Blood-based Screening Test Research Articles

Cost-Effectiveness of Serum Pepsinogen as a Gastric Cancer Targeted Screening Strategy in the United States

Background and AimsCurrent gastric cancer (GC) screening modalities are invasive and expensive. Noninvasive screening for GC precursors with serum pepsinogen (PG) may improve early detection and prevention. Test characteristics of PG based on US prospective data was recently reported and used to study the cost-effectiveness of PG screening versus no screening in the US. MethodsA patient-level state transition microsimulation of gastric adenocarcinoma analyzed noninvasive screening versus no screening in a hypothetical cohort of average risk US individuals. Primary outcomes included life expectancy, quality-adjusted life years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs). Secondary outcomes included total GC incidence and mortality. Base-case PG sensitivity and specificity were 34.1% and 94.7%, respectively, with a wide range of PG performance characteristics also examined. ResultsOne-time serum PG screening at age 40 was cost-effective compared to no screening with an ICER of $4,913.29 per QALY. PG screening resulted in 10.9% relative reduction in lifetime GC incidence and 10.8% relative decrease in cumulative GC mortality. Localized stage at diagnosis increased from 30.5% to 33.6% and metastatic stage decreased from 40.8% to 37.4%. Sensitivity analysis showed PG screening was most sensitive to endoscopy costs, chronic atrophic gastritis quality of life, and PG prevalence. PG screening remained cost-effective across a wide range of test values. ConclusionPG screening is a cost-effective strategy to improve GC mortality, however, mortality benefit will depend on the test characteristics of the biomarker. Future blood-based screening tests that have better performance characteristics could further improve GC prevention.

S558 Test Performance and Lesion Characteristics in a Large Clinical Validation Study of a Blood-Based Screening Test for the Early Detection of Colorectal Cancer

S558 Test Performance and Lesion Characteristics in a Large Clinical Validation Study of a Blood-Based Screening Test for the Early Detection of Colorectal Cancer

A blood-based screening test for colorectal cancer (CRC) using methylation sequencing.

e15089 Background: Diagnosis of CRC is biased towards later stages in India (3.8% Stage I, 16.7% Stage II, 50.7% Stage III, 28.8% Stage IV), and five-year survival at < 40% is one of the lowest in the world. A blood-based non-invasive screening test for CRC using cell-free DNA (cfDNA) methylation sequencing is developed here from the blood of 212 controls and 67 treatment naive CRC patients from 21 sites across India and processed in Strand’s reference lab in Bangalore. Methods: Steps involved cfDNA extraction, NEB Enzymatic Methyl-Seq library preparation, Twist Human Methylome hybridisation capture, 2x150bp sequencing on NovaSeq 6000/X. Methylation + fragmentomic features were calculated for each target region. Samples were split randomly into a leave-in set of 170 controls + 53 cancers (I: 8, II 16, III: 23, IV: 6) and a leave-out set of 42 controls + 14 cancers, (I: 5, II: 4, III: 2, IV: 3) with 20 rounds of 4-fold cross-validation done on the leave-in set (random splits). Feature selection per fold was performed using the KS test without access to ¼ of the leave-in set and to the entire leave-out set. Gradient boosted trees with monotonic constraints reflecting the expected association of the scores with cancer were used to build “explainable” models. Test robustness was assessed using differentially methylated regions (DMRs) from other studies, and by assessing predictability using sample metadata alone. Results: At a 91% specificity level, the ensemble model had a median sensitivity of 62.5% for Stage I (95%CI 38%-86%), 87% for Stage II (95% CI 75%-95%), 87% for Stage III (95% CI 75%-95%) and 83.4% for Stage IV (95% CI 84%-100%) in cross-validation, and 60% for Stage I (95%CI 60%-80%), 100% for Stage II (95% CI 80%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 100%-100%) on the leave-out set. At a ~98% specificity level, the model had a median sensitivity of 37.5% for Stage I (95%CI 37%-50%), 69% for Stage II (95% CI 56%-75%), 69% for Stage III (95% CI 60%-84%) and 67% for Stage IV (95% CI 50%-84%) in cross-validation, and 40% for Stage I (95%CI 20%-60%), 75% for Stage II (95% CI 75%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 66%-100%) with a slight decrease in specificity to 95.2% on the leave-out set. Using DMRs derived from TCGA data and other publications, yielded a comparable (to our models) cross-validation area under the curve (AUC: 0.93-0.95). Cross-validation performance using only the sample metadata in table 1 and without access to the data was significantly poorer (AUC 0.75-0.81). Conclusions: cfDNA-based methylation profiles are consistent across studies and ethnicities, leading to robust and “explainable” CRC screening predictions. [Table: see text]

Blood-based colorectal cancer screening in an integrated health system: a randomised trial of patient adherence

ObjectiveWe evaluated whether people who had not completed a faecal immunochemical test (FIT) for colorectal cancer (CRC) screening would complete a blood-based testing option if offered one during health encounters....

Enhanced blood-based colorectal cancer screening with improved performance in detection of early stage disease.

68 Background: Blood based colorectal cancer (CRC) screening has been validated for use in average risk populations (ECLIPSE NCT#04136002; Guardant Health, USA). Here we present the performance of an enhanced version of a blood-based screening test developed to optimize detection of low shedding tumors by leveraging epigenomic features of cell-free DNA (cfDNA). Test performance was assessed across screen-relevant individuals from the intended use population, including a collection of screen-detected CRC and enriched cohort of individuals with endoscopy finding of CRC. Methods: We trained a regression model to classify whether aberrant cfDNA originated from individuals with CRC or non-ACN individuals and compared performance to an original model in a fixed set of screen-relevant samples sequenced to a median of 11M reads per sample across a panel approximately 1Mb in size. Model optimization focused on identifying training settings and samples to maximize detection of low shedding screen-relevant tumors and introduced noise reduction techniques to minimize technical variation. The final enhanced model was trained in over 4500 samples; the calling cut-off was set targeting 90% specificity in the average-risk population following US-Census age distribution. Analytical Limit of Detection (LoD) was estimated using ~5,000 in silico dilution samples generated from blood samples from 25 CRCs and ~1,650 non-ACNs. Results: This training approach yielded a 2X improvement in the analytical LoD95 (0.004% vs 0.008%) compared to the original model validated in the ECLIPSE trial. The model also yielded an increase in overall CRC clinical sensitivity from 84% to 91%, N=45, with notable sensitivity improvement from 76% to 88% in detecting early localized stage I/II CRC, N = 25, while maintaining specificity at 91%. Conclusions: This enhanced cfDNA-based CRC screening blood test shows improved performance in early stage CRC detection demonstrating the potential of continuous improvement in the performance of cfDNA-based screening tests powered by data and clinical insights.

"I was screaming hallelujah": Patient and provider perceptions of blood-based testing for colorectal cancer screening.

Blood-based tests for colorectal cancer (CRC) screening can offer many advantages over stool-based tests such as FIT. Yet, we know little about patients' and providers' perceptions of this type of test. We report findings from a qualitative study comparing patient and provider perceptions of blood-based testing for CRC screening. Patient participants were aged 45-75 years and members of a large, integrated health system. Participants were mailed, but did not complete, a FIT through an organized FIT-screening program and were scheduled for a health-care encounter at any of nine clinical sites. Participants were consented to complete a blood draw. We used purposive sampling to select and recruit patients (who did and did not complete the blood test) and providers/specialists who would be involved in offering the blood test to patients or explaining results. We administered telephone interviews using a semi-structured interview guide and recorded and transcribed all interviews, then coded and analyzed content. We interviewed 15 patients (11 completed and 4 did not complete the blood test) and 5 providers (3 primary care providers, one gastroenterologist (GI), and one GI medical assistant). Patients were enthusiastic about completing a blood test, citing the simplicity, ease, convenience, and high perceived accuracy of the test. Providers were also receptive to a blood-based option, if adequate test performance could be achieved and if they have information that informs patients about the pros and cons of blood-based screening versus other screening tests. Patients and providers were willing and enthusiastic about blood-based CRC screening tests. Future research focusing on performance and communication is needed.

Assessment of the Cepheid 3-gene Host Response Fingerstick Blood Test (MTB-HR) on rapid diagnosis of tuberculosis

ABSTRACT The World Health Organization has identified high-priority target product profiles for new TB diagnostics which include rapid biomarker-based, non-sputum-based diagnostic testing, using an easily accessible sample. The Cepheid 3-gene Host Response Fingerstick Blood Prototype Test (MTB-HR) quantifies relative mRNA levels of a 3-gene signature (GBP5, DUSP3, and KLF2) from a whole-blood sample on the GeneXpert platform. The objective of the present study was to evaluate the performance of the MTB-HR to distinguish between active tuberculosis (ATB), latent Mycobacterium tuberculosis infection (LTBI), other pulmonary diseases, and healthy volunteers at a tertiary care centre. Among 653 participants enrolled in this study, 192 were diagnosed as having ATB, and the remaining 461 were classified as non-ATB, including 137 cases of LTBI, 224 cases of other pulmonary diseases, and 100 healthy volunteers. The corresponding AUCs of the MTB-HR in distinguishing untreated ATB from non-ATB, LTBI, other pulmonary diseases, and healthy volunteers were 0.814 (95% CI, 0.760-0.868, sensitivity 76.1%, specificity 71.6%), 0.739 (95% CI, 0.667-0.812, sensitivity 59.7%, specificity 78.1%), 0.825 (95% CI, 0.770-0.880, sensitivity 82.1%, specificity 65.6%), 0.892 (95% CI, 0.839-0.945, sensitivity 76.1%, specificity 88.0%), respectively. When only samples with TAT of less than 1 h were included, the AUC of the MTB-HR in distinguishing untreated ATB from non-ATB was largest, 0.920 (95% CI, 0.822-1.000, sensitivity 81.3%, specificity 87.7%). In conclusion, the MTB-HR assay shows potential as a rapid, blood-based screening and triage test for ATB, especially for untreated ATB, with the advantage of increased diagnostic yield since blood is more readily available.

A plasma protein signature associated with cognitive function in men without severe cognitive impairment

BackgroundA minimally invasive blood-based assessment of cognitive function could be a promising screening strategy to identify high-risk groups for the incidence of Alzheimer’s disease.MethodsThe study included 448 cognitively unimpaired men (mean age 64.1 years) drawn from the Geelong Osteoporosis Study. A targeted mass spectrometry-based proteomic assay was performed to measure the abundance levels of 269 plasma proteins followed by linear regression analyses adjusted for age and APOE ε4 carrier status to identify the biomarkers related to overall cognitive function. Furthermore, two-way interactions were conducted to see whether Alzheimer’s disease-linked genetic variants or health conditions modify the association between biomarkers and cognitive function.ResultsTen plasma proteins showed an association with overall cognitive function. This association was modified by allelic variants in genes ABCA7, CLU, BDNF and MS4A6A that have been previously linked to Alzheimer’s disease. Modifiable health conditions such as mood disorders and poor bone health, which are postulated to be risk factors for Alzheimer’s disease, also impacted the relationship observed between protein marker levels and cognition. In addition to the univariate analyses, an 11-feature multianalyte model was created using the least absolute shrinkage and selection operator regression that identified 10 protein features and age associated with cognitive function.ConclusionsOverall, the present study revealed plasma protein candidates that may contribute to the development of a blood-based screening test for identifying early cognitive changes. This study also highlights the importance of considering other risk factors in elucidating the relationship between biomarkers and cognition, an area that remains largely unexplored.

Understanding patient acceptance and compliance of a blood-based colorectal cancer screening test.

TPS6654 Background: The Covid-19 pandemic has caused a significant disruption in healthcare utilization. The halt and delay of CRC screening have led to a substantial decline in CRC screening rates. The backlog and the slow resuming of CRC screening will have significant consequences. Although COVID-19 created challenges in CRC screening, it also presents an opportunity for potential innovative approaches that may improve patient compliance and screening rates, such as a blood-based CRC screening test which can be done at the point of care without preparation. Adherence to CRC screening is poor among vulnerable populations even before COVID-19, and these populations disproportionately receive health care in safety-net settings, such as federally qualified health centers (FQHCs). Thus, FQHCs play a significant role in improving CRC-related outcomes and ensuring health equity. This study will examine patient compliance with CRC screening by offering another option, a blood-based screening test, after failing to complete a stool-based screening test or colonoscopy in six months at three FQHCs. Methods: The study will use a stepped wedge cluster trial design and include an initial period of no exposure. Each FQHC will have a cluster of 10 to 17 primary care clinics. After the initial no-exposure period, two FQHCs will implement a blood-based CRC screening test at their primary care clinics. Another FQHC will follow nine months later. Each FQHC will contribute to exposed and unexposed observations and function as its own control. This study will collect quarterly data to capture the impact, feasibility, and acceptability over time. The primary endpoint will be assessed by calculating the number of participants who, otherwise, will not have participated in the CRC screening. In addition, the effectiveness of the implementation strategies will be assessed since transferring innovations into real-world settings is complex, and practical strategies are critical to accelerating future implementation and assisting decision-making. The study will recruit patients who fail to complete a CRC screening after six months and meet the inclusion criteria: between 45-75 years of age, average risk for CRC, capable of and willing to give informed consent, and willing to provide a blood sample. For eligible patients, a blood-based CRC screening test developed by a CLIA-certified laboratory and made commercially available (Guardant Health, CA) will be offered at no cost. An order will be obtained from the participant’s primary care provider before the blood sample is collected. This study plans to enroll up to 2,400 patients over a 3-year period. Patient compliance is a significant barrier to improving CRC screening, and the key to increasing screening participation is patient acceptance of the screening method. A blood-based screening test may offer an alternative for patients who fail to comply with other CRC screening modalities. Clinical trial information: NCT05536713 .

Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population.

3069 Background: Globally, cancer results in 10.08 million deaths per year. A single blood-based screening tool that detects multiple cancer types could significantly reduce cancer burden. We systematically reviewed and statistically examined both the accuracy and applicability of blood-based MCED tests to strategize their utilization in improving cancer detection. Methods: Original articles were searched from PubMed, Cochrane, and Embase for blood-based screening tests analyzing multiple cancer types and asymptomatic human subjects. We excluded studies with small sample sizes (n<30), hypothesis-generating/diagnostic tests, and non-blood-based tests. For cfDNA-based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Results: Of 1,074 records identified and screened, 15 case-control and 4 cohort studies were analyzed, most of which utilized cfDNA-based diagnostic tests. Twelve cfDNA studies selected for meta-analysis had pooled sensitivity of 0.623 (95%CI 0.517 - 0.719) and specificity of 0.975 (0.942 - 0.990). Summary ROC curve shows variability in sensitivity and specificity between studies. However, sensitivity and specificity were not affected by study type, gender, or assay type. Sensitivity was higher for advanced staged cancers (III/IV 0.774 (0.697 - 0.837)) than early-stage cancers (I/II 0.503 (0.366 - 0.639)). Among cancer types, no significant differences were detected. Lastly, false positive and false negative rates were 0.025 (0.010 - 0.058) and 0.447 (0.438 - 0.456), respectively. Conclusions: Given high sensitivities and specificities, MCED tests show promise as additional screening tools. However, in the general population, misdiagnosis burden from false positive and negative rates is anticipated. Although multiple barriers exist to their application in the clinic, MCED tests may improve patient outcomes for cancers with no conventional screening tools and provide additional credibility when combined with existing tools. Future prospective studies with large and diverse populations are warranted. [Table: see text]

Cost-effectiveness of ColoSTAT for primary colorectal cancer screening in the United States.

e15525 Background: Colorectal cancer (CRC) screening is at the cornerstone of strategies for reducing the mortality, healthcare and societal cost burden of CRC, the third most common cancer in the United States (US). ColoSTAT immunoassay is a simple, highly accurate, minimally invasive blood-based screening test for CRC that will be launched in the US market. Using a de novo decision analytic model, we compared the health benefits and cost-effectiveness of CRC screening with ColoSTAT with current screening offered by private insurers assuming a 5-yearly colonoscopy (COL) or biennial fecal immunochemical test (FIT) for the US population. Methods: For the three screening strategies, the expected number of CRC cases detected, and total screening program cost were estimated using a decision-analytic model based on: published CRC incidence in the US, tests performance characteristics, adherence rates to screening (61% for COL; 46% for FIT) and to diagnostic assessment via COL after a positive FIT or ColoSTAT test (80.4%). The gain in quality-adjusted life year (QALY) associated with every CRC case detected through screening, and confirmed by diagnostic assessment, was estimated by linking US-specific estimates of: CRC deaths by age-subgroups, life expectancies at the time of CRC death, quality of life projections for the general population and reduction in CRC mortality associated with screening. Healthcare cost savings associated with every CRC case detected through screening were estimated based on the distribution of CRC across disease stages by diagnosis method (screening versus symptomatically) and stage-specific CRC treatment costs. Results: Biennial screening with ColoSTAT, compared with 5-yearly COL screening offered by private insurers, is estimated to generate cost savings on screening programs of around $40 million per 100,000 people of screening age (PoSA) per one-off screening. When scaled up to the total US population within screening age covered by private insurance (66%), the estimated cost savings with ColoSTAT exceed $30 billion per one-off screening. The reduction in the number of CRC cases detected would generate a modest loss of 58 discounted QALYs per 100,000 people, that could be mitigated if ColoSTAT were to boost screening uptake. In the context of government-sponsored screening programs, replacing FIT with ColoSTAT is estimated to increase the number of CRC cases detected via screening by 9% (to 50 cases per 100,000 PoSA), assuming an unchanged screening uptake of 46%. At the commonly used value of $100,000 per QALY, this would equate to a discounted benefit of $834,820 per 100,000 PoSA per one-off screening. Conclusions: CRC screening with ColoSTAT as an alternative to COL could result in multi-billion-dollar cost savings to US private insurers while still detecting most CRC cases and generate population-health gains if used as an alternative to FIT in government-sponsored screening programs.

Systematic review and meta-analysis of accuracy of tumor origin detection in blood cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) assays in the general population.

e15053 Background: Among recently developed blood-based MCED tests, the ability to determine the location of tumors is pivotal to guiding appropriate treatment. We systematically reviewed and statistically examined the accuracy of tumor of origin predictions among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n < 30), non-screening, and non-blood-based tests. For cfDNA-based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Results: Of 1,074 records identified and screened, five case-control studies and one cohort study that used cfDNA-based diagnostic tests were analyzed. Accuracy of tissue-of-origin (TOO) prediction for 3,895 cancer samples across cancer types was 0.79 (95% CI 0.66 - 0.90). Among six cancer types, colorectal cancers had the highest accuracy and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). The information for localizing TOO was derived from methylation patterns of cfDNA in four studies, fragmentation profiles of cfDNA in another study, and combination of mutations in cfDNA and protein markers in the last study. Conclusions: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, performance varies across cancer types. Further research on performance based on cancer stages and in combination with other molecular profiling is warranted. [Table: see text]

Abstract 783: Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population

Abstract Background: Globally, cancer results in 10.08 million deaths per year. A single blood-based screening tool that detects multiple cancer types could greatly reduce cancer burden. We aim to systematically review and statistically examine both the accuracy and applicability of blood-based MCED tests to strategize their utilization in improving cancer detection. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests analyzing multiple cancer types and asymptomatic human subjects. We excluded studies with small sample size (n<30), hypothesis-generating tests, and non-blood based tests. For cell-free DNA (cfDNA) based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Findings: Of 1,074 records screened, 10 case-control and 6 cohort studies were analyzed, most of which utilized cfDNA-based diagnostic tests. Ten cfDNA studies selected for meta-analysis had a joint sensitivity of 0.66 (95%CI 0.54-0.75) and specificity of 0.98 (0.94-0.99) with an area under the curve of 0.883. For cohort studies, the joint positive and negative predictive values were 0.96 (0.29-1.00) and 0.81 (0.37-0.97) respectively. Sensitivity was higher for advanced staged cancers (III/IV 0.84 (0.84-0.86)) with breast cancer having the lowest sensitivity (0.42 (0.31-0.55)). Sensitivity and specificity were not affected by study type, gender, or assay type. Lastly, accuracy of tumor origin prediction was 0.792 (0.64-0.91) without significant differences across cancer types. Interpretation: Given high sensitivities and specificities, MCED tests show promise as additional screening tools. Although there exist multiple barriers to their application in clinic, MCED tests may improve patient outcomes for cancers with no conventional screening tools. Future prospective studies with large and diverse populations are warranted. Summarization of meta-analysis results on cfDNA based multi cancer early detection tests Sensitivity Specificity DOR PPV NPV No. of study included 10 10 10 4 4 Events/Total 5778/10033 14797/15020 Experimental group: 5778/6001 901/1373 10148/11216 Control group: 4202/19052 Proportion (95% CI) 0.652 [0.537; 0.751] 0.978 [0.936; 0.992] 69.290 [25.208; 190.457] 0.961 [0.293; 0.999] 0.812 [0.365; 0.970] Heterogeneity (p value) 98% (<0.01) 97% (<0.01) 96% (<0.01) 99% (<0.01) 100% (<0.01) Abbreviations: CI = confidence interval; DOR = diagnostic odds ratio; PPV = positive predictive value; NPV = negative predictive value Citation Format: Joo Hee Park, Youjin Oh, Liam Il-Young Chung, Richard Duan, Trie A. Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Young Kwang Chae. Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 783.

Abstract 995: Evaluation of plasma cytokines and chemokines as potential biomarkers for colorectal cancer detection

Abstract Despite evidence suggesting that current Colorectal Cancer (CRC) screening strategies reduce mortality rates, screening compliance is suboptimal; for this, our study aimed to evaluate the discriminatory potential of plasma cytokine and chemokine levels for CRC detection in plasma samples in a Hispanic subpopulation. Using a retrospective case-control study design, we evaluated plasma samples in 20 CRC cases and 20 age-gender matched controls from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). BD CBA Human Th1/Th2/Th17 Cytokine and Human Chemokine kits were used to prepare plasma samples for flow cytometric analysis (Becton-Dickinson & Co). Mann-Whitney-U test was used to detect differences between biomarkers and case-control groups. Measures of diagnostic accuracy were estimated for comparisons according to CRC disease stage. We compared multivariable models to determine the best CRC case-classifier. The median levels of six of the cytokines evaluated (IL-2, IL-4, IL-6, IL-10, TNF, and IL-17A) and one chemokine (CXCL10-/IP-10) significantly differed between cases and controls (P<0.05). ROC plots and logistic regression analysis showed that these seven biomarkers displayed good to excellent accuracy (AUC: 0.6-0.9). Multivariate analysis showed that the best-case classifying model included the seven statistically significant markers. Our findings suggest that discriminatory biomarker levels between CRC cases and controls observed show their great potential as targets in novel blood-based screening tests for CRC. The development of a non-invasive CRC screening test will provide an alternative to increasing adherence, early detection, survivorship, and a tool for a population-based prevention strategy approach. Citation Format: Elba V. Caraballo, Hilmaris Centeno-Girona, Yilda Macias, Madeline M. Mártir Ocasio, Marcia R. Cruz-Correa. Evaluation of plasma cytokines and chemokines as potential biomarkers for colorectal cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 995.

Abstract 784: Systematic review and meta-analysis of the accuracy of tumor origin detection in blood-based multi-cancer early detection (MCED) in the general population

Abstract Background: Among the recently developed blood-based multi-cancer early detection (MCED) tests, determining the location of tumors is pivotal to guiding appropriate treatment. We aim to systematically review and statistically examine the accuracy of tumor of origin prediction among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase that featured blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n<30), non-screening tests, and non-blood-based tests. For cell-free DNA (cfDNA) based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Findings: Of 1,074 records identified and screened, 4 cohort studies were analyzed using cfDNA-based diagnostic tests. The accuracy of tissue-of-origin (TOO) prediction for 3,762 cancer samples across cancer types was 0.79 (95% CI 0.64 - 0.91). Among six cancer types, colorectal cancers had the highest accuracy, and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). Lastly, two studies reported increased prediction accuracies when two sites of origin were assigned rather than a single site. The information for localizing TOO was derived from methylation patterns of cfDNA in two studies, fragmentation profiles of cfDNA in another study, and protein markers in the other research. Interpretation: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, the performance varies across cancer types. Further research on performance according to cancer stages and in combination with other molecular profiling is warranted. Table 1. Events/Total Accuracy of prediction (95% CI) misclassification type freqeuncy Total 3,129/3,762 0.79 (0.64 - 0.91) Colorectal 638/723 0.89 (0.79 - 0.97) stomach & esophagus 26/553 breast 8/553 Breast 443/538 0.86 (0.64 - 0.99) colorectal 20/349 pancreas & GB 4/349 lung 4/349 Ovarian Breast 132/159 0.85 (0.62 - 0.99) colorectal 39/261 uterus 13/147 Pancreatic & GB 289/338 0.82 (0.69 - 0.93) colorectal 12/300 stomach & esophagus 10/300 Stomach & Esophagus 225/311 0.75 (0.48 - 0.95) colorectal 39/261 lung 10/261 Lung 530/656 0.72 (0.45 - 0.92) colorectal 29/560 head and neck 8/560 Liver & Bile duct 95/144 0.68 (0.40 - 0.90) colorectal 13/220 pancreatic & GB 8/220 Abbreviations: CI = confidence interval; GB = gallbladder Citation Format: Youjin Oh, Joo Hee Park, Liam Il-Young Chung, Richard Duan, Trie Arni Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Horyun Choi, Young Kwang Chae. Systematic review and meta-analysis of the accuracy of tumor origin detection in blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 784.

Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer's Disease.

Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N. Plasma Aβ42/Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ42/Aβ40 to predict amyloid PET positivity in A4 Study participants. Plasma Aβ42/Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.

Cost effectiveness of liquid biopsy for colorectal cancer screening.

73 Background: Despite established screening guidelines, adherence to colonoscopy is approximately 60%. Blood-based screening tests, or Liquid Biopsies (LB), have the potential to close this screening gap. Our aim was to determine the cost-effectiveness of LB tests for CRC screening in the US. Methods: We developed a Markov model to compare four CRC screening strategies: no screening, or natural history (NH), colonoscopy (Colo) only, LB only, and colonoscopy to LB hybrid (C-LB). US SEER CRC incidence and mortality data were used to develop and validate the model. Many LB tests are in development awaiting validation; we used the preliminary performance characteristics for CRC screening of 82% sensitivity and 99.5% specificity (base case) from the Galleri multi-cancer early detection test (GRAIL). Screening ran from age 45 to 75; polyp surveillance ended at 85. We assumed 60.6% of the US population would undergo a screening colonoscopy, and 100% adherence for LB. In Colo, nonadherent patients were not offered other screening; in C-LB those who refused colonoscopy underwent LB. Primary outcomes were overall survival, total cost, incremental cost-effectiveness ratio (ICER), number of CRCs, and CRC deaths. Results: In the NH strategy, 5.2% of the population developed CRC and 1.8% died from CRC, with a cost of $7,802.15/individual. Compared to NH, in Colo, 40% of CRCs and 44% of CRC deaths were prevented, at a cost of $10,610.43/individual. In C-LB, 42% of CRCs and 50% of CRC deaths were prevented compared to NH, costing $13,762.61/individual. LB only prevented 2.0% of CRCs and 11% of CRC deaths compared to NH, and cost $34,339.85/individual. While LB showed an incremental benefit of 0.01 life years gained compared to NH, the ICER compared to NH is $2,653,770. Colo was most cost-effective with an ICER of $30,191.04. Although C-LB prevented the greatest number of CRCs, this strategy had an ICER of $457,057.64, above the accepted US willingness to pay threshold of $100,000/life year. We performed sensitivity analysis around base case estimates for LB. At both 70% and 90% test sensitivity, all outcomes remained largely constant. Conclusions: CRC screening with LB alone or with LB in conjunction with colonoscopy among nonadherent patients is not cost-effective in the US context. At this time, LB is unable to detect pre-cancerous colon polyps, which may limit its effectiveness as a CRC screening strategy. [Table: see text]

Contextualizing and optimizing novel strategies to improve the latent TB continuum of care: Insights from people living with HIV and health care providers in Brazil.

Tuberculosis (TB) causes 1 in 3 deaths among people living with HIV (PLHIV). Diagnosing and treating latent tuberculosis infection (LTBI) is critical to reducing TB incidence and mortality. Blood-based screening tests (e.g., QuantiFERON-TB Gold Plus (QFT+)) and shorter-course TB preventive therapy (TPT) regimens such as 3HP (3 months weekly isoniazid-rifapentine) hold significant promise to improve TB outcomes. We qualitatively explored barriers and solutions to optimizing QFT+ and 3HP among PLHIV in three cities in Brazil. We conducted 110 in-depth interviews with PLHIV, health care providers (HCP) and key informants (KI). Content analysis was conducted including the use of case summaries and comparison of themes across populations and contexts. LTBI screening and treatment practices were dependent on HCP's perceptions of whether they were critical to improving TB outcomes. Many HCP lacked a strong understanding of LTBI and perceived the current TPT regimen as complicated. HCP reported that LTBI screening and treatment were constrained by clinic staffing challenges. While PLHIV generally expressed willingness to consider any test or treatment that doctors recommended, they indicated HCP rarely discussed LTBI and TPT. TB testing and treatment requests were constrained by structural factors including financial and food insecurity, difficulties leaving work for appointments, stigma and family responsibilities. QFT+ and 3HP were viewed by all participants as tools that could significantly improve the LTBI cascade by avoiding complexities of TB skin tests and longer LTBI treatment courses. QFT+ and 3HP were perceived to have challenges, including the potential to increase workload on over-burdened health systems if not implemented alongside improved supply chains, staffing, and training, and follow-up initiatives. Multi-level interventions that increase understanding of the importance of LTBI and TPT among HCP, improve patient-provider communication, and streamline clinic-level operations related to QFT+ and 3HP are needed to optimize their impact among PLHIV and reduce TB mortality.

S287 Comparison of Cost-Effectiveness Outcomes Between a Novel Multitargeted Stool-Based RNA Test and Alternative Non-Invasive Stool and Blood Tests for Colorectal Cancer Screening

Introduction: Colorectal cancer (CRC) mortality has been significantly mitigated by increased CRC screening via colonoscopy. Colonoscopy has low compliance rates due to invasiveness, procedure-associated risks, bowel preparation, and time requirements. Existing non-invasive screening methods are limited by relatively low sensitivity for precancerous lesions, especially advanced adenomas (AAs). Using a Markov model, cost-effectiveness outcomes were compared between a novel multitargeted stool RNA (mt-sRNA) test, existing stool-based screening tests (fecal immunochemical test [FIT], and multitarget stool DNA [mt-sDNA]), no screening, and a recently introduced triennial blood-based screening test. Methods: The Markov model compared morbidity, mortality, and cost using 1,000 average-risk patients 45-75 years of age over a 30-year time horizon. The model input included test-specific sensitivity and specificity with a fixed incidence and prevalence of CRCs/AAs to assess lesion detection rates across each screening method. Reimbursement rates were assumed equal for blood, mt-sDNA, and mt-sRNA tests ($508). Data on distribution across disease stages and five-year survival rates predicted long-term outcomes for patients with CRC. The model accounts for the cost of screening, complications associated with colonoscopy, surveillance/follow-up requirements, and the cost of CRC treatment. For the primary analysis, adherence was assumed to be 100%. For secondary research, adherence was set at 40%, 60%, and 80%. Results: At 100% adherence, the mt-sRNA test resulted in an additional reduction in CRC cases by 68.1% (blood test), 42.5% (mt-sDNA test), 30.8% (FIT test), and 82.1% (no screening). The mt-sRNA screening strategy also resulted in the reduction of deaths by 64.7% (blood test), 39.8% (mt-sDNA test), 29.8% (FIT test), and 78.3% (no screening). When adherence is set at 40%, 60%, or 80%, use of the mt-sRNA test results in an increased number of pre-cancerous adenomas detected relative to all other screening strategies. Incremental costs associated with the mt-sRNA test were intermediary with higher costs associated with follow-on colonoscopy/surveillance, and lower costs associated with CRC treatment. Conclusion: This model suggests that CRC screening tests that target advanced adenomas detection have superior cost-effectiveness due to better cancer prevention. The mt-sRNA test is a more cost-effective alternative for colorectal cancer screening in the average-risk population than other non-invasive strategies (Table). Table 1. - Cost-effectiveness of mt-sRNA against other screening modalities at variable adherence rates, per 1000 patients over a 30-year time horizon Adherence rate mt-sRNA test vs. Incremental CRC cases prevented CRC cases reduction (%) CRC deaths reduction (%) Incremental costs per CRC case prevented Incremental costs per CRC case prevented 40% for all tests Blood test 14 39.5% 35.1% -$175,379 -$311,289 mt-sDNA 6 22.7% 19.9% -$168,747 -$302,667 FIT 6 21.2% 19.0% $8,666 $14,681 No screening 20 48.1% 42.8% $67,232 $122,252 60% for all tests Blood test 16 51.5% 47.0% -$182,381 -$309,202 mt-sDNA 7 30.8% 27.7% -$178,940 -$293,907 FIT 5 23.0% 21.2% $188,435 $296,188 No screening 27 63.6% 58.3% $29,789 $52,683 80% for all tests Blood test 17 60.3% 56.2% -$188,028 -$306,278 mt-sDNA 7 37.2% 34.2% -$182,141 -$284,899 FIT 4 26.1% 24.6% $409,606 $607,669 No screening 31 73.9% 69.2% $19,817 $34,312 100% for all tests Blood test 16 68.1% 64.7% -$3,104,328 -$103,478 mt-sDNA 6 42.5% 39.8% -$1,073,985 -$35,799 FIT 3 30.8% 29.8% $2,289,314 $76,310 No screening 35 82.1% 78.3% $612,243 $20,408

Reduced DNA Repair Capacity in Prostate Cancer Patients: A Phenotypic Approach Using the CometChip.

Simple SummaryProstate cancer (PCa) is the most commonly diagnosed cancer type in Hispanic men in the US. Among Hispanics, Puerto Rican (PR) men show the highest PCa-specific mortality. Various studies have shown that having low DNA repair capacity (DRC) is a significant risk factor for cancer development. The aim of this study was to evaluate variations in DRC, through the nucleotide excision repair (NER) pathway, in PR men with PCa using the CometChip. Overall, PCa cases had lower DRC than controls. When PCa cases were stratified into aggressive and indolent, controls had higher DRC than both groups. The contributions of additional factors (i.e., age and prostate-specific antigen levels) to DRC were also considered. Our data suggest that DRC levels may have the potential to discriminate between aggressive and indolent cases. Our results represent an innovative step in the development of a blood-based screening test for PCa based on DRC levels.Prostate cancer (PCa) accounts for 22% of the new cases diagnosed in Hispanic men in the US. Among Hispanics, Puerto Rican (PR) men show the highest PCa-specific mortality. Epidemiological studies using functional assays in lymphocytes have demonstrated that having low DRC is a significant risk factor for cancer development. The aim of this study was to evaluate variations in DRC in PR men with PCa. Lymphocytes were isolated from blood samples from PCa cases (n = 41) and controls (n = 14) recruited at a hospital setting. DRC levels through the nucleotide excision repair (NER) pathway were measured with the CometChip using UVC as a NER inductor. The mean DRC for controls and PCa cases were 20.66% (±7.96) and 8.41 (±4.88), respectively (p < 0.001). The relationship between DRC and tumor aggressiveness was also evaluated. Additional comparisons were performed to evaluate the contributions of age, anthropometric measurements, and prostate-specific antigen levels to the DRC. This is the first study to apply the CometChip in a clinical cancer study. Our results represent an innovative step in the development of a blood-based screening test for PCa based on DRC levels. Our data also suggest that DRC levels may have the potential to discriminate between aggressive and indolent cases.