) subjected to a rigorous study of diagnostic performance.
For other aspects of this Special Report, we drew from the 2008 USPSTF guidelines for screening for
1
colorectal cancer. In addition to guidelines, USPSTF has published systematic reviews and
6,11
commissioned a decision analysis.
The decision analysis allows for comparison of different screening
methods and predicts which screening methods might be most effective.
Medical Advisory Panel Review
This Special Report was reviewed by the Blue Cross and Blue Shield Association Medical Advisory Panel
(MAP) on September 18, 2014. To maintain the timeliness of the scientific information in this Special
Report, literature search updates were performed subsequent to the Panel's review (see Search Strategy
section above). If the search updates identified any additional studies that met the criteria for detailed
review, the results of these studies were included in the tables and text where appropriate. There were no
studies that would change the conclusions of this Special Report.
REVIEW OF EVIDENCE
Overview of Available Evidence
Review of Pivotal Fecal DNA Study
2
The study by Imperiale et al (2014) compared the fecal DNA test previously developed and evaluated in
9
10
the studies by Ahlquist et al and Lidgard et al with FIT in persons at average risk for colorectal cancer.
All enrolled subjects were scheduled to undergo screening colonoscopy. Stool specimens were collected
and tested no more than 90 days prior to the screening colonoscopy. Screening colonoscopy findings
were considered the reference standard for determining the diagnostic characteristics of the fecal DNA
test and FIT for detecting colorectal cancer and cancer precursors.
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Quality of the Study
2
The study by Imperiale et al (2014) is of good quality for an evaluation of a diagnostic test. The reference
standard was predetermined without knowledge of the prior tests. The fecal DNA test score was
generated from a prespecified logistic regression algorithm with a prespecified cutoff value. The FIT is a
standard, commercially available test and uses a standard cutoff score.
The study population enrolled had no colorectal cancer risk factors other than age. The enrolled subjects
were a screening population, weighted toward persons older than age 65 to increase the prevalence of
cancer. This entry criterion should not cause severe spectrum bias. Of 12,776 who originally consented to
participate, 11,016 underwent both colonoscopy and submitted a stool sample. Six hundred eighty-nine
participants’ stool samples were excluded; the majority (n=474) were due to leakage during shipping and
technical failures (n=213). Another 304 colonoscopic examinations were excluded for various reasons. Of
the remaining 11,016 subjects, 9989 (91%) were included. Although the number of subjects excluded is a
relatively small proportion of the total number of subjects, these exclusions could potentially bias
evaluation of the diagnostic accuracy of the test. In clinical practice, the excluded stool samples would
need to be repeated, or assumed to be positive or negative. If imputed to be positive, the sensitivity of the
test would improve and the specificity would worsen. Conversely, if imputed to be negative, the sensitivity
would worsen and the specificity would improve. The FDA Summary of Safety and Effectiveness Data
document states that an analysis was conducted to rule out bias caused by excluded subjects, but does
not disclose the results of that analysis.
Study Results
Principal results of the study are shown in Table 1. The prevalence of colorectal cancer was 0.7%
(65/9989). The prevalence of advanced precancerous lesions was 7.6% (757/9989). The sensitivity for
detection of colorectal cancer was higher for the fecal DNA test than for FIT (92.3% vs 73.8%). The
sensitivity for detection of advanced cancerous lesions was higher for the fecal DNA test than for FIT
(42.4% vs 23.8%).
In analyses of specific types of lesions, sensitivity of the fecal DNA test did not vary by cancer stage or
cancer location. Among patients with advanced precancerous lesions, the sensitivity of Cologuard was
higher for distal lesions than for proximal lesions. Fecal DNA test sensitivity increased as lesion size
increased.
The specificity of the fecal DNA test was lower than that of FIT. For identification of patients with
insignificant lesions and negative colonoscopy, specificity of the fecal DNA test was 86.6% versus 94.9%
for FIT. For identification of patients with negative colonoscopy, specificity of the fecal DNA test was
89.8% versus 96.4% for FIT.
As measured by the area under the receiver operating characteristic curve, for discrimination of colorectal
cancer versus all other findings, the fecal DNA test had a significantly higher area under the curve than
FIT (0.94 vs 0.89, p=0.04). For discrimination between colorectal cancer plus advanced cancerous
lesions versus all other findings, the fecal DNA test had a significantly higher area under the curve than
FIT (0.73 vs 0.67, p<0.001). The significantly higher area under the curve for fecal DNA indicates that its
higher sensitivity is not simply a trade-off between sensitivity and specificity, which would occur by
altering the cutoff point for a positive test, but is due to improved discrimination compared with FIT.
The inference of improved sensitivity of the fecal DNA test compared with FIT is strengthened by the
diagnostic characteristics of FIT reported in this study. The sensitivity and specificity of FIT are consistent
with values that have been reported in other studies, and matched closely to values used in the USPSTF
11
decision analysis described below.
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Table 1: Diagnostic Test Characteristics of Fecal DNA Test and FIT
Type of Lesion
N
Colorectal cancer
Colorectal cancer (n=65) + high-grade dysplasia (n=39)
Advanced precancerous lesions (includes high-grade
dysplasia)
Nonadvanced adenoma
Nonadvanced adenoma, non-neoplastic findings, and
negative colonoscopy
Negative results on colonoscopy
CI: confidence interval; FIT: fecal immunochemical test.
2
Fecal DNA Test
Sensitivity (95% CI), %
92.3 (83.0 to 97.5)
83.7 (75.1 to 90.2)
42.4 (38.9 to 46.0)
FIT Sensitivity
(95% CI), %
73.8 (61.5 to 84.0)
63.5 (53.5 to 72.7)
23.8 (20.8 to 27.0)
9167
17.2 (15.9 to 18.6)
Fecal DNA Test
Specificity (95% CI), %
86.6 (85.9 to 87.2)
7.6 (6.7 to 8.6)
FIT Specificity
(95% CI), %
94.9 (94.4 to 95.3)
4457
89.8 (88.9 to 90.7)
96.4 (95.8 to 96.9)
65
104
757
2893
Although the fecal DNA test has higher sensitivity than FIT, its specificity is lower, and this results in more
false-positive tests. The number of positive tests is not directly presented in the study, but can be
calculated from other available data. The number of positive fecal DNA tests was 1612, which is 16% of
the study sample. The number of positive FITs was 700, which is 7% of the study sample. This represents
more than twice the number of colonoscopies that would be recommended to patients undergoing fecal
DNA screening versus FIT. This large increase in the number of positive tests results in lower positive
predictive values, despite the improved discrimination of the test. The positive predictive value of the fecal
DNA test for cancerous and advanced precancerous lesions was 24% (381/1612), whereas the positive
predictive value of FIT for the same lesions was 33% (228/700).
Modeling to Determine the Comparative Efficacy of Colorectal Cancer Screening Methods
The study by Imperiale et al compares the fecal DNA test with FIT in a head-to-head comparison in a
2
single screening. However, the 2 tests are not intended to be used in the same manner. The fecal DNA
test is intended to be used less frequently than FIT. Thus the results of this study do not directly translate
into a conclusion that fecal DNA testing is a more effective screening test than FIT. Ideally, different
colorectal cancer screening methods should be compared over a long period of time using the intended
frequency of screening for each method. Absent direct comparative evidence, mathematical modeling
techniques have been developed to estimate the effects of screening strategies.
The mathematical models integrate the best current evidence on the diagnostic characteristics of the
screening tests, numeric estimates of the biologic progression of cancer precursors to cancer, along with
other pertinent population characteristics. The value of such models for evaluating a screen such as fecal
DNA testing is that, with only knowledge of the diagnostic test characteristics, an estimate of the test’s
effectiveness in preventing colorectal cancer mortality can be generated and compared with other
methods that may differ in diagnostic characteristics and intended frequency of screening.
Although it would it be most useful to incorporate the diagnostic characteristics of the fecal DNA test
formally into a modeling exercise, we can still gain some understanding about what fecal DNA testing
11
would show in such a model by examining the modeling analysis done by Zauber et al on behalf of
USPSTF. The Zauber et al study modeled the efficacy of various colorectal cancer screening methods.
11
Table 2 shows selected diagnostic characteristics used by Zauber et al. FIT was assumed to have 70%
sensitivity to detect cancer, but very low sensitivities (5%-22%) for various sizes of adenomas.
Colonoscopy was assumed to have 95% sensitivity for cancer, and lower but still high sensitivity for
various sizes of adenomas (75%-95%). The diagnostic sensitivity for sigmoidoscopy (not shown) was
assumed to be identical to colonoscopy for all lesion sizes within reach of the sigmoidoscope, and
specificity was assumed to be only slightly higher at 92%.
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TEC SPECIAL REPORT
Fecal DNA Analysis for Colorectal Cancer Screening
Table 2: Diagnostic Characteristic Parameters of Selected Screening Tests in U.S. Preventive
Services Task Force Decision Analysis
Test (Lesion Detected)
Fecal immunochemical testing
Fecal immunochemical testing (adenoma ≤5 mm)
Fecal immunochemical testing (adenoma 6-9 mm)
Fecal immunochemical testing (adenoma ≥10 mm)
Fecal immunochemical testing (cancer)
Fecal immunochemical testing
Colonoscopy
Colonoscopy (adenoma ≤5 mm)
Colonoscopy (adenoma 6-9 mm)
Colonoscopy (adenoma ≥10 mm)
Colonoscopy (cancer)
Colonoscopy
Sensitivity, %
Specificity for Any Lesion, %
5.0
10.1
22.0
70.0
95
75.0
85.0
95.0
95.0
90
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The screening strategies evaluated in Zauber et al were examined in an iterative fashion, exploring
different age ranges to commence and terminate screening and varying screening intervals of various
tests. Despite the differences in diagnostic characteristics between screening tests, when performed at
the specified screening intervals, 4 strategies produced optimal and similar reductions in colorectal
cancer mortality when used in persons ages 50 to 75 years. Although no formal cost-effectiveness
threshold was used to determine optimal screening methods, the recommended strategies appear to
have been chosen based on efficacy in reducing colorectal cancer mortality, with some consideration of
reasonable resource use. The 3 strategies given grade A recommendation by USPSTF (plus the fourth,
which is another type of high-sensitivity FOBT called Hemoccult SENSA) were all estimated to produce a
mortality reduction between 64.6% and 66.0% according to the MISCAN modeling analysis. According to
a different modelling strategy (Simulation Model of Colorectal Cancer), screening with these 4 strategies
was estimated to produce similar magnitudes of mortality reduction, but all at higher values, between
79.3% and 84.4%. In both models, screening with flexible sigmoidoscopy alone every 5 years and annual
screening with a lower sensitivity FOBT (Hemoccult II) produced large reductions in colorectal cancer
mortality compared with no screening, but below those of the 4 preferred strategies (see Table 3).
Table 3: Selected Model Outcomes for U.S. Preventive Services Task Force Recommended
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Strategies for Colorectal Cancer Screening (MISCAN Model Analysis)
Screening Strategy From Age 50-75 Years
Colonoscopy every 10 y
FOBT (Hemoccult SENSA) every year
Fecal immunochemical test every year
Flexible sigmoidoscopy every 5 y, FOBT (SENSA) every 3 y
FOBT: fecal occult blood test.
Mortality
Reduction,
%
64.6
66.0
64.6
65.7
Colonoscopies
per 1000 Over
Period
4136
3350
2949
2870
Noncolonoscopy
Tests per 1000
Over Period
0
9541
11,773
5822
11
A cost-effectiveness analysis was not presented by Zauber et al, but a measure of the burden of
screening associated with each strategy was estimated in terms of the number of colonoscopies required
per 1000 persons between the ages of 50 and 75 years. Because the outcomes of the recommended
strategies are all roughly similar, a cost-effectiveness analysis is not actually necessary; rather, a simple
summing up of total screening and evaluation costs would approximate a cost comparison between
strategies. The least expensive strategy will be the most cost-effective strategy. The number of
colonoscopies is an important driver of cost. The degree to which noncolonoscopy tests drive cost
depends on the cost of those tests.
Colonoscopies are required after positive FOBT and flexible sigmoidoscopy findings. If adenomas are
found, colonoscopies are then performed at 3- to 5-year intervals. If the test is false positive and
colonoscopy results are normal, then no further screening is needed for 10 years. As expected, the
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highest number of colonoscopies needed over the 25-year period was for the 10-year colonoscopy
screening strategy, at 4136 procedures per 1000 persons. However, for all the other strategies, the
number of colonoscopies needed over time is considerable; the fewest among the recommended
strategies was 2870 per 1000 persons for sigmoidoscopy and FOBT. The probability of a positive test
(true or false positive) increases as the number of FOBTs or FITs are performed; the authors estimated
that with a Hemoccult SENSA specificity of 92.5%, the probability of a positive test (and, therefore, the
need for colonoscopy and the subsequent switch to a colonoscopy screening program thereafter) is about
79% after 20 annual FOBT tests. In addition to the high probability of eventually needing a colonoscopy
with the noncolonoscopy screening strategies, the number of screening tests required is large.
The potential for the fecal DNA test to reduce colorectal mortality emerges from these model results when
2
examining the diagnostic characteristics of the test. The recent study by Imperiale et al showed that the
sensitivity for colorectal cancer was 92.3% and the specificity was 86.6% for negative colonoscopy and
noncancerous precursors, and 89.8% for negative colonoscopy. The efficacy of the fecal DNA test in
reducing colorectal mortality depends on these diagnostic characteristics and the recommended
screening interval, which currently is unknown. However, if the test is more sensitive than FIT and it is
hypothetically performed every year, it must be at least as effective as FIT every year in reducing
mortality. However, the poorer specificity of fecal DNA testing than FIT would also increase the probability
of a false-positive finding, with more than twice as many persons being referred for colonoscopy at each
screen. Over time, assuming false positives are statistically independent events, the probability of
needing a colonoscopy (and not needing fecal DNA tests any more) would approach 100% after relatively
few rounds of screening). A strategy of annual fecal DNA screening, given the diagnostic characteristics
of the test, although effective, might be inefficient in terms of the number of patients who end up needing
colonoscopy, in addition to the cost and burden of the fecal DNA test.
Determining the efficacy and downstream effects of less than annual screening with fecal DNA testing will
require formal modeling analysis of its diagnostic characteristics using specific screening intervals. A
screening interval likely will be found that the model estimates can produce a similar mortality reduction to
the USPSTF recommended strategies. However, it is uncertain what the additional downstream effects, in
terms of colonoscopies, additional tests, and costs, will be at this screening interval. An additional
uncertainty regarding the effectiveness of fecal DNA testing is patient adherence to (1) the recommended
screening interval and (2) follow-up to positive tests.
DISCUSSION
The results of a recent large-scale study of a fecal DNA test (Cologuard) in a screening population have
shown that the test has higher sensitivity and lower specificity than FIT, an established screening method.
Study quality was good, though the exclusion of some indeterminate fecal DNA test results from the
analysis may have biased results slightly. In addition, this study of the diagnostic characteristics of a test
for detecting cancer and cancer precursors does not establish efficacy for prevention of colorectal cancer.
Effective screening for colorectal cancer requires a program with established screening intervals and
appropriate follow-up for positive tests.
Given what is known about the relative efficacy of different screening strategies from the results of
modeling studies, the fecal DNA test would produce equivalent or better outcomes than FIT if both were
used annually. However, the fecal DNA test has a considerably higher false-positive rate and would
therefore consume greater health care resources than FIT at this screening frequency. Formal modeling
studies of the fecal DNA test are needed to estimate the efficacy of the test in preventing colorectal
cancer and to help determine the optimal strategy for its use.
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