Background and Aims Polyp size ≥1 cm triggers more frequent colonoscopic surveillance, yet size is typically based on subjective endoscopic estimates. We sought to compare contemporary assessments of ...polyp size by endoscopic estimation and pathology measurement. Methods Colonoscopy and pathology reports were reviewed from the 2012 medical records at a large institution. Only polyps resected in toto with both endoscopic estimates and pathology measurements were included. Pathology measurements were considered the criterion standard. Factors affecting endoscopic miscall rates were assessed by multivariate analyses. Results From 6067 polyps resected, both endoscopic and pathology sizes were available on 1528. Distribution of polyp size appraised by endoscopy but not by pathology revealed modal clustering, particularly around 1 cm. Among 99 polyps endoscopically called 1 cm, 72% were <1 cm on pathology. Of all 222 polyps estimated as ≥1 cm on endoscopy, 46% were <1 cm on pathology; of 1306 polyps estimated as <1 cm, 3.9% were ≥1 cm on pathology. By histology, 39% of adenomatous, 59% of sessile serrated, and 73% of hyperplastic polyps were overcalled; P = .008. By configuration, 34% of pedunculated, 49% of sessile, and 61% of flat polyps were overcalled; P = .014. Endoscopic overestimation was more common in women (54%) than in men (40%) ( P = .03) and with proximal (56%) than distal (40%) sites; P = .02. Miscall rates were unaffected by endoscopist covariates. Conclusions Substantial discordance exists between endoscopic and pathology-based assessments of polyp size. Almost half of polyps called advanced on endoscopic estimates of size ≥1 cm fell below this threshold on actual pathology measurements.
To estimate the cost-effectiveness of multitarget stool DNA testing (MT-sDNA) compared with colonoscopy and fecal immunochemical testing (FIT) for Alaska Native adults.
A Markov model was used to ...evaluate the 3 screening test effects over 40 years. Outcomes included colorectal cancer (CRC) incidence and mortality, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). The study incorporated updated evidence on screening test performance and adherence and was conducted from December 15, 2016, through November 6, 2019.
With perfect adherence, CRC incidence was reduced by 52% (95% CI, 46% to 56%) using colonoscopy, 61% (95% CI, 57% to 64%) using annual FIT, and 66% (95% CI, 63% to 68%) using MT-sDNA. Compared with no screening, perfect adherence screening extends life by 0.15, 0.17, and 0.19 QALYs per person with colonoscopy, FIT, and MT-sDNA, respectively. Colonoscopy is the most expensive strategy: approximately $110 million more than MT-sDNA and $127 million more than FIT. With imperfect adherence (best case), MT-sDNA resulted in 0.12 QALYs per person vs 0.05 and 0.06 QALYs per person by FIT and colonoscopy, respectively. Probabilistic sensitivity analyses supported the base-case analysis. Under varied adherence scenarios, MT-sDNA either dominates or is cost-effective (ICERs, $1740-$75,868 per QALY saved) compared with FIT and colonoscopy.
Each strategy reduced costs and increased QALYs compared with no screening. Screening by MT-sDNA results in the largest QALY savings. In Markov model analysis, screening by MT-sDNA in the Alaska Native population was cost-effective compared with screening by colonoscopy and FIT for a wide range of adherence scenarios.
Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case‐control and cohort studies. These demonstrations of feasibility herald the ...potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.
Minimally invasive, molecular biomarkers demonstrate feasibility for the early detection of multiple cancers in large‐scale case control and cohort studies. Here the paradigm‐changing opportunities and the challenges facing the preclinical development and clinical validation of multicancer early‐detection test strategies are discussed.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk ...patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease.
Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex.
In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively).
The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651.
Nonendoscopic Barrett's esophagus (BE) screening may help improve esophageal adenocarcinoma outcomes. We previously demonstrated promising accuracy of methylated DNA markers (MDMs) for the ...nonendoscopic diagnosis of BE using samples obtained from a capsule sponge-on-string (SOS) device. We aimed to assess the accuracy of these MDMs in an independent cohort using a commercial grade assay.
BE cases had ≥ 1 cm of circumferential BE with intestinal metaplasia; controls had no endoscopic evidence of BE. The SOS device was withdrawn 8 minutes after swallowing, followed by endoscopy (the criterion standard). Highest performing MDMs from a previous study were blindly assessed on extracted bisulfite-converted DNA by target enrichment long-probe quantitative amplified signal (TELQAS) assays. Optimal MDM combinations were selected and analyzed using random forest modeling with in silico cross-validation.
Of 295 patients consented, 268 (91%) swallowed the SOS device; 112 cases and 89 controls met the pre-established inclusion criteria. The median BE length was 6 cm (interquartile range 4-9), and 50% had no dysplasia. The cross-validated sensitivity and specificity of a 5 MDM random forest model were 92% (95% confidence interval 85%-96%) and 94% (95% confidence interval 87%-98%), respectively. Model performance was not affected by age, gender, or smoking history but was influenced by the BE segment length. SOS administration was well tolerated (median interquartile range tolerability 2 0, 4 on 10 scale grading), and 95% preferred SOS over endoscopy.
Using a minimally invasive molecular approach, MDMs assayed from SOS samples show promise as a safe and accurate nonendoscopic test for BE prediction.
We aimed to assess the concordance of colorectal cancer-associated methylated DNA markers (MDM) in primary and metastatic colorectal cancer for feasibility in detection of distantly ...recurrent/metastatic colorectal cancer in plasma.
A panel of previously discovered colorectal cancer-associated MDMs was selected. MDMs from primary and paired metastatic colorectal cancer tissue were assayed with quantitative methylation-specific PCR. Plasma MDMs were measured blindly by target enrichment long-probe quantitative-amplified signal assays. Random forest modeling was used to derive a prediction algorithm of MDMs in archival plasma samples from primary colorectal cancer cases. This algorithm was validated in prospectively collected plasma samples from recurrent colorectal cancer cases. The accuracy of the algorithm was summarized as sensitivity, specificity, and area under the curve (AUC).
Of the 14 selected MDMs, the concordance between primary and metastatic tissue was considered moderate or higher for 12 MDMs (86%). At a preset specificity of 95% (91%-98%), a panel of 13 MDMs, in plasma from 97 colorectal cancer cases and 200 controls, detected stage IV colorectal cancer with 100% (80%-100%) sensitivity and all stages of colorectal cancer with an AUC of 0.91 (0.87-0.95), significantly higher than carcinoembryonic antigen AUC, 0.72 (0.65-0.79). This panel, in plasma from 40 cases and 60 healthy controls, detected recurrent/metastatic colorectal cancer with 90% (76%-97%) sensitivity, 90% (79%-96%) specificity, and an AUC of 0.96 (0.92-1.00). The panel was positive in 0.30 (0.19-0.43) of 60 patients with no evidence of disease in post-operative patients with colorectal cancer.
Plasma assay of novel colorectal cancer-associated MDMs can reliably detect both primary colorectal cancer and distantly recurrent colorectal cancer with promising accuracy.
Surveillance for hepatocellular carcinoma (HCC) has been recommended in patients with cirrhosis. In this study, we examined the extent to which the competing risk of hepatic decompensation influences ...the benefit of HCC surveillance by investigating the impact of availability of liver transplantation (LTx) and the rate of progression of hepatic decompensation on survival gain from HCC surveillance. A multistate Markov model was constructed simulating a cohort of 50‐year‐old patients with compensated cirrhosis. The primary outcome of interest was all‐cause and HCC‐specific mortality. The main input data included incidence of HCC, sensitivity of screening test, and mortality from hepatic decompensation. Treatment modalities modeled included LTx, resection, and radiofrequency ablation. In the base case scenario, LTx would be available to prevent death in a certain proportion of patients. In the absence of surveillance, 68.2% of the cohort members died within 15 years; of these decedents, 25.1% died from HCC and 43.6% died from hepatic decompensation. With surveillance, the median survival improved from 10.4 years to 11.2 years. The number of subjects under surveillance needed to reduce one all‐cause and one HCC‐specific death over 15 years was 28 and 18, respectively. In sensitivity analyses, incidence of HCC and progression of cirrhosis had the strongest effect on the benefit of surveillance, whereas LTx availability had a negligible effect. Conclusion: HCC surveillance decreases all‐cause and tumor‐specific mortality in patients with compensated cirrhosis regardless of LTx availability. In addition, incidence of HCC and sensitivity of surveillance test also had a substantial impact on the benefits of surveillance. (Hepatology 2018;68:78‐88).
Abstract
Background and Aims
The FDA-approved multitarget stool-DNA mt-sDNA test is a successful colorectal cancer CRC screening tool in average-risk individuals but is not indicated for patients ...with inflammatory bowel disease IBD. We determined the performance of the mt-sDNA assay without the haemoglobin component mt-sDNAHgb- in patients with IBD, while measuring sensitivity for colorectal cancer and advanced colorectal neoplasia ACRN.
Methods
This was a multi-centre, proof-of-concept investigation in persons aged 18–84 years with a diagnosis of IBD, or primary sclerosing cholangitis PSC with IBD. Enrolment occurred between March 2013 and May 2016. Stool was tested with the mt-sDNA molecular markers only, minus the immunochemical haemoglobin component.
Results
The analysis set contained 355 samples. The median age was 52 range 39–62 years, 45.6% were female and 93% were White. Two-thirds 63% had ulcerative colitis UC and 10.1% had PSC/IBD. Colonoscopy revealed cancer in 8.5% N = 30, advanced precancerous lesions APLs in 9.3% N = 33 and non-advanced precancerous lesions in 7.6% N = 27, and three-quarters 74.7%, N = 265 had negative findings. mt-sDNAHgb- sensitivity was 73.3% for any stage cancers, and 76.2% for ACRN. Sensitivity was highest for IBD-associated high-grade dysplasia at 100% and 84.6% for IBD-associated low-grade dysplasia ≥1 cm. The test showed higher sensitivity and lower specificity in UC than in Crohn’s disease. Increasing inflammation score was associated with a significant decrease in mt-sDNAHgb- test score = 0.028 amongst neoplasia-negative individuals, but not in patients with ACRN.
Conclusions
These data highlight the potential of multitarget stool-DNA marker testing as an important addition to colorectal cancer surveillance by complementing colonoscopic evaluations in IBD patients.
Graphical Abstract
Graphical Abstract
We aimed to assess whether endometrial cancer (EC) can be detected in shed DNA collected with vaginal tampon by analyzing copy number, methylation markers, and mutations.
Tampons were collected prior ...to hysterectomy from 38 EC patients and 28 women with benign indications. Extracted tampon DNA underwent the following: 1) low-coverage whole genome sequencing (LC-WGS) to assess copy number, 2) pyrosequencing to measure percent promotor methylation of HOXA9, RASSF1, and CDH13 and 3) next generation sequencing (NGS) to identify mutations in 19 genes associated with EC identified through The Cancer Genome Atlas. Sensitivity and specificity for each test and test combinations were calculated.
Methylation analysis yielded the highest specificities but lowest sensitivities (37–40% sensitivity; 100% specificity for HOXA9, RASSF1 and HTR1B) while mutation analysis had improved sensitivity (50% sensitivity; 83% specificity). Only one “false positive” result for copy number variants was identified among women with benign surgical indications, which was based on detection of copy number changes, and associated with a leiomyosarcoma that was only recognized at hysterectomy. Considering any of the 3 biomarker classes as a positive, resulted in a sensitivity of 92% and specificity of 86%. Mutation analysis did not add sensitivity to the combination of analysis of copy number and methylation.
This study demonstrates a proof-of-principle for non-invasive yet precise detection of endometrial cancer. We propose that with improved biomarker testing, it may be possible to develop a clinically useful test for detecting EC.
•A combined CNV, methylation, and mutation panel in tampon samples is sensitive and specific for endometrial cancer.•This sensitivity and specificity is preserved with the combination of CNV and methylation alone.•One patient with a clinically unsuspected leiomyosarcoma diagnosed at hysterectomy yielded a false positive via CNV.
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