Multi-cancer Early Detection Research Articles

Multicancer Early Detection Technologies: A Review Informed by Past Cancer Screening Studies.

More than 75% of cancer-related deaths occur from cancers for which we do not screen. New screening liquid biopsies may help fill these clinical gaps, although evidence of benefit still needs to be assessed. Which lessons can we learn from previous efforts to guide those of the future? Screening trials for ovarian, prostate, pancreatic, and esophageal cancers are revisited to assess the evidence, which has been limited by small effect sizes, short duration of early-stage disease relative to screening frequency, study design, and confounding factors. Randomized controlled trials (RCT) to show mortality reduction have required millions of screening-years, two-decade durations, and been susceptible to external confounding. Future RCTs with late-stage incidence as a surrogate endpoint could substantially reduce these challenges, and clinical studies demonstrating safety and effectiveness of screening in high-risk populations may enable extrapolation to broader average-risk populations. Multicancer early detection tests provide an opportunity to advance these practical study designs. Conditional approvals based on RCTs with surrogate endpoints, contingent upon real world evidence generation and continuation of trials to definitive endpoints, may lower practical barriers to innovation in cancer screening and enable greater progress.

A Novel Blood-Based microRNA Diagnostic Model with High Accuracy for Multi-Cancer Early Detection.

Simple SummaryDevelopment of noninvasive diagnostic tests capable of detecting multiple cancer types early is urgently needed. Majority of the tests that are currently in development for multi-cancer early detection are based on next generation sequencing technology to evaluate methylation or fragmentation patterns of circulating tumor DNAs. Here, we developed a serum-based 4-microRNA diagnostic model, which when compared to the existing next generation sequencing-based tests, demonstrated superior performance in detecting 12 cancer types in the largest case-control validation cohort to date. The simplicity of our model also makes it feasible to develop an in vitro diagnostic (IVD) test capable of decentralized testing, supporting the wide adoption and compliance in the at-risk general population.Early detection is critical to reduce cancer deaths as treating early stage cancers is more likely to be successful. However, patients with early stage diseases are often asymptomatic and thus less likely to be diagnosed. Here, we utilized four microarray datasets with a standardized platform to investigate comprehensive microRNA expression profiles from 7536 serum samples. A 4-miRNA diagnostic model was developed from the lung cancer training set (n = 416, 208 lung cancer patients and 208 non-cancer participants). The model showed 99% sensitivity and specificity in the lung cancer validation set (n = 3328, 1358 cancer patients and 1970 non-cancer participants); and the sensitivity remained to be >99% for patients with stage 1 disease. When applied to the additional combined dataset of 3792 participants including 2038 cancer patients across 12 different cancer types and 1754 independent non-cancer controls, the model demonstrated high sensitivities ranging from 83.2 to 100% for biliary tract, bladder, colorectal, esophageal, gastric, glioma, liver, pancreatic, and prostate cancers, and showed reasonable sensitivities of 68.2 and 72.0% for ovarian cancer and sarcoma, respectively, while maintaining 99.3% specificity. Our study provided a proof-of-concept data in demonstrating that the 4-miRNA model has the potential to be developed into a simple, inexpensive and noninvasive blood test for early detection of multiple cancers with high accuracy.

Evaluating the impact of multicancer early detection testing on health and economic outcomes: Toward a decision modeling strategy.

Emerging data provide initial support for the concept that a single, minimally invasive liquid biopsy test, performed in conjunction with confirmatory radiologic or other diagnostic testing, when indicated, could be deployed on a broad scale to screen individuals for multiple types of cancer. Ideally, such a test could do this in a way that yields a clinically important percentage of true-positive indications of cancer while minimizing false-positive signals. Modern decision modeling approaches can and should be deployed to investigate the health and economic consequences of such multicancer early detection (MCED) testing within defined at-risk populations. In this paper, through small-scale analyses involving 3 hypothetical MCED-detectible cancers, the authors illustrate the potential for MCED testing to be cost-effective, along with the pivotal role of test-induced stage shift on results. The time is ripe for additional, prospective investigations of the clinical value of MCED testing, the benefits versus the risks for screened populations, and the overall projected impact on health outcomes and costs over time.

Multicancer early detection: International summit to Clarify the Roadmap.

To expedite the development and application of potentially transformative multicancer early detection assays, an international summit was hosted by the Mayo Clinic Cancer Center, the American Cancer Society, and the Union for International Cancer Control on World Cancer Day 2020 at the historic Mayowood Mansion in Rochester, Minnesota. Insights shared during this unique summit have been formulated into a series of expert‐authored commentaries, which accompany this introductory article.

International perspectives on the development, application, and evaluation of a multicancer early detection strategy.

The development and implementation of a multicancer early detection (MCED) test that is effective and affordable has the potential to change cancer care systems around the world. However, careful consideration is needed within the context of different health care settings (both low- and middle-income countries and high-income countries) to roll out an MCED test and promote equity in access.

Patient engagement and advocacy considerations in development and implementation of a multicancer early detection program.

Advocacy organizations are poised to ensure that patients' needs and preferences inform the development, planning, and implementation of multicancer early detection technologies. Engaging patients and cancer advocacy organizations throughout the research, development, and implementation of multicancer early detection technologies is critical to optimize public health impact and health equity.

Multicancer early detection test: Preclinical, translational, and clinical evidence-generation plan and provocative questions.

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.

Opportunities for Early Cancer Detection: The Rise of ctDNA Methylation-Based Pan-Cancer Screening Technologies.

The efficiency of conventional screening programs to identify early-stage malignancies can be limited by the low number of cancers recommended for screening as well as the high cumulative false-positive rate, and associated iatrogenic burden, resulting from repeated multimodal testing. The opportunity to use minimally invasive liquid biopsy testing to screen asymptomatic individuals at-risk for multiple cancers simultaneously could benefit from the aggregated diseases prevalence and a fixed specificity. Increasing both latter parameters is paramount to mediate high positive predictive value—a useful metric to evaluate a screening test accuracy and its potential harm-benefit. Thus, the use of a single test for multi-cancer early detection (stMCED) has emerged as an appealing strategy for increasing early cancer detection rate efficiency and benefit population health. A recent flurry of these stMCED technologies have been reported for clinical potential; however, their development is facing unique challenges to effectively improve clinical cost–benefit. One promising avenue is the analysis of circulating tumour DNA (ctDNA) for detecting DNA methylation biomarker fingerprints of malignancies—a hallmark of disease aetiology and progression holding the potential to be tissue- and cancer-type specific. Utilizing panels of epigenetic biomarkers could potentially help to detect earlier stages of malignancies as well as identify a tumour of origin from blood testing, useful information for follow-up clinical decision making and subsequent patient care improvement. Overall, this review collates the latest and most promising stMCED methodologies, summarizes their clinical performances, and discusses the specific requirements multi-cancer tests should meet to be successfully implemented into screening guidelines.

POSC356 Pilot Study for Assessment of Health State Utilities Associated with False-Positive Cancer Screening Results

A novel multi-cancer early detection (MCED) test can screen for multiple types of cancer via a single blood draw. This screening test could be implemented in a broad segment of the population. As with any screening, there is potential for false positive (FP) Results: Economic modeling to assess the value of incorporating MCED testing with conventional cancer screening would need to consider the impact of FPs. The purpose of this study was to pilot-test health state vignettes and procedures that could be used to estimate the disutility (i.e., decrease in health state utility) associated with FPs.

Towards responsible ctDNA-based multi-cancer screening: a preliminary exploration and discussion of ethically relevant aspects

While testing for easily accessible biomarkers in the circulation (“liquid biopsy”) has found its way to clinical cancer care, a further expected development is its use as a “universal” early detection test in population screening for cancer. A promising marker for such screening is circulating cell-free fragments of tumor DNA, shed into the circulation during tumor cell turnover. Several blood-based “multicancer early detection (MCED) tests” have recently been developed - but still need validation in large-scale studies involving non-patient populations. In this paper, we proactively explore the ethical aspects of this development. We refer to an often quoted synthesis of the internationally accepted framework of principles for responsible screening as first drawn up for the World Health Organisation (WHO) by Wilson and Junger 50 years ago and further developed and fine-tuned ever since. As our analysis suggests, some specific ethical issues and concerns about potential MCED screening connect to the fact that cancer is not just one disease. As a consequence, not all findings will have the same clinical utility. We discuss this against the background of earlier debates pertaining to broad scope forms of screening in other contexts, specifically newborn and reproductive genetic screening. We highlight the guidance provided by some of the criteria from the screening framework that seems most relevant in this connection: the need for screening objectives to be defined at the outset, the need for mechanisms to minimize potential risks, and the requirement that, for those participating in the screening, the overall benefits outweigh the harm.

Systematic Review and Meta-Analysis of the Accuracy and Applicability of Blood-Based Multi-Cancer Early Detection (MCED) in the General Population

Systematic Review and Meta-Analysis of the Accuracy and Applicability of Blood-Based Multi-Cancer Early Detection (MCED) in the General Population

POSB44 Drivers of Value-Based Price (VBP) for a Multi-Cancer Early Detection (MCED) Test

MCED testing could increase detection of cancer at early stages when survival outcomes are better and treatment costs are lower, but is expected to increase screening costs. This modeling study explores key drivers of the potential range of VBP for a multi-cancer test in a US population.

P18 Patient Preferences for Attributes of a Multi-Cancer Early Detection Test: A Discrete Choice Experiment (DCE) Quantitative Pilot Study

Early cancer detection and intervention can significantly improve patient outcomes and reduce mortality rates. Evidence shows that emerging blood-based multi-cancer early detection (MCED) tests can detect a variety of cancer types across stages and provide a predicted cancer signal origin with high specificity. However, little is known about patients’ preferences for MCED tests. This study aimed to quantify preferences for attributes of blood-based MCED tests among the US general population aged 50-80 years. A DCE consisting of five attributes (true positives, false negatives, false positives, likelihood of the cancer type unknown [e.g., inaccurate cancer signal origin], and number of cancers tested for) was administered online to US general population members to elicit preferences to quantitatively pilot test the DCE. Data were analyzed using an error-component multinomial logit model and relative attribute importance (RAI) was obtained. Participants (N=303) were 62.0% male (n=188), mean age 68.2 years (SD=6.4). RAI indicated that the rank order of attribute importance was false negatives (35.7%), true positives (27.6%), false positives (17.3%), number of cancers tested for (16.8%), and cancer type unknown (2.7%). Attributes related to improved test accuracy were important and participants strongly preferred screenings that tested for more cancer types (all p < 0.05). Preferences were non-significant for the likelihood of cancer type unknown attribute levels. Overall, 71.9% of participants reported that they would prefer to receive the MCED test in addition to their currently recommended cancer screenings. Participants’ preferences were strongly driven by the desire for a screening test with fewer false negatives and more true positives, with these 2 attributes comprising 63.3% of the RAI. False positive results and number of types of cancer tested for also impacted preferences but were of lower importance. The majority of participants preferred adding a MCED test to supplement current cancer screenings.

Examining developments in multicancer early detection: highlights of new clinical data from recent conferences.

Cancer remains the second leading cause of death in the United States despite decades of treatment advances. While death rates have fallen for breast, cervical, and colorectal cancers, death rates remain high for the majority of malignancies, primarily given the late stage at which they are diagnosed. The US Preventive Services Task Force currently recommends routine screening for just 4 cancers: breast, cervical, colorectal, and lung (for high-risk individuals); for prostate cancer, recommendations support individual decision making. However, cancers without recommended screening tests account for 71% of cancer deaths in the United States. In addition, screening rates remain below national goals, with numerous barriers to population-based screening. Recently, initial results of studies on blood-based multicancer early detection tests, which rely on measurement of a range of analytes, demonstrate the potential to identify multiple cancers in a single blood test and detect many cancers for which no screening tests are currently recommended. Blood-based tests have the potential to be more accessible and easier to disseminate than organ-specific tests. However, it remains unclear if their use can reduce deaths from these cancers. Other issues include cost-effectiveness, the impact of false-positive and false-negative results on patients and costs, and uptake among individuals and clinicians. Research and development of blood-based multicancer early detection tests continue.

A Quantitative Framework to Study Potential Benefits and Harms of Multi-Cancer Early Detection Testing.

Multi-cancer tests offer screening for multiple cancers with one blood draw, but the potential population impact is poorly understood. We formulate mathematical expressions for expected numbers of: (i) individuals exposed to unnecessary confirmation tests (EUC), (ii) cancers detected (CD), and (iii) lives saved (LS) given test performance, disease incidence and mortality, and mortality reduction. We add colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer, approximating prevalence at ages 50, 60, or 70 using incidence over the next 5 years and mortality using corresponding probabilities of cancer death over 15 years in the Surveillance, Epidemiology, and End Results registry. EUC is overwhelmingly determined by specificity. For a given specificity, EUC/CD is most favorable for higher prevalence cancers. Under 99% specificity and sensitivities as published for a 50-cancer test, EUC/CD is 1.1 for breast + lung versus 1.3 for breast + liver at age 50. Under a common mortality reduction associated with screening, EUC/LS> is most favorable when the test includes higher mortality cancers (e.g., 19.9 for breast + lung vs. 30.4 for breast + liver at age 50 assuming a common 10% mortality reduction). Published multi-cancer test performance suggests a favorable tradeoff of EUC to CD, yet the full burden of unnecessary confirmations will depend on the posttest work-up protocol. Harm-benefit tradeoffs will be improved if tests prioritize more prevalent and/or lethal cancers for which curative treatments exist. The population impact of multi-cancer testing will depend not only on test performance but also on disease characteristics and efficacy of early treatment.See related commentary by Duffy and Sasieni, p. 3.

1135P Impact of MCED screening interval on reduction in late-stage cancer diagnosis and mortality

Cancer is a leading cause of death worldwide, but at present, screening is recommended for few cancer types. Multi-cancer early detection (MCED) tests can screen for many cancers simultaneously. We use a model1 of a cell-free DNA (cfDNA) MCED test to examine impact of screening intervals on stage at diagnosis and mortality outcomes.

Multi-cancer early detection blood test + current screening may be cost effective in the USA and UK

Multi-cancer early detection blood test + current screening may be cost effective in the USA and UK

1123O Evaluation of cell-free DNA approaches for multi-cancer early detection

1123O Evaluation of cell-free DNA approaches for multi-cancer early detection

Multicancer Early Detection: Learning From the Past to Meet the Future.

Multicancer early detection (MCED) tests may soon be available to screen for many cancers using a single blood test, yet little is known about these tests beyond their diagnostic performance. Taking lessons from the history of cancer early detection, we highlight 3 factors that influence how performance of early detection tests translates into benefit and benefit-harm trade-offs: the ability to readily confirm a cancer signal, the population testing strategy, and the natural histories of the targeted cancers. We explain why critical gaps in our current knowledge about each factor prevent reliably projecting the expected clinical impact of MCED testing at this point in time. Our goal is to communicate how much uncertainty there is about the possible effects of MCED tests on population health so that patients, providers, regulatory agencies, and the public are well informed about what is reasonable to expect from this potentially important technological advance. We also urge the community to invest in a coordinated effort to collect data on MCED test dissemination and outcomes so that these can be tracked and studied while the tests are rigorously evaluated for benefit, harm, and cost.

Clinical correlates of circulating cell-free DNA tumor fraction.

BackgroundOncology applications of cell-free DNA analysis are often limited by the amount of circulating tumor DNA and the fraction of cell-free DNA derived from tumor cells in a blood sample. This circulating tumor fraction varies widely between individuals and cancer types. Clinical factors that influence tumor fraction have not been completely elucidated.Methods and findingsCirculating tumor fraction was determined for breast, lung, and colorectal cancer participant samples in the first substudy of the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978; multi-cancer early detection test development) and was related to tumor and patient characteristics. Linear models were created to determine the influence of tumor size combined with mitotic or metabolic activity (as tumor mitotic volume or excessive lesion glycolysis, respectively), histologic type, histologic grade, and lymph node status on tumor fraction. For breast and lung cancer, tumor mitotic volume and excessive lesion glycolysis (primary lesion volume scaled by percentage positive for Ki-67 or PET standardized uptake value minus 1.0, respectively) were the only statistically significant covariates. For colorectal cancer, the surface area of tumors invading beyond the subserosa was the only significant covariate. The models were validated with cases from the second CCGA substudy and show that these clinical correlates of circulating tumor fraction can predict and explain the performance of a multi-cancer early detection test.ConclusionsPrognostic clinical variables, including mitotic or metabolic activity and depth of invasion, were identified as correlates of circulating tumor DNA by linear models that relate clinical covariates to tumor fraction. The identified correlates indicate that faster growing tumors have higher tumor fractions. Early cancer detection from assays that analyze cell-free DNA is determined by circulating tumor fraction. Results support that early detection is particularly sensitive for faster growing, aggressive tumors with high mortality, many of which have no available screening today.