Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Analytical Validation of NavDx, a cfDNA-Based Fragmentomic Profiling Assay for HPV-Driven Cancers.

The NavDx® blood test analyzes tumor tissue modified viral (TTMV)-HPV DNA to provide a reliable means of detecting and monitoring HPV-driven cancers. The test has been clinically validated in a large number of independent studies and has been integrated into clinical practice by over 1000 healthcare providers at over 400 medical sites in the US. This Clinical Laboratory Improvement Amendments (CLIA), high complexity laboratory developed test, has also been accredited by the College of American Pathologists (CAP) and the New York State Department of Health. Here, we report a detailed analytical validation of the NavDx assay, including sample stability, specificity as measured by limits of blank (LOBs), and sensitivity illustrated via limits of detection and quantitation (LODs and LOQs). LOBs were 0-0.32 copies/µL, LODs were 0-1.10 copies/µL, and LOQs were <1.20-4.11 copies/µL, demonstrating the high sensitivity and specificity of data provided by NavDx. In-depth evaluations including accuracy and intra- and inter-assay precision studies were shown to be well within acceptable ranges. Regression analysis revealed a high degree of correlation between expected and effective concentrations, demonstrating excellent linearity (R2 = 1) across a broad range of analyte concentrations. These results demonstrate that NavDx accurately and reproducibly detects circulating TTMV-HPV DNA, which has been shown to aid in the diagnosis and surveillance of HPV-driven cancers.

Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study.

Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings. PREVENTION RELEVANCE: Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.

Novel Coagulation Test Detects Anticoagulation Resistance and Is Associated With Thrombotic Events in Pediatric Patients Requiring Extracorporeal Membrane Oxygenation.

Bivalirudin, an IV direct thrombin inhibitor, and unfractionated heparin (UFH) are frequently used anticoagulants in the pediatric critical care setting. An accurate, specific, point-of-care test to quantify and detect anticoagulation resistance is not currently available. This study evaluates the ability of a rapid (< 10 min), micro-volume (< 50 uL) coagulation test to detect and quantify the anticoagulation effect of bivalirudin and UFH using a functional, clot time endpoint in pediatric critical care patients. DESIGN: Single-site retrospective laboratory sample analysis and chart review. SETTING: A 105-bed pediatric and cardiac ICUs delivering extracorporeal membrane oxygenation. SUBJECTS: Forty-one citrated, frozen, biobanked plasma specimens comprising 21 with bivalirudin and 20 with UFH from 15 anticoagulated pediatric patients were analyzed. Thirteen patients were on extracorporeal membrane oxygenation, one had a submassive pulmonary embolism, and one was on a left ventricular assist device. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A Clotting Time Score (CTS) was derived on each sample. The CTS detected patients that had developed a pathologic clotting event with 100% sensitivity and 82% specificity compared with prothrombin time with 25% sensitivity/76% specificity and activated partial thromboplastin time with 0% sensitivity/0% specificity. Additionally, the CTS detected subtherapeutic anticoagulation in response to UFH in patients that were clinically determined to be UFH resistant requiring alternative anticoagulation with bivalirudin. CONCLUSIONS: The CTS appears to be a clinically valuable indicator of coagulation status in patients treated with either UFH or bivalirudin. Results outside of the therapeutic range due to inadequate dosing or anticoagulation resistance appeared to be associated with clot formation. CTS testing may reduce the risk of anticoagulation-related complications via the rapid identification of patients at high risk for pathologic thrombotic events.

Detection of Occult Recurrence Using Circulating Tumor Tissue Modified Viral HPV DNA among Patients Treated for HPV-Driven Oropharyngeal Carcinoma.

PURPOSE: Despite generally favorable outcomes, 15% to 25% of patients with human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) will have recurrence. Current posttreatment surveillance practices rely on physical examinations and imaging and are inconsistently applied. We assessed circulating tumor tissue modified viral (TTMV)-HPV DNA obtained during routine posttreatment surveillance among a large population of real-world patients. EXPERIMENTAL DESIGN: This retrospective clinical case series included 1,076 consecutive patients across 108 U.S. sites who were ≥ 3 months posttreatment for HPV-driven OPSCC and who had one or more TTMV-HPV DNA tests (NavDx, Naveris Laboratories) obtained during surveillance between February 6, 2020, and June 29, 2021. Test results were compared with subsequent clinical evaluations. RESULTS: Circulating TTMV-HPV DNA was positive in 80 of 1,076 (7.4%) patients, with follow-up available on all. At first positive surveillance testing, 21 of 80 (26%) patients had known recurrence while 59 of 80 (74%) patients were not known to have recurrent disease. Among these 59 patients, 55 (93%) subsequently had a confirmed recurrence, 2 patients had clinically suspicious lesions, and 2 had clinically "no evidence of disease" (NED) at last follow-up. To date, the overall positive predictive value of TTMV-HPV DNA testing for recurrent disease is 95% (N = 76/80). In addition, the point-in-time negative predictive value is 95% (N = 1,198/1,256). CONCLUSIONS: These findings highlight the clinical potential for circulating TTMV-HPV DNA testing in routine practice. As a surveillance tool, TTMV-HPV DNA positivity was the first indication of recurrence in the majority of cases, pre-dating identification by routine clinical and imaging exams. These data may inform future clinical and guideline-endorsed strategies for HPV-driven malignancy surveillance. See related commentary by Colevas, p. 4171.

Colorectal Neoplasia Detection in Individuals With Positive Multitarget Stool DNA Tests: Data From the New Hampshire Colonoscopy Registry.

BACKGROUND: The US Preventive Services Task Force (USPSTF) includes multitarget stool DNA (mt-sDNA) testing as a colorectal cancer (CRC) screening option in average-risk individuals, but data on colonoscopy outcomes after positive mt-sDNA tests in community settings are needed. AIM: The aim of this study was to investigate colonoscopy outcomes and quality following positive mt-sDNA in the population-based New Hampshire Colonoscopy Registry. METHODS: We compared colonoscopy outcomes and quality between age-matched, sex-matched, and risk-matched patients from 30 endoscopy practices with and without a preceding positive mt-sDNA test. Main outcomes were colonoscopy findings of CRC, advanced noncancerous neoplasia, nonadvanced neoplasia, or normal examination. Quality measures included withdrawal time, bowel preparation quality, examination completion, and percentage of average-risk individuals with normal colonoscopies receiving a USPSTF-recommended 10 year rescreening interval. RESULTS: Individuals with positive mt-sDNA tests (N=306, average age 67.0 y; 61.8% female) were significantly more likely than colonoscopy-only patients (N=918, 66.2 y; 61.8% female) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%) (P<0.0001). Neoplasia was found in 68.0% of patients having colonoscopy after a positive mt-sDNA test, (positive predictive value, was 68.0%), versus 42.3% of patients with colonoscopy only (P<0.0001). No significant differences in colonoscopy quality measures were observed between cohorts. CONCLUSIONS: Colonoscopy after a positive mt-sDNA test was more frequently associated with CRC and colorectal neoplasia than colonoscopy alone. Positive mt-sDNA tests can enrich the proportion of colonoscopies with clinically relevant findings. Follow-up recommendations suggest that endoscopists do not inappropriately shorten rescreening intervals in mt-sDNA-positive patients with normal colonoscopy. These findings support the clinical utility of mt-sDNA for CRC screening in community practice.

Specificity of the Multi-Target Stool DNA Test for Colorectal Cancer Screening in Average-Risk 45-49 Year-Olds: A Cross-Sectional Study.

High-specificity colorectal cancer screening is desirable to triage patients <50 years for colonoscopy; however, most endorsed colorectal cancer screening tests have not been rigorously evaluated in younger populations. This prospective cross-sectional study determined the specificity of the multitarget stool DNA (mt-sDNA) test in an average-risk screening population of 45 to 49 year-olds. Specificity was the primary outcome and was measured in participants without colorectal cancer or advanced precancerous lesions [APL- advanced adenomas (AA), and sessile serrated lesions ≥10 mm], and in the subgroup of participants with negative colonoscopic findings. APL sensitivity was a secondary outcome. The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. Of 983 enrolled participants, 816 formed the evaluable cohort, with a mean age of 47.8 (SD, 1.5) years; 47.7% were women. No participants had colorectal cancer, 49 had APL, 253 had nonadvanced adenomas (NAA), and 514 had negative colonoscopic findings. mt-sDNA test specificity was 95.2% (95% CI, 93.4-96.6) in participants with NAA or negative findings [96.3% (confidence interval (CI), 94.3%-97.8%)] in those with negative findings, and did not differ by sex (P = 0.75) or race (P = 0.36) in participants with NAA or negative findings. Sensitivity for APL was 32.7% (CI, 19.9-47.5%), with most APL (83.7%) measuring 10-19 mm and none having high-grade dysplasia. The area under the ROC curve for discriminating between APL and lesser findings was 0.72 (CI, 0.64-0.81). mt-sDNA's high specificity would help minimize risk from unnecessary diagnostic procedures in this age group. This study shows that mt-sDNA has high specificity among average-risk 45 to 49-year olds, supporting its use as a noninvasive option for colorectal cancer screening. PREVENTION RELEVANCE: This study shows that mt-sDNA has high specificity among average-risk 45-49 year olds, supporting its use as a non-invasive option for colorectal cancer screening.

Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening: Real-world data from a large cohort of older adults.

OBJECTIVE: To determine cross-sectional adherence with the multi-target stool DNA test used for colorectal cancer screening in a large, fully insured Medicare population. METHODS: All patients aged 65-85 with a valid multi-target stool DNA test order from 1 September 2016 to 31 August 2017 identified from the Exact Sciences Laboratories (Madison, WI; sole-source national multi-target stool DNA test provider) database were evaluated for test adherence. Cross-sectional adherence, defined as multi-target stool DNA test completion within 365 days from order date, was analyzed overall and by time to adherence, as well as by available patient (age, sex, test order date, Medicare coverage type) and provider (specialty, year of first multi-target stool DNA test order, multi-target stool DNA test order frequency, and practice location) factors. RESULTS: Among 368,494 Medicare beneficiaries (64% female), overall cross-sectional adherence was 71%. Cumulative adherence rates increased more rapidly at 30 (44%) and 60 (65%) days, followed by more gradual increases at 90 (67%), 180 (70%), and 365 (71%) days. By provider specialty, primary care clinicians represented a higher percentage of multi-target stool DNA orders than gastroenterologists (88% vs. 6%), but had a lower associated patient adherence rate (71% vs. 78%). CONCLUSIONS: In this large, national sample of Medicare insured older adults, nearly three-quarters of patients adhered with a multi-target stool DNA order for colorectal cancer screening. These real-world data should inform further clinical and population health applications, reimbursement model simulations, and guideline-endorsed colorectal cancer screening strategies adherence.

Low Incidence of Aerodigestive Cancers in Patients With Negative Results From Colonoscopies, Regardless of Findings From Multitarget Stool DNA Tests.

BACKGROUND & AIMS: We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence. METHODS: We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test. Outcomes included aerodigestive cancers in discordant vs concordant groups and comparison of observed aerodigestive cancer incidence between the groups and compared with expected incidence for the population, based on the Surveillance, Epidemiology, and End Results (SEER) data. RESULTS: Median follow-up times were comparable between subjects in the discordant (5.3 y; interquartile range, 3.5-5.8 y) and concordant (5.4 y; interquartile range, 3.7-5.8 y) groups. Aerodigestive cancers developed in 5 subjects in the discordant group vs 11 subjects in the concordant group (crude risk ratio, 2.3; 95% CI, 0.8-6.6; adjusted risk ratio, 2.2; 95% CI, 0.8-6.2; P = .151). The incidence of aerodigestive cancer was lower in the concordant group than the expected incidence based on SEER data (risk ratio, 0.4; 95% CI, 0.2-0.6; P = .0008). The incidence of aerodigestive cancer was not significantly greater in the population in the discordant group than the expected incidence based on SEER data (risk ratio, 0.8; 95% CI, 0.3-1.9; P = .599). CONCLUSIONS: In a retrospective study with a median follow-up time of 5.4 years, incident aerodigestive cancers were uncommon among subjects with negative findings from colonoscopies, regardless of discordant or concordant results from multitarget stool DNA tests. Patients with negative results from high-quality colonoscopies therefore should not undergo further testing.

Performance of multitarget stool DNA testing in African American patients.

BACKGROUND: Multitarget stool DNA (mt-sDNA) is an approved method for colon cancer screening that is especially relevant for patients who cannot undergo colonoscopy. Although the test performance has been evaluated in a large clinical trial, it was limited to a predominantly white population. Given differences in the epidemiology and biology of colon cancer in African American individuals, the authors sought to compare the performance of mt-sDNA between racial groups. METHODS: The authors prospectively identified patients aged ≥40 years who were referred for colonoscopy at an academic medical center and 2 satellite facilities. Prior to the colonoscopy, the authors collected stool for mt-sDNA and fecal immunochemical testing (FIT). They compared the sensitivity, specificity, and receiver operating characteristic curve between African American and white patients for the detection of advanced lesions or any adenoma. RESULTS: A total of 760 patients were included, 34.9% of whom were African American. The prevalence of any adenoma (38.9% for African American patients and 33.9% for white patients) and that for advanced lesions (6.8% and 6.7%, respectively) were similar between groups. The overall sensitivities of mt-sDNA for the detection of advanced lesions and any adenoma were 43% and 19%, respectively, and the specificities were 91% and 93%, respectively. In general, mt-sDNA was more sensitive and less specific than FIT. When stratified by race, the sensitivity, specificity, and receiver operating characteristic curve area were similar between African American and white patients for both mt-sDNA and FIT. CONCLUSIONS: Test performance characteristics of mt-sDNA were comparable in African American and white patients. Given the lower uptake of colonoscopy in African American individuals, mt-sDNA may offer a promising screening alternative in this patient population.

Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing.

BACKGROUND: There is uncertainty as to the appropriate follow-up of patients who test positive on multimarker stool DNA (sDNA) testing and have a colonoscopy without neoplasia. AIMS: To determine the prevalence of missed colonic or occult upper gastrointestinal neoplasia in patients with an apparent false positive sDNA. METHODS: We prospectively identified 30 patients who tested positive with a commercially available sDNA followed by colonoscopy without neoplastic lesions. Patients were invited to undergo repeat sDNA at 11-29 months after the initial test followed by repeat colonoscopy and upper endoscopy. We determined the presence of neoplastic lesions on repeat evaluation stratified by results of repeat sDNA. RESULTS: Twelve patients were restudied. Seven patients had a negative second sDNA test and a normal second colonoscopy and upper endoscopy. In contrast, 5 of 12 subjects had a persistently positive second sDNA test, and 3 had positive findings, including a 3-cm sessile transverse colon adenoma with high-grade dysplasia, a 2-cm right colon sessile serrated adenoma with dysplasia, and a nonadvanced colon adenoma (p = 0.045). These corresponded to a positive predictive value of 0.60 (95% CI 0.17-1.00) and a negative predictive value of 1.00 (95% CI 1.00-1.00) for the second sDNA test. In addition, the medical records of all 30 subjects with apparent false positive testing were reviewed and no documented cases of malignant tumors were recorded. CONCLUSIONS: Repeat positive sDNA testing may identify a subset of patients with missed or occult colorectal neoplasia after negative colonoscopy for an initially positive sDNA. High-quality colonoscopy with careful attention to the right colon in patients with positive sDNA is critically important and may avoid false negative colonoscopy.

Genetic Biomarker Prevalence Is Similar in Fecal Immunochemical Test Positive and Negative Colorectal Cancer Tissue.

BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.

Multitarget stool DNA for colorectal cancer screening: A review and commentary on the United States Preventive Services Draft Guidelines.

Multitarget stool DNA (mt-sDNA) testing was approved for average risk colorectal cancer (CRC) screening by the United States Food and Drug Administration and thereafter reimbursed for use by the Medicare program (2014). The United States Preventive Services Task Force (USPSTF) October 2015 draft recommendation for CRC screening included mt-sDNA as an "alternative" screening test that "may be useful in select clinical circumstances", despite its very high sensitivity for early stage CRC. The evidence supporting mt-sDNA for routine screening use is robust. The clinical efficacy of mt-sDNA as measured by sensitivity, specificity, life-years gained (LYG), and CRC deaths averted is similar to or exceeds that of the other more specifically recommended screening options included in the draft document, especially those requiring annual testing adherence. In a population with primarily irregular screening participation, tests with the highest point sensitivity and reasonable specificity are more likely to favorably impact CRC related morbidity and mortality than those depending on annual adherence. This paper reviews the evidence supporting mt-sDNA for routine screening and demonstrates, using USPSTF's modeling data, that mt-sDNA at three-year intervals provides significant clinical net benefits and fewer complications per LYG than annual fecal immunochemical testing, high sensitivity guaiac based fecal occult blood testing and 10-year colonoscopy screening.

USPSTF colorectal cancer screening guidelines: an extended look at multi-year interval testing.

OBJECTIVES: The US Preventive Services Task Force (USPSTF) released draft recommendations regarding colorectal cancer (CRC) screening in October 2015. Despite evidence that annual fecal blood testing test use is uncommon in screen eligible adults, with only 10.4% reporting the use of such a test in 2012, and features poor adherence over time, the USPSTF recommended only 3 noninvasive screening strategy options, all including annual fecal occult blood testing: 1) annual fecal immunochemical test (FIT) alone; 2) annual FIT in combination with flexible sigmoidoscopy every 10 years; and 3) annual high-sensitivity fecal occult blood test (hsFOBT). Mt-sDNA is the only FDA-approved CRC screening test, is covered by Medicare every 3 years, and is included as an every-3-year (3y) option in the American Cancer Society guidelines. We demonstrate that USPSTF modeling includes an embedded sensitivity analysis of less frequent than annual test adherence, which provides support for the inclusion of mt-sDNA 3y as a recommended test. STUDY DESIGN: A descriptive analysis of USPSTF modeling of the clinical impact of various stool based CRC screening strategies. METHODS: We analyzed the data generated by the USPSTF CRC screening models describing the impact of noninvasive CRC screening strategies on CRC incidence, CRC related mortality, life years gained (LYG), colonoscopy volume and associated complication, test efficiency (a measure of benefits (LYG) and harms (colonoscopies generated), and identified strategies that provide 90% or more of the LYG by screening with colonoscopy every 10 years. We compared mt-sDNA at 3y intervals and FIT and hsFOBT at 2-year (2y) and 3y intervals and did not consider annual testing. RESULTS: We found that only mt-sDNA 3y, FIT 2y, and FIT 3y were within 98% of the efficiency frontier. However, only mt-sDNA 3y generates more than 90% of the life-years gained with screening colonoscopy. These results meet the USPSTF criteria for a recommendation for mt-sDNA 3y for routine screening. CONCLUSIONS: Given poor adherence to annual testing, any screening opportunity with a test, such as mt-sDNA, that has high sensitivity for CRC and for the most significant precancerous lesions would be an important screening option for patients for maximizing screening effectiveness in reducing CRC incidence and mortality.

Screening for Colorectal Cancer Using a Multitarget Stool DNA Test: Modeling the Effect of the Intertest Interval on Clinical Effectiveness.

BACKGROUND: A multitarget stool DNA (mt-sDNA) test was recently approved for colorectal cancer (CRC) screening for men and women, aged ≥ 50 years, at average risk of CRC. The guidelines currently recommend a 3-year interval for mt-sDNA testing in the absence of empirical data. We used clinical effectiveness modeling to project decreases in CRC incidence and related mortality associated with mt-sDNA screening to help inform interval setting. MATERIALS AND METHODS: The Archimedes model (Archimedes Inc., San Francisco, CA) was used to conduct a 5-arm, virtual, clinical screening study of a population of 200,000 virtual individuals to compare the clinical effectiveness of mt-sDNA screening at 1-, 3-, and 5-year intervals compared with colonoscopy at 10-year intervals and no screening for a 30-year period. The study endpoints were the decrease in CRC incidence and related mortality of each strategy versus no screening. Cost-effectiveness ratios (US dollars per quality-adjusted life year [QALY]) of mt-sDNA intervals were calculated versus no screening. RESULTS: Compared with 10-year colonoscopy, annual mt-sDNA testing produced similar reductions in CRC incidence (65% vs. 63%) and related mortality (73% vs. 72%). mt-sDNA testing at 3-year intervals reduced the CRC incidence by 57% and CRC mortality by 67%, and mt-sDNA testing at 5-year intervals reduced the CRC incidence by 52% and CRC mortality by 62%. At an average price of $600 per test, the annual, 3-year, and 5-year mt-sDNA screening costs would be $20,178, $11,313, and $7388 per QALY, respectively, compared with no screening. CONCLUSION: These data suggest that screening every 3 years using a multitarget mt-sDNA test provides reasonable performance at acceptable cost.

Multitarget stool DNA testing for colorectal-cancer screening.

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and ß-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P=0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; ClinicalTrials.gov number, NCT01397747.).

Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT).

OBJECTIVES: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) ≥ 1 cm by sDNA and an occult blood fecal immunochemical test (FIT). METHODS: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP ≥ 1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, ß-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab ≤ 2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). RESULTS: MEDIAN AGES: cases 61 (range 57-77), controls 62 (52-70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1-3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP ≥ 1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP ≥ 1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001). CONCLUSIONS: In a screening and surveillance setting, SSP ≥ 1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.