Victoria M. Raymond

PURPOSE: The Shield test is a blood-based assay that uses multimodal analysis of cell-free DNA (cfDNA) to enable noninvasive colorectal cancer (CRC) detection. The aim of this study was to assess the diagnostic performance of the cfDNA test for CRC and advanced precancerous lesions (APLs) and evaluate its potential clinical utility, particularly in early-stage disease. METHODS: In this prospective, multicenter study, 451 patients with histologically confirmed CRC or APLs were enrolled across eight institutions. Blood samples collected before treatment were analyzed using the cfDNA test (Shield, Guardant Health, United States). We assessed the sensitivity of the test for different CRC stages and APLs. In addition, we examined the correlation between test positivity and clinicopathologic factors in stage I and T1 CRC. RESULTS: The test showed 87.9% sensitivity for CRC overall, with stage-specific sensitivities of 71.2% for stage I and 97.4% for stages II-IV. Sensitivity for APLs was 37.0%. In stage I CRC, test positivity was significantly associated with tumor depth (T2: 88.6% v T1: 59.7%, P < .01). Among 70 patients with T1 CRC, the test detected all to have lymph node metastasis (LNM; 100% sensitivity). Compared with guideline-based pathologic criteria, the cfDNA test achieved higher specificity for LNM prediction (38.7% v 11.3%), thereby potentially reducing the frequency of unnecessary radical surgery from 78.6% to 54.3%. CONCLUSION: This cfDNA blood-based test shows a robust diagnostic performance in CRC detection. It may improve risk stratification and support more tailored clinical decision making, particularly in the management of T1 CRC.

In recent years, there has been a surge in the development of new, blood-based, single- and multi-cancer detection tests (SCD and MCD), which can detect cancer signals prior to the onset of symptoms or clinical diagnosis of cancer. Recognizing the need for consensus definitions and standardized evidence development frameworks for these new types of blood tests, the Early Detection and Screening Working Group of the Blood Profiling Atlas in Cancer Consortium, a collaborative initiative dedicated to advancing standards and best practices, developed and published a lexicon for liquid biopsy–based SCD and MCD tests. During the preparation of the lexicon, the group recognized challenges with regard to the definitions of key terms and concepts describing absolute and RR assessment of intended use populations for cancer screening tests. This article captures the working group’s discussions on (i) risk assessment including considerations for adapting historical SCD risk terminology like “average risk” and “elevated risk” to MCD tests, (ii) the implications of this terminology for describing intended use populations, and (iii) the existing gaps in evidence for determination of absolute risks.

Although U.S. Preventive Services Task Force (USPSTF) recommended CRC screenings are effective; patient reluctance reduces adherence. Most cost-effectiveness models assume perfect adherence, yet one-third of eligible individuals aren't current with CRC screening. Our study assesses the cost-effectiveness of Shield, an FDA-approved blood-based CRC screening test, using real-world adherence. The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, a validated discrete-event simulation, evaluated clinical and economic outcomes of CRC screening under real-world adherence scenarios. We compared the Shield blood-based test administered every 3 years to no screening, considering it cost-effective if the incremental cost-effectiveness ratio (ICER) was under $100,000 per quality-adjusted life-year (QALY) gained. Shield increased QALYs by 154 and raised costs by $7.5 million per 1,000 individuals, with an ICER of $48,662 per QALY, meeting the $100,000/QALY threshold. Shield remained cost-effective up to a unit cost of $3,241 (at $100,000/QALY) and $4,942 (at $150,000/QALY). Sensitivity analyses confirmed cost-effectiveness with lower adherence to diagnostic colonoscopy (56.1%) and annual screenings. The CAN-SCREEN model shows that Shield is cost-effective compared to no screening. Including real-world adherence improves accuracy in assessing screening strategies. Shield's noninvasive approach offers a promising, cost-effective way to increase adherence and reduce CRC mortality.

Insufficient adherence to colorectal cancer (CRC) screening impedes individual and population health benefits, with about one-third of individuals non-adherent to available screening options. The impact of poor adherence is inadequately considered in most health economics models, limiting the evaluation of real-world population-level screening outcomes. This study introduces the CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, utilizing real-world adherence scenarios to assess the effectiveness of a blood-based test (BBT) compared to existing strategies. The CAN-SCREEN model evaluates various CRC screening strategies per 1,000 screened individuals for ages 45-75. Adherence is modeled in two ways: 1) full adherence and 2) longitudinally declining adherence. BBT performance is based on recent pivotal trial data, while existing strategies are informed using literature. The full adherence model is calibrated using previously published Cancer Intervention and Surveillance Modeling Network (CISNET) models. Outcomes, including life-years gained (LYG), CRC cases averted, CRC deaths averted, and colonoscopies, are compared to no screening. Longitudinal adherence modeling reveals differences in the relative ordering of health outcomes and resource utilization, as measured by the number of colonoscopies performed per 1,000, between screening modalities. BBT outperforms fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT yields fewer CRC deaths averted compared to colonoscopy (13, 15) but requires fewer colonoscopies (1,053 vs. 1,928). Due to limited data, the CAN-SCREEN model with longitudinal adherence leverages evidence-informed assumptions for the natural history and real-world longitudinal adherence to screening. The CAN-SCREEN model demonstrates that amongst non-invasive CRC screening strategies, those with higher adherence yield more favorable health outcomes as measured by CRC deaths averted, CRC cases averted, and LYG.

Supplementary Figure S1. Schema of ctDNA sampling.

Purpose:Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell–free DNA detection status with radiographic disease recurrence.Experimental Design:Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS).Results:From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31–12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6–45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4–15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure.Conclusions:In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

Supplementary Figure S4. Survival outcomes and recurrence rates stratified by CEA status.

Supplementary Figure S3. ctDNA dynamic changes for patients pre-and post-curative intent therapy (CI) (left) or adjuvant chemotherapy (ACT) (right).

Supplementary Figure S2. Kaplan-Meier curves for patients with pre-procedure ctDNA stratified by ctDNA status.

Supplementary Table S3. Univariate analysis by pre-operative ctDNA status. Depicted are multiple clinicopathologic variables analyzed by ctDNA status.