Cancer-screening tests that can detect multiple cancer types, or multi-cancer early detection (MCED) tests, have emerged recently as a potential new tool in decreasing cancer morbidity and mortality. Most MCED assays are based on detecting cell-free tumor DNA (CF-DNA) in the blood. MCEDs offer the potential for screening for cancer organ sites with high mortality, both with and without recommended screening. However, their clinical utility has not been established. Before clinical utility can be established, the clinical validity of MCEDs, i.e., their ability to predict cancer status, must be demonstrated. In this study we performed a systematic review of the predictive ability for cancer of cell-free-nucleic acid-based MCED tests.We searched PubMed for relevant publications from January 2017 to February 2023, using MeSH terms related to multi-cancer detection, circulating DNA, and related concepts. Of 1811 publications assessed, 61 were reviewed in depth and 20 are included in this review. For almost all studies, the cancer cases were assessed at time of diagnosis. Most studies reported specificity (generally 95% or higher) and overall sensitivity (73% median). The median number of cancer types assessed per assay was 5. Many studies also reported sensitivity by stage and/or cancer type. Sensitivity generally increased with stage.To date, relatively few published studies have assessed the clinical validity of MCED tests. Most used cancer cases assessed at diagnosis, with generally high specificity and variable sensitivity depending on cancer type and stage. The next steps should be testing in the intended-use population, i.e., asymptomatic persons. 

Predictive Performance of Cell-Free Nucleic Acid-Based Multi-Cancer Early Detection Tests: A Systematic Review.

<h2>Abstract</h2> Patients benefit considerably from early detection of cancer. Existing single-cancer tests have various limitations, which could be effectively addressed by circulating cell-free DNA (cfDNA)-based multi‐cancer early detection (MCED). With sensitive detection and accurate localization of multiple cancer types at a very low and fixed false-positive rate (FPR), MCED has great potential to revolutionize early cancer detection. Herein, we review state-of-the-art approaches for cfDNA-based MCED and their limitations and discuss both technical and clinical challenges in the development and application of MCED tests. Given the constant improvements in technology and understanding of cancer biology, we propose that a cfDNA-based targeted sequencing assay that integrates multimodal features should be optimized for MCED. 

Circulating cell-free DNA-based early detection.

Circulating tumor DNA (ctDNA, DNA shed by cancer cells) is emerging as one of the most transformative cancer biomarkers discovered to-date. Although potentially useful at all the phases of cancer detection and patient management, one of its most exciting possibilities is as a relatively noninvasive pan-cancer screening test. Preliminary findings with ctDNA tests such as Galleri or CancerSEEK suggest that they have high specificity (> 99.0%) for malignancy. Their sensitivity varies depending on the type of cancer and stage of disease but it is generally low in patients with stage I disease. A major advantage of ctDNA over existing screening strategies is the potential ability to detect multiple cancer types in a single test. A limitation of most studies published to-date is that they are predominantly case-control investigations that were carried out in patients with a previous diagnosis of malignancy and that used apparently healthy subjects as controls. Consequently, the reported sensitivities, specificities and positive predictive values might be lower if the tests are used for screening in asymptomatic populations, that is, in the population where these tests are likely be employed. To demonstrate clinical utility in an asymptomatic population, these tests must be shown to reduce cancer mortality without causing excessive overdiagnosis in a large randomized prospective randomized trial. Such trials are currently ongoing for Galleri and CancerSEEK.

Circulating tumor DNA (ctDNA): can it be used as a pan-cancer early detection test?

Metabolic changes precede malignant histology. However, it remains unclear whether detectable characteristic metabolome exists in esophageal squamous cell carcinoma (ESCC) tissues and biofluids for early diagnosis. Here, we conduct NMR- and MS-based metabolomics on 1,153 matched ESCC tissues, normal mucosae, pre- and one-week post-operative sera and urines from 560 participants across three hospitals, with machine learning and WGCNA. Aberrations in 'alanine, aspartate and glutamate metabolism' proved to be prevalent throughout the ESCC evolution, consistently identified by NMR and MS, and reflected in 16 serum and 10 urine metabolic signatures in both discovery and validation sets. NMR-based simplified panels of any five serum or urine metabolites outperform clinical serological tumor markers (AUC = 0.984 and 0.930, respectively), and are effective in distinguishing early-stage ESCC in test set (serum accuracy = 0.994, urine accuracy = 0.879). Collectively, NMR-based biofluid screening can reveal characteristic metabolic events of ESCC and be feasible for early detection (ChiCTR2300073613). 

NMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection

Cell-free DNA (cfDNA) sequencing has demonstrated great potential for early cancer detection. However, most large-scale studies have focused only on either targeted methylation sites or whole-genome sequencing, limiting comprehensive analysis that integrates both epigenetic and genetic signatures. In this study, we present a platform that enables simultaneous analysis of whole-genome methylation, copy number, and fragmentomic patterns of cfDNA in a single assay. Using a total of 950 plasma (361 healthy and 589 cancer) and 240 tissue samples, we demonstrate that a multifeature cancer signature ensemble (CSE) classifier integrating all features outperforms single-feature classifiers. At 95.2% specificity, the cancer detection sensitivity with methylation, copy number, and fragmentomic models was 77.2%, 61.4%, and 60.5%, respectively, but sensitivity was significantly increased to 88.9% with the CSE classifier (p value < 0.0001). For tissue of origin, the CSE classifier enhanced the accuracy beyond the methylation classifier, from 74.3% to 76.4%. Overall, this work proves the utility of a signature ensemble integrating epigenetic and genetic information for accurate cancer detection. 

Cancer signature ensemble integrating cfDNA methylation, copy number, and fragmentation facilitates multi-cancer early detection

Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies.

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Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies.