| Coverage Policy Manual | |
| Policy #: | 2003018 |
| Category: | Laboratory |
| Initiated: | June 2003 |
| Last Review: | June 2025 |
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| Genetic Test: Fecal and Serologic Genetic Testing to Detect Colorectal Cancer, Screening | |
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| Description: |
Detection of DNA or RNA abnormalities associated with colorectal cancer (CRC) in stool samples has been proposed as a screening test for CRC. This technology is another potential alternative to currently available screening approaches such as fecal occult blood testing, fecal immunochemical testing (FIT), and colonoscopy. The currently available stool tests combine FIT and DNA or RNA analysis and are referred to as FIT-DNA or FIT-RNA in this review, though other publications use terms such as stool DNA (sDNA)-FIT, multitarget stool DNA (mt-sDNA) or multitarget stool RNA (mt-sRNA) test.
Screening blood tests for genetic alterations associated with CRC have also been developed and may have the potential to encourage screening and decrease mortality if associated with increased screening compliance.
Colorectal Cancer
Several cellular genetic alterations have been associated with colorectal cancer (CRC). In the proposed multistep model of carcinogenesis, the tumor suppressor gene p53 and the proto-oncogene KRAS are most frequently altered. Variants in APC (adenomatous polyposis coli) genes and epigenetic markers (e.g., hypermethylation of specific genes) have also been detected. Colorectal cancer is also associated with DNA replication errors in microsatellite sequences (termed microsatellite instability or MSI) in patients with Lynch Syndrome (formerly known as hereditary nonpolyposis colorectal cancer) and in subgroups of patients with sporadic colon carcinoma.
Tumor- associated gene variants and epigenetic markers can be detected in exfoliated intestinal cells in stool specimens. Because cancer cells are shed into stool, tests have been developed to detect these genetic alterations in the DNA from shed colorectal cancer cells isolated from stool samples.
Blood serum testing for colorectal cancer screening is currently available, including, but not limited to
testing to detect methylated Septin9 DNA (e.g., ColoVantage and Epi proColon 2.0); multi-modal
approaches to detect circulating tumor DNA (e.g., Shield, Guardant Health); the BeScreened-CRC
which tests for three cancer-related blood-based proteins; and to assess the expression of genes to
calculate relative risk of having colorectal cancer (e.g., seven-gene test ColonSentry).
Regulatory Status
FDA Approved Colorectal Cancer Screening Tests Evaluating DNA or RNA in Stool Samples
Cologuard™
Cologuard Plus™
Colosense®
Serologic Genetic and Molecular Screening for Colorectal Cancer
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests evaluated in this evidence review are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. FDA has chosen not to require any regulatory review of these tests.
The Epi proColon test is the only SEPT9 DNA test that has received FDA approval. It was approved in 2016 for use in average-risk patients who decline other screening methods.
In 2024, the FDA approved a test to detect colorectal cancer derived alterations in cell-free DNA (cfDNA), Shield (Guardant Health,Palo Alto, CA). ColonSentry (Stage Zero Life Science) is a proprietary liquid biopsy (blood sample) test that uses advance gene expression (mRNA) technology to detect the expression of 7 genes found to be differentially expressed in individuals with CRC compared with controls. BeScreened-CRC (Beacon Biomedical) is a PCR assay blood-based test to detect 3 protein biomarkers for colorectal cancer screening. BeScreened-CRC is available for clinical use, and it does not require FDA clearance or approval.
Coding
See CPT/HCPCS section
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Policy/ Coverage: |
Effective June 15, 2025
The use of Stool DNA FIT test (e.g., Cologuard (81528)] testing is covered as a preventive service for the purpose of colorectal cancer screening. Please refer to ABCBS policy 2011045.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Stool-based protein marker or molecular genetic testing, other than Cologuard Stool DNA FIT test as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to the following:
For contracts without primary coverage criteria, stool-based protein marker or molecular genetic testing, other than Cologuard Stool DNA FIT test as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
Serologic genetic and molecular screening (including circulating Tumor (Cell-free) DNA and RNA) as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to the following:
For contracts without primary coverage criteria, circulating Tumor (Cell-free) DNA and RNA as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
January 2023 to June 14, 2025 Archived -
Cologuard is now addressed in ABCBS policy 2011045
Effective January 2022 to December 2022
For contracts subject to Arkansas Act 779, the use of MT-DNA + FIT [e.g., Cologuard (81528)] testing is covered for the purpose of colorectal cancer screening in asymptomatic members 45 years old or greater with an average risk of colorectal cancer once every 3 years when no other colorectal cancer screening service (as recommended by the USPSTF) has been provided in the preceding 12 months. This coverage is effective January 1, 2022.
Colonoscopy remains the recommended test for those with a family history of the disease, for those whose previous screenings have uncovered lesions or polyps, or for those otherwise acknowledged as high risk for colorectal cancer [including but not limited to a personal history of colorectal cancer, a personal history of inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, a personal diagnosis of a genetic condition causing and increased risk of colorectal cancer].
Effective October 2019 to December 2021
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Analysis of DNA in stool samples as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer does not meet Primary Coverage Criteria.
For contracts without primary coverage criteria, analysis of DNA in stool samples as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer is considered not medically necessary.
Effective prior to October 2019
Analysis of DNA in stool samples as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, analysis of DNA in stool samples as a technique for detecting colorectal cancer or as a screening technique for colorectal cancer is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
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| Rationale: |
This policy has been regularly updated with reviews of the MEDLINE database. The most recent literature search was performed through May 2025.
As with any diagnostic test, the key outcomes are the diagnostic performance (i.e., sensitivity, specificity, positive and negative predictive value) compared to a gold standard, and consideration of how the results of the test will be used to benefit patient management. Of the various screening options (fecal occult blood testing, fecal immunochemical testing, flexible sigmoidoscopy, double contrast barium enema, colonoscopy), colonoscopy is considered the gold standard. For example, in patients considered at high risk for colorectal cancer, due either to a family history or hereditary nonpolyposis colorectal cancer (HNPCC) mutation, colonoscopy at varying intervals is recommended by the American Society of Colorectal Surgeons, the American Gastroenterological Society, and the American Cancer Society. Therefore, for patients at high risk of colorectal cancer with suspected or known mutations of the HNPCC gene, the diagnostic performance of DNA analysis of stool samples will be compared with colonoscopy. In addition, the role of DNA analysis in the context of the recommended colonoscopic screening must be explored. Will this test be offered in lieu of colonoscopy, such that patients with a negative test can defer a scheduled colonoscopy, or will this test be offered as an adjunct to colonoscopy screening, for example during the intervals between colonoscopies?
For patients at average to moderate risk for colorectal cancer, these organizations also recommend colonoscopy starting at age 50 years, with an interval of 10 years, as one screening option. In addition, other screening techniques are also considered options, and the choice of screening option may be dictated in part by patient preference. Many authors have noted the low patient acceptance of current colorectal cancer screening options, particularly flexible sigmoidoscopy and colonoscopy; at the present time, only approximately 40% of eligible patients undergo screening for colon cancer. Advocates of genetic testing of stool samples have hypothesized that the relative simplicity of collecting a stool sample might increase the overall compliance with screening recommendations. Therefore, for patients at average to moderate risk of colon cancer, genetic testing of stool samples will be compared to colonoscopy and also to fecal immunochemical testing and fecal occult blood testing, the other entirely noninvasive technique. Patient acceptance of the different options is also a relevant outcome as a technique to increase screening compliance
Stool-based protein marker or molecular genetic testing
Clinical Validity
A systematic review and meta-analysis conducted by Dolatkhah et al (2022) assessed the sensitivity and specificity of FIT-DNA compared to colonoscopy. Data were pooled from 11 studies, including the Redwood 2016, Imperiale 2014, Lidgard 2013, and Ahlquist 2012 studies discussed in the subsequent sections. Outcomes evaluated were detection of CRC and any precancerous lesions. The meta-analyses of FIT-DNA found a combined sensitivity of 89% (95% confidence interval [CI], 76% to 96%), 51% (95%CI, 39% to 63%), and 76% (95% CI, 61% to 86%) for the detection of CRC, advanced adenoma, and combined CRC and advanced adenoma, respectively. The overall specificity was 91% (95% CI, 86% to 95%), 89% (95% CI, 84% to 92%), and 90% (95% CI, 87% to93%) for the detection of CRC, advanced adenoma, and combined CRC and advanced adenoma, respectively. The I2 was 100 for the CRC subgroup, 99 for advanced adenoma, and 100 for combined CRC and advanced adenoma. The sensitivity and specificity of FIT-DNA, while indicating its diagnostic accuracy, were lower than colonoscopy for CRC and diagnosis of advanced adenoma.
A systematic review conducted by Lin et al (2021) (used to inform the U.S. Preventive Services Task Force 2021 CRC screening recommendation statement) pooled data from 1 good- and 3 fair-quality studies (including the Imperiale (2014), Redwood (2016), and Cooper (2018) assessing the accuracy of CRC screening with FIT-DNA testing. The Imperiale 2014 study accounted for >80% of the data included in the pooled analyses. The studies all used colonoscopy as the reference standard. When pooled, FIT-DNA had a sensitivity of 93% (95% confidence interval [CI], 87.0% to 100%; I2=0%) and a specificity of 85% (95% CI,84.0% to 86.0%; I2=37.3%) for detection of CRC, based on 3 studies. For advanced neoplasia, sensitivity was 47% (95% CI, 44.0% to 55.0%; I2=0%) and specificity was 89% (95% CI, 87.0% to 92.0%; I2=88.8%) based on 4 studies. Pooled sensitivity and specificity for detection of advanced adenoma, based on 3 studies, was 43% (95% CI, 40.0% to 46.0%; I2=0%) and 89% (95% CI, 86.0% to 92.0%; I2=87.8%).
A next-generation stool test has been developed by EXACT Sciences and has been evaluated in a study by Ahlquist et al. (2012). This test detects 4 methylated genes, a mutant form of KRAS, and the alpha-actin gene. In a study of 252 patients with colorectal cancer, 133 patients with adenomas >= 1 cm, and 293 subjects with normal colonoscopy, the test detected 85% of colon cancer cases and 54% of subjects with adenomas, with 90% specificity. Another smaller study of this same test showed a sensitivity of 87% for detecting colorectal cancer and 82% sensitivity for detecting adenomas.
Lidgard et al (2013) reported on another study by Exact Sciences. In this multicenter, blinded, case-control study of 1003 patients, there were 207 cases with CRC or advanced adenomas (>1 cm), and 796 control patients with no polyps or nonadvanced adenomas (<1 cm). In the case group, 93 subjects had CRC, 84 had advanced adenoma 1 cm or larger and 30 had sessile serrated adenoma 1 cm or larger. In the control group, 155 subjects had nonadvanced adenomas and 641 did not have any colonic lesions. Stool samples were drawn from 544 patients before bowel prep for colonoscopy, and from 459 patients 1 week after colonoscopy but before any treatment had been given. An automated fecal DNA assay measured ß-actin, mutant K-ras, aberrantly methylated BMP3 and NDRG4, along with fecal hemoglobin. Using a logistic regression algorithm that incorporates 11 markers into one regression score and a fixed specificity of 90%, the fecal DNA test identified 84 of 86 (98% sensitivity) CRCs and 41 of 73 (56% sensitivity) advanced adenoma cases.
Cologuard
The largest population screening study was published in 2014 by Imperiale et al. and compared the fecal DNA test (previously developed and evaluated in the studies by Ahlquist et al (2012) and Lidgard et al (2013) discussed next) with FIT in 12,000 asymptomatic persons at average risk for CRC. The results of this study supported the U.S. Food and Drug Administration (FDA, 2014) approval of this fecal DNA test (Cologuard™) in August 2014. This multitarget stool DNA test consists of quantitative measurements of molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and ß-actin in a logistic-regression algorithm. All enrolled subjects were scheduled to undergo screening colonoscopy. Stool specimens were collected and tested no more than 90 days before 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 CRC and cancer precursors. 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. 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 fecal DNA testing 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.
Following FDA approval for use of FIT-DNA (Cologuard) in asymptomatic adults aged 45 to 49 years, Imperiale et al (2021) published results from a screening study that included 983 adults aged 45 to 49 years (mean age, 48 years) at average risk of CRC. Among 816 participants who had evaluable FIT-DNA and colonoscopy results, 49 participants (6%) were found to have advanced precancerous lesions; no cases of CRC were detected. Sensitivity of FIT-DNA was 32.7% (95% CI, 19.9% to 47.5%) for detection of advanced precancerous lesions and 7.1% (95% CI, 4.3% to 11.0%) for detection of nonadvanced adenoma. When analyzed according to lesion type, FIT-DNA was most sensitive for villous growth pattern adenomas (60%; 95% CI, 26.2% to 87.8%). Specificity was 96.3% (95% CI, 94.3% to 97.8%) in participants with a negative colonoscopy, and 95.2% (95% CI, 93.4% to 96.6%) in those with non-advanced adenomas, non-neoplastic findings, and negative results on colonoscopy. FIT testing without DNA analysis was not included in the study.
Imperiale et al (2023) also published a longitudinal cohort study evaluating a 3-year interval for the multitarget stool DNA test(mt-sDNA) for CRC screening. Participants enrolled in the study had a valid baseline mt-sDNA result (N=2044); those with a negative baseline test (n=1760) were followed up to 3 years and asked to undergo repeat mt-sDNA testing and colonoscopy. Patients contributed to the baseline intention to screen (ITS) analysis population if they were mt-sDNA positive at baseline and had an evaluable colonoscopy result or if they were mt-sDNA negative at baseline, had a valid mt-sDNA test result at year 3, and evaluable colonoscopy result. Following attrition, the ITS cohort at year 3 included 591 of 1,760 patients with valid mt-sDNA and colonoscopy results; 122 of these patients were mt-sDNA positive. The Predictive Summary Index (PSI) year 3 value for CRC was 0% (95% CI, -3.62% to 1.02%; p=1); the PSI for advanced precancerous lesions was 9.3% (95% CI, 1.83 to 17.63; two-sided p=.01).The observed 3-year colorectal cancer yield was lower than expected (one-sided p=.09), while the yield for advanced precancerous lesions was higher than expected (two-sided p=.009). The detection of advanced precancerous lesions increased and was statistically significant after repeat mt-sDNA screening at a 3-year interval.
In 2014, Shah et al published a systematic review of biomarkers for early detection of polyps and CRC. This review included 44 studies published from 2007 through June 2013 and thus did not include the 2014 Imperiale study. Sixty-seven different tumor markers were included in the studies. Shah et al found overall sensitivities of fecal DNA markers ranged from 53% to 87% for detecting CRC detection. The sensitivity of detecting CRC and adenoma increased when fecal DNA markers were combined. The authors noted a need for well-structured population-based studies to validate biomarkers for CRC and adenoma detection further.
However, the results of earlier study by Imperiale et al (2004) suggest that fecal DNA analysis offers an improved sensitivity, and thus the question arises as to whether fecal DNA should be considered an alternative to FOBT for patients who are unwilling to undergo, or do not have access to, colonoscopy. The authors comment on the large percentage of patients who forego recommended screening for colorectal cancer, particularly the gold standard of colonoscopy, and propose that a simple noninvasive screening test with an improved sensitivity compared to FOBT would be a viable alternative.
These issues are addressed in an accompanying editorial by Woolf, who urges caution in interpreting the results of the Imperiale et al. study. For example, Woolf notes the wide confidence intervals around the sensitivity of fecal DNA, ranging from 35–68%, which preclude any firm estimates of the magnitude of benefit associated with fecal DNA testing. Fecal DNA testing does provide some advantages in that, unlike FOBT, the patient does not have to undergo a specialized diet prior to the test. However, the patient must collect, refrigerate, and mail an entire bowel movement, which may be unacceptable to some patients. Woolf suggests that increasing screening rates is an important outcome but one that may be achieved by improving the accessibility and delivery of current screening methods.
A second evaluation of FIT-DNA was published in 2016 by Redwood et al. Asymptomatic Alaska natives undergoing screening or surveillance colonoscopy were enrolled in the study. Colonoscopy findings were considered the reference standard for determining the diagnostic characteristics of the FIT-DNA and FIT for detecting CRC and cancer precursors. In 661 evaluable subjects, FIT-DNA sensitivity for cancer was 100% and for FIT it was 85%. For screening-relevant neoplasms (defined as adenoma or sessile serrated adenoma or polyp =1 cm, any adenoma with =25% villous component, or cancer), FIT-DNA sensitivity was 49% and 28% for FIT. Specificities for FIT-DNA were lower than FIT. When all patients with no screening-relevant neoplasms were considered normal, specificities were 91% for FIT-DNA and 94% for FIT. When only patients without any polyps were considered normal, specificities were 93% for FIT-DNA and 96% for FIT.
Cologuard Plus
Imperiale et al (2024) reported results of the pivotal study (BLUE-C; NCT04144738) of the next generation FIT-DNA test (Cologuard Plus). BLUE-C prospectively enrolled 26,758 asymptomatic persons 40 years of age or older (mean, 63 years) who were scheduled to or planned to undergo screening colonoscopy at 186 sites across the United States between 2019 and 2023. Stool specimens were obtained before colonoscopy. Submitted tissue specimens, colonoscopy reports, histopathological
reports, and relevant post-colonoscopy follow-up procedures or imaging reports were reviewed centrally by independent pathologists and were considered to be the reference standard. Central readers were unaware of the results of the stool tests. An independent FIT test was conducted by a separate central laboratory. Of 26,758 enrolled participants, 20,176 (75%) had results included in the primary analysis. 62 adults ages 40 to 44 were enrolled but not included in the primary analysis. The most common exclusions were incomplete screening colonoscopy (8%), unusable stool sample (3%), and nonreceipt of stool sample (3%). 60% of participants identified as White; 16% as Hispanic or Latino; 13% as Black or African American; and 9% as Asian. 32% of the participants had a previous colonoscopy (>9 years prior to enrollment) and 4% had a prior FIT-DNA test. The Cologuard Plus FIT-DNA test sensitivity for CRC was 94% (95% CI, 87 to 98). In subgroup analyses, sensitivity for CRC was greater than 90% for all age categories. The sensitivity for advanced precancerous lesions (APL) was 43% (95% CI, 41 to 46). Specificity for the Cologuard Plus FIT-DNA test was 91% (95% CI, 90 to 91). Sensitivity for CRC and APL was greater for the Cologuard Plus test compared to FIT but Cologuard Plus had lower specificity compared to FIT for advanced neoplasia. A sensitivity analysis using multiple imputation for missing data was performed and reported to yield results consistent with primary results (Imperiale et al, 2024; FDA, 2024).
Clinical Utility
There are no studies evaluating direct health outcomes of a longitudinal screening program using Cologuard or Cologuard Plus. Voyage, a longitudinal prospective, cohort study with a planned enrollment of 150,000 individuals designed to address the real-world impact of Cologuard on CRC screening and mortality, is currently recruiting (Olsen et al, 2020).
A retrospective cohort study conducted by Berger et al (2020) provides some limited evidence on the clinical implications of a false-positive FIT-DNA test. Of 1,216 participants, 206 had a positive FIT-DNA test and a negative colonoscopy. After a median 5 years follow up, individuals with discordant results (positive FIT-DNA test, negative colonoscopy) showed a nonsignificant trend towards increased risk of aerodigestive cancer relative to individuals with concordant results (negative FIT-DNA, negative colonoscopy; adjusted risk ratio, 2.2; 95% CI, 0.8 to 6.2), but the rate of aerodigestive cancer in the discordant group was lower than the expected rate based on the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) data (risk ratio, 0.8; 95% CI, 0.3 to1.9).
Knudsen et al (2021) compared different CRC screening strategies using microsimulation modeling techniques to inform the U.S.Preventive Services Task Force CRC screening recommendations
Screening outcomes from various screening strategies beginning at age 45 years were estimated and compared. FIT-DNA was evaluated in these models using both a yearly screening strategy and an every 3 year strategy. The modeling results suggested that FIT-DNA screening produces outcomes withinthe range of other screening strategies. In terms of life-years gained according to screening strategy, FIT-DNA every 3 years is at the lower range of effectiveness, only higher than flexible sigmoidoscopy, and testing every year is at the higher range of effectiveness, only lower than colonoscopy every 10 years. In terms of complications or lifetime burden as expressed as colonoscopies, the modeling results found FIT-DNA to be in the range of other CRC screening strategies, with every year screening having higher complication and colonoscopy rates than every 3 year screening. Both measures of harm were estimated to be lower with FIT-DNA testing than the screening strategy of colonoscopy every 10 years.
D'Andrea et al (2020) compared different CRC screening strategies using microsimulation modeling techniques to quantify CRC incidence and mortality, incremental life years gained (LYG), number of colonoscopies, and adverse events for men and women 50 years or older over their lifetime. Modeling was conducted under 100% adherence rates and reported adherence rates at the population level. Adherence rates of 42.6% were assumed for FIT-DNA screening every 3 years and adherence to colonoscopy screening every ten years was modeled on data from the National Health Interview Survey suggesting that 62.4% of individuals become up to date with screening within a 10-year period. With 100% adherence, colonoscopy averted 46 CRC cases and 25-26 deaths compared to 42-45 cases and 25-26 deaths with FIT-DNA per 1000 individuals. Assuming reported adherence, colonoscopy averted 34 cases and 20 deaths compared to 16-25 cases and 10-16 deaths with FIT-DNA per 1000 individuals. LYG were proportional to the effectiveness of each strategy. Adverse events were more frequent for colonoscopy (3.7 per 1000 screened). Colonoscopy was found to have a larger benefit when compared to other screening methods including FIT-DNA. The authors note that screening adherence rates higher than 65-70% would be necessary for any stool-based screening modality to match the benefits of colonoscopy. However, a major limitation of this study is that the population adherence rate for FIT-DNA was assumed to be similar to FIT, which underestimates recently observed adherence rates. A cross-sectional screening study in a large, national sample of Medicare beneficiaries (n=368,494) by Weiser and colleagues (2020) reported a real-world FIT-DNA adherence rate of 71%. Kisiel et al (2020) note that existing modeling strategies may additionally be limited by input assumptions that fail to account for aspects of neoplasia and adenoma progression, adenoma detection rates, and other patient, polyp, and provider characteristics that may impact simulated outcomes of lifetime screening and surveillance.
Fendrick et al (2022) compared the life-years gained (LYG) per screening colonoscopy and follow-up colonoscopy after a positive stool-based test (FIT-DNA or FIT). Modeling was used to estimate CRC outcomes from screening and follow-up colonoscopies versus no screening in a simulated population of average-risk individuals aged 45 to 75 years. The LYG/colonoscopy per 1000individuals was 0.09 for screening colonoscopy and 0.29 for follow-up colonoscopy. The number of CRC cases and CRC deaths averted per colonoscopy were 0.01 and 0.01 for screening colonoscopy, respectively, and 0.04 and 0.02 for follow-up colonoscopy, respectively. .
In 2016, Knudsen at al compared different CRC screening strategies using microsimulation modeling techniques to inform the U.S. Preventive Services Task Force CRC screening recommendations. Diagnostic characteristics of FIT-DNA from the Imperiale study were incorporated into the model and screening outcomes from various screening strategies were estimated and compared. FIT-DNA was evaluated in these models using both a yearly screening strategy and an every 3-year strategy. The modeling results suggested that stool DNA screening produces outcomes within the range of the other screening strategies. FIT-DNA every 3 years is at the lower range of effectiveness, only higher than flexible sigmoidoscopy, and testing every year is at the higher range of effectiveness, only lower than colonoscopy every 10 years. In terms of complications or lifetime burden as expressed as colonoscopies, FIT-DNA appears to be in the range of other CRC screening strategies, with every year screening having higher complication and colonoscopy rates than every 3 year screening. Both measures of harm were estimated to be lower than the screening strategy of colonoscopy every 10 years. The analysis proposed a set of screening modalities that were considered model-recommendable, based on having at least 90% of the life-year gain of colonoscopy, and having met certain efficiency criteria. FIT-DNA was not selected as a model-recommended strategy because it was not considered as efficient as other stool-based strategies.
A study was conducted by Anderson et al (2022) using data from the New Hampshire Colonoscopy Registry to evaluate colonoscopy outcomes between age-, sex-, and risk-matched patients with and without a preceding positive FIT-DNA test. The investigators found that individuals in the positive FIT-DNA group (n=306) were significantly more likely than the colonoscopy-only cohort (n=918) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%; p<.0001). Colorectal neoplasia was found in68.0% of individuals who underwent colonoscopy after a positive FIT-DNA test versus 42.3% of individuals with colonoscopy alone(p<.0001).
Another modeling study (Berger, 2016), sponsored by the manufacturer of Cologuard, showed similar findings. Compared with colonoscopy every 10 years, yearly FIT-DNA was estimated to produce similar reductions in CRC incidence and mortality. Every 3-year and every 5-year testing produced less reduction in CRC incidence and mortality. Colonoscopy every 10 years was estimated to decrease CRC incidence by 65%, whereas FIT-DNA every 3 years reduced CRC incidence by 57% and FIT-DNA every 5 years reduced CRC incidence by 52%.
A 2017 comparative effectiveness modeling study by Barzi et al found that colonoscopy was the most effective screening strategy with the highest life years gained (0.022 life years) and CRCs prevented (n=1068), and the lowest total cost.9 Modeling for FIT-DNA every year or every other year found 0.011 life years gained, 647 CRCs prevented, and a higher total cost. The main reason for the difference in CRCs prevented was due to the detection of precancerous polyps. The study found that if the sensitivity of FIT-DNA for adenomas increased, it could surpass the sensitivity of colonoscopy. An unexpected consequence of a positive FIT-DNA test may be to improve the quality of the subsequent colonoscopy.
Updated modeling studies of health outcomes including Cologuard Plus have not yet been published. The modeling studies described in the previous paragraphs assume performance characteristics (sensitivity and specificity) for FIT-DNA from the original Cologuard test. Given that the performance characteristics of the next generation FIT-DNA test (Cologuard Plus) appear similar with respect to sensitivity and perhaps better with respect to specificity, the expected clinical outcomes would be at least as good with the new FIT-DNA test compared to the original FIT-DNA test.
Colosense
Barnell et al (2023) reported results of the pivotal study (CRC-PREVENT; NCT04739722) of the FIT-RNA (Colosense) test. CRC-PREVENT prospectively enrolled 14,263 participants ages 45 and older (mean, 55 years) who were willing to undergo a colonoscopy from 49 US states using decentralized recruitment through a online social media platform from 2021 to 2022. Stool samples were collected prior to participants completing a colonoscopy at their local endoscopy center. The reference standard was colonoscopy results, which were based on histopathological review of all lesions either biopsied or resected during the colonoscopy, or negative results by colonoscopy. Participants were navigated to complete a routine colonoscopy at a local endoscopy center. 68% of participants did not have a colonoscopy scheduled prior to enrollment and many required assistance with obtaining a colonoscopy appointment at a local endoscopy center. 8920 participants were included in the analysis in the publication. The most common exclusions were: 2179 did not submit a valid stool sample; 852 had insufficient RNA; 1263 did not complete a colonoscopy; and 297 had inadequate colonoscopy preparation. 60% of participants were women. 4% of participants identified as Asian, 11% as Black or African American, 7% as Hispanic or Latino, and 84% as White. 34% had a prior or current history of smoking. Overall, the sensitivity of the FIT-RNA test for CRC was 94% (95% CI, 81 to 99) and for advanced adenomas (AA) was 46% (95% CI, 42 to 50). Overall, specificity for the FIT-RNA test was 87% (95% CI, 86 to 88). The primary outcome for regulatory approval reported in the Summary of Safety and Effectiveness Data (SSED) was the sensitivity and specificity in the average risk population (n=7,763), excluding 526 enrolled participants with first-degree relatives with CRC. In the average risk population, the CRC sensitivity of the FIT-RNA test was 93% (95% CI, 76 to 99) and the AA sensitivity was 45% (95% CI, 41 to 49). The specificity of the FIT-RNA test in the average risk population was 86% (95% CI, 85 to 86). Sensitivity for CRC and AA was greater for the FIT-RNA test compared to FIT alone but the FIT-RNA test had lower specificity compared to FIT (Barnell et al, 2023; FDA, 2024).
Serologic Genetic and Molecular Screening for Colorectal Cancer
The 2021 USPSTF recommendations for colorectal cancer screening specifically indicates that the
recommendation does not include serum-based tests for colorectal cancer screening due to limited
available evidence on these tests, that other effective tests are available, and additional more
research is needed on the accuracy and effectiveness of emerging screening technologies such as
serum-based tests.
Shaukat et al (2025) published the results of a prospective, observational study of 37,010 participants aged 45 to 85 years to assess the clinical performance of a circulating tumor DNA–based blood test for colorectal cancer detection in average-risk individuals. The study found that the blood test demonstrated 79.2% sensitivity for colorectal cancer and 91.5% specificity for advanced colorectal tumors using colonoscopy as the reference standard. The authors concluded that, “in an average-risk colorectal cancer screening population, a blood-based test demonstrated acceptable accuracy for colorectal cancer detection, but detection of advanced precancerous lesions remains a challenge, and ongoing efforts are needed to improve test sensitivity”.
Chung and colleagues (2024) conducted an industry-sponsored study to assess the performance
characteristics of the Shield (Guardant Health), a cell-free DNA (cfDNA) blood-based test for
colorectal cancer screening. Of the 7,861 average-risk screening participants who met eligibility
criteria and were evaluable, the authors reported that the Shield (Guardant Health) cfDNA blood-based test had 83% sensitivity for the detection of CRC, 90% specificity for advanced neoplasia, and
13 % sensitivity for advanced pre-cancerous lesions. The false positive rate of the Shield blood-based
test was 10.1%. The authors noted evaluating these percentages in the real-world setting will be important to understand population effect, and that future studies to understand the effect of
longitudinal testing on sensitivity for advanced neoplasia warrant consideration.
SEPT9 Methylated DNA With ColoVantage and Epi proColon
The diagnostic performance of SEPT9 methylation for colon cancer has been reported in meta-analyses. The systematic reviews identified from 2016 and 2017 included 14 to 39 studies (Harihan and Jenkins, 2020; Nian et al, 2017; Li et al2016; Yan et al, 2016). Pooled sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93%. The systematic review by Nian et al (2017) found that study designs (case-control vs cross-sectional), assays or kits used (Epi proColon vs other), country (Asia or other), sample sizes (n >300 or <300), and risk of bias of included studies all contributed to heterogeneity. Most included studies were case-control with the exclusion of difficult to diagnose patients, which may lead to a spectrum bias and overestimation of diagnostic accuracy. Reviewers included 20 studies of Epi proColon test 1.0, 2.0, or a combination of the 2. When only looking at studies of Epi ProColon 2.0, sensitivity was 75% compared with 71% in the overall analysis, with a specificity of 93%. Sensitivity and specificity may be additionally affected by the specific algorithm used, with the 1/3 algorithm resulting in higher sensitivity and the 2/3 algorithm resulting in higher specificity (Song et al, 2017). A 2020 systematic review of Epi proColon 2.0 by Hariharan and Jenkins found high specificity (92%) and negative predictive value (NPV) (99.9%) for CRC so that a negative test would rule out CRC. However, a test with sensitivity of 69% would accurately diagnose only 21 of 30 CRC cases in a sample of 10,000 people at average risk. Sensitivity for precancerous lesions would be lower.
ColoVantage (various manufacturers) blood tests for serum SEPT9 methylated DNA are offered by several laboratories (ARUP Laboratories, Quest Diagnostics, Clinical Genomics). Epi proColon (Epigenomics) received U.S. Food and Drug Administration (FDA) approval in April 2016. Epigenomics has licensed its Septin 9 DNA biomarker technology to ARUP and Quest. ColoVantage and Epi proColon are both PCR assays; however, performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes). Sensitivity as high as 90%, with 88% specificity and 99.9% negative predictive value (4% positive predictive value) have been reported for ColoVantage (ARUP Laboratories, 2016; Potter et al, 2014). By comparison, reported sensitivity and specificity for Epi proColon were 68% and 80%, respectively (Targan et al, 2005). Serum SEPT9 methylated DNA testing is intended for individuals 50 years of age or older who have an average risk of CRC.
The evidence review for the 2016 U.S. Preventive Services Task Force update on CRC screening included studies on blood tests for methylated SEPT9 DNA. The inclusion criteria were fair- or good-quality English-language studies, asymptomatic screening populations, age of 40 years or older, and at average risk for CRC or not selected for inclusion based on CRC risk factors. The only study found to meet these inclusion criteria was the Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT).
In 2014, Church et al reported an international prospective screening study of Epi proColon®, called PRESEPT (Church, 2014). Patients 50 years of age or older with average risk of CRC who were scheduled for colonoscopy were enrolled (N=7941). Of these, 1516 (19%) were selected for laboratory analysis in stratified random sampling; colonoscopy identified 53 patients (3%) with invasive adenocarcinoma, 315 (21%) with advanced adenoma, 210 (14%) with nonadvanced adenoma, and 938 (62%) with no evidence of disease. Overall sensitivity, specificity, PPV, and NPV for Epi proColon® detection of invasive adenocarcinoma were 48%, 92%, 5%, and 100%, respectively. Sensitivity for advanced adenoma was low (11%). As observed by the study authors, detection of only half of preclinical cancers and a small proportion of advanced adenomas limits clinical utility of the test.
Song et al (2018) conducted a prospective study of the colorectal tumor detection rate from methylated
SEPT9 levels by Epi proColon 2.0 using the 2/3 algorithm. All 1,347 individuals who met criteria and
were to undergo colonoscopy provided a blood sample prior to evaluation of clinical status. The level of
methylated SEPT9 increased as the severity of disease increased, and the detection rate increased with disease severity. The detection rate was less than 20% for serrated adenoma and tubular adenoma, 41% for tubulovillous adenoma, 54% for stage I CRC, and then increased to 84% as the stage of CRC increased to stage IV CRC. Results suggested potential utility for monitoring treatment response, but limited utility as a screening tool.
ColonSentry
Test Description: ColonSentry (GeneNews, Ontario, Canada; Innovative Diagnostic Laboratory, Richmond, VA)
ColonSentry® is a PCR assay that uses a blood sample to detect expression of 7 genes found to be differentially expressed in CRC patients compared with controls (Yip et al, 2010): ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, and IL2RB. Per the company website, these genes are early warning signs of colon cancer, and test results can indicate the odds of having CRC compared with an average-risk person. An average-risk person is defined as one who is “at least 50 years old, is asymptomatic for CRC, has no personal history of benign colorectal polyps, colorectal adenomas, CRC, or inflammatory bowel disease, and does not have a first degree relative with CRC” (Innovative Diagnostic Laboratory, 2015). The test is intended for use in adults who are averse to colonoscopy and/or fecal occult blood testing. “Because of its narrow focus, the test is not expected to alter clinical practice for patients who comply with recommended screening schedules.” (Chao et al, 2013).
Marshall et al (2010) conducted a genome-wide association study in 189 whole blood samples (98 controls, 91 patients with CRC) and identified 45 differentially expressed gene biomarker candidates using microarray hybridization.53 Through logistic regression and bootstrapping (subsampling with replacement) in a training set of 232 samples (120 controls, 112 patients with CRC), 7 genes were selected for further development. Sensitivity, specificity, PPV, and NPV for detecting CRC were 82%, 64%, 68%, and 79%, respectively. AUC was 0.80 (95% CI, 0.74 to 0.85). In a test set of 410 samples (208 controls, 202 patients with CRC), sensitivity, specificity, PPV, and NPV were 72%, 70%, 70%, and 72%, respectively. AUC was 0.80 (95% CI, 0.76 to 0.84). The authors applied subsequent Bayesian modeling to incorporate the prevalence of CRC in the average-risk population (0.7%) and proposed relative risk categories to further stratify average-risk patients for CRC screening. Because of its cross-sectional design, follow-up of controls to determine which strata developed CRC was not reported, limiting conclusions that can be drawn about the accuracy of the test for risk prediction. In a subsequent publication, the investigators reported test performance stratified by left- versus right-sided cancers and tumor stage (Chao et al, 2013).
Yip et al (2010) conducted a similar cross-sectional study in 210 blood samples (111 controls, 99 CRC) from patients in Malaysia. The Malaysian population has different ethnic groups with different CRC incidences (eg, 0.02% in Chinese Malaysians, 0.01% in ethnic Malays), and CRC in Asian populations is more likely to be nonpolypoid (ie, flat or depressed) compared with western populations in whom the test was developed. Sensitivity and specificity for detecting CRC were 61% and 77%, respectively. AUC was 0.76 (95% CI, 0.70 to 0.82). With optimized cut points, sensitivity and specificity were 72% and 71%, respectively. As previously, the cross-sectional design of the study limits conclusions that can be drawn.
No studies examining the clinical utility of ColonSentry® were identified. Factors that support an indirect chain of evidence for predicting CRC risk are lacking, primarily because evidence for clinical validity of the test is lacking.
BeScreened™-CRC(Beacon Biomedical, Inc.)
BeScreened™-CRC is an ELISA-based multiplexed, CLIA laboratory test developed for colorectal cancer (CRC) screening. It consists of a panel of 3 blood tests for tumor-associated protein biomarkers that are involved in CRC tumorigenesis and progression: carcinoembryonic antigen (CEA), extracellular matrix protein (EMP) and teratocarcinoma derived growth factor-1 genetic expression profiling (TDGF-1, Cripto-1).
No studies examining the clinical utility of BeScreened-CRC were identified.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov registry identified several currently unpublished trials that might influence this policy.
PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
The National Comprehensive Cancer Network guidelines (v.1.2024) for colorectal cancer (CRC) screening includes use of fecal immunochemical testing-DNA (FIT-DNA) to screen patients with average risk for colon cancer. Following a negative test, the recommendation is to rescreen with any modality after 3 years. Use of FIT-DNA tests is not described for screening of high-risk individuals. Follow-up colonoscopy is recommended within 6 to 10 months after a positive test.
Current National Comprehensive Cancer Network (NCCN) (v.1.2024) guidelines on CRC screening also state that "A blood test that detects circulating methylated SEPT9 DNA has been U.S. Food and Drug Administration approved for CRC screening for those who refuse other screening modalities...the interval for repeating testing is unknown/unclear".
Multi-Society Task Force on Colorectal Cancer
A U.S. Multi-Society task force representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy provided recommendations for colorectal cancer screening in 2017. The recommended first-tier tests for individuals with average risk were colonoscopy every 10 years, and for individuals who decline colonoscopy, annual fecal immunochemical testing (FIT). Recommended second-tier tests in patients who declined the first-tier tests were computed tomography (CT) colonography every 5 years, FIT-DNA every 3 years, or flexible sigmoidoscopy every 5 to 10 years. Capsule colonoscopy was listed as a third-tier test. The task force recommended “CT colonography every 5 years or FIT-fecal DNA every 3 years (strong recommendation, low quality evidence, or flexible sigmoidoscopy every 5-10 years (strong recommendation, high quality evidence) in patients who refuse colonoscopy and FIT.”
In 2022, a focused update to the 2017 CRC screening recommendations from the task force was published that addressed the age to begin and stop CRC screening in average-risk individuals (Patel et al, 2022). The task force now suggests CRC screening in average-risk individuals aged 45 to 49 years. Unchanged from 2017 are the following recommendations: a) offer CRC screening to all average-risk individuals aged 50 to 75 years, b) consider starting or continuing screening for individuals aged 76 to 85 years on an individualized basis (depending on patient and disease factors), and c) screening is not recommended after age 85 years.
In 2017, the Task Force's clinical guidelines stated that the advantage of SEPT9 assays for CRC screening is convenience. The disadvantage is "markedly inferior performance characteristics compared with FIT [fecal immunochemical test]." The guidelines also stated that the best frequency for performing the test is unknown and that the task force recommended not using SEPT9 assays for CRC screening (Rex et al, 2017).
American Gastroenterological Association
In 2022, the AGA published a clinical practice update commentary that reviewed the evidence on noninvasive CRC screening options (Burke et al, 2022). Similar to the U.S. Multi-Society task force, the ACG recommends FIT-DNA every 3 years as an average-risk option for CRC screening. The commentary compares this recommendation to that of the U.S. Preventive Services Task Force (USPSTF), which recommends FIT-DNA every 1 to 3 years.
In 2023, the AGA published a clinical practice update reviewing risk stratification for CRC screening and post-polypectomy surveillance (Issaka et al, 2023). Similar to other guidelines, the following best practice advice was provided: "Screening options for individuals at average risk for CRC should include colonoscopy, fecal immunochemical test (FIT), flexible sigmoidoscopy plus FIT, multitarget stool DNA test, and computed tomography colonography, based on availability and individual preference."
American Cancer Society
In 2018, the American Cancer Society updated its guidelines for CRC screening for average-risk adults (Wolf et al, 2018). Regular screening with either a structural examination (ie colonoscopy) or high-sensitivity stool-based test is recommended to start in adults who are 45 years and older (qualified recommendation) or who are 50 years and older (strong recommendation). Recommendations for screening with stool-based tests include FIT repeated every year, high-sensitivity guaiac-based fecal occult blood test repeated every year, or multitarget stool DNA test repeated every 3 years.
American College of Physicians
In 2023, the American College of Physicians (ACP) released updated guidance on screening for CRC in asymptomatic, average-risk adults (Qaseem et al, 2023). The ACP stated that "Clinicians should not use stool DNA, computed tomography colonography, capsule endoscopy, urine, or serum screening tests for colorectal cancer". A guidance statement of approved tests is as follows: “Clinicians should select among a fecal immunochemical or high-sensitivity guaiac fecal occult blood test every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a fecal immunochemical test every 2 years as a screening test for colorectal cancer".
U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
In 2021, the U.S. Preventive Services Task Force (USPSTF) published updated recommendations for CRC screening in asymptomatic, average risk adults (defined as no prior diagnosis of CRC, adenomatous polyps, or inflammatory bowel disease; no personal diagnosis or family history of known genetic disorders that predispose them to a high lifetime risk of CRC [such as Lynch syndrome or familial adenomatous polyposis]) (Davidson et al, 2021). The USPSTF recommended universal screening for average risk adults aged 45 to 49 years (B recommendation) and for adults aged 50 to 75 years (A recommendation). For adults aged 76 to 85 years, the USPSTF recommends selective screening due to the small magnitude of net benefit (C Recommendation). The USPSTF reviewed evidence for 6 screening strategies, including FIT-DNA. They do not recommend one screening strategy over another and noted the lack of direct evidence on clinical outcomes when comparing screening strategies.
Clinical considerations given by the U.S. Preventative Services Task Force for Fecal Immunochemical-DNA Testing:
Recommended screening interval: 1 to 3 years
Efficacy:
Other considerations:
The guideline states that "because of limited available evidence, the USPSTF recommendation does not include serum tests, urine tests, or capsule endoscopy for colorectal cancer screening." The evidence review supporting the recommendations included a search for studies of serum-based tests (eg, methylated SEPT9 DNA tests) but concluded that the strength of evidence was low, based on a single case-control study (Davidson et al, 2021; Lin et al, 2021).
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