Liquid biopsy (LB) is gaining momentum in its application for the early detection of cancer because it is noninvasive, can detect multiple cancers, and is likely to be acceptable in clinical practice either as an adjunct or a stand-alone test in combination with the standard of care. The opportunities for such testing to change the paradigm for cancer screening will be presented, along with challenges that need to be addressed.

Multi-cancer early detection, with the promise of screening and/or diagnosing more than 50 cancers from a single, non-invasive patient sample, has implications that vary by geography and tool performance. In high-income countries with dense, complex cancer treatment systems, a near perfect MCED tool could lead to disruptive innovation, creative destruction, and massive downstaging of cancer in the population. In low-income countries where fragile, limited cancer treatment systems are evolving, a moderately performing MCED tool would lead to disruptive innovation and low-cost, global systems for screening and diagnosing patients with enormous impact on morbidity and mortality – importantly, creative destruction is irrelevant where these limited systems exist. Why there is such a massive difference in impact, the barriers that exist for both, and an ethical way forward will be discussed.

As the pace of technical advancement in new cancer screening technology accelerates, we are presented with an exciting potential to not only make early cancer detection more feasible and accessible, but to expand that opportunity to a larger list of cancers and further reduce suffering and premature deaths. These technologies must be evaluated in the population to ensure their efficacy and favorable balance of benefits to harms. Yet, we are facing this challenge with a traditional methodology that is slow to launch, prohibitively costly, and commonly requiring more than a decade under the most optimal conditions to measure outcomes. To avoid stifling innovation and to bring these technologies to the population sooner if they are efficacious, we must embrace the challenge to develop new approaches to evaluation, including trustworthy new endpoints and rethinking the influence of known biases, based on experience with evaluating cancer screening to date.

Patterns of gene expression are proving to be a powerful class of RNA biomarkers with the capability to detect cancer at the earliest stages. While some of the portfolio’s 223 biomarkers have been biologically correlated with cancer, the vast majority are truly novel and have never before been implicated in oncological pathways. The breast cancer program is a perfect embodiment of the novel biomarker discovery methods, resulting in 26 mRNA markers, successfully translating to clinical development. From biofluids, these mRNA biomarkers have detected the earliest stage breast cancers within a diverse population of women. This clinical success is currently extending into other cancer types, as well as metabolic diseases.   

Pancreatic cancer has poor survival rates, largely driven by late diagnosis. Our epigenetics technology platform, which measures DNA hydroxymethylation generated by active demethylation, delivers the first-of-its-kind cancer detection test. With a robust performance further validated in an independent cohort with high sensitivity and specificity, our pancreatic cancer test is specifically designed to improve patient outcomes by enabling early detection of occult pancreatic cancer in high-risk populations such as patients with new-onset diabetes.

The diagnosis of cancer in patients with nonspecific symptoms is a major clinical challenge leading to poorer prognoses as patients are diagnosed late. Here we show that biofluid metabolomics using nuclear magnetic resonance (NMR) can identify cancer in a cohort of 300 at-risk patients with high sensitivity and specificity, before considering the larger possibilities for biofluid metabolomics in the diagnosis and management of cancer.

Multi-cancer early detection (MCED) is an emerging paradigm to curb cancer mortality through a single test diagnosing all cancer types when still in stage I. Liquid biopsies based on genomic biomarkers could make MCED realistic, but limitations include ~10% stage I sensitivity; the inability to detect specific types like gliomas; complex assays; and potential over-diagnosis. In this talk, I will illustrate the potential of metabolism for MCED. Our studies indicate that free glycosaminoglycan profiles (GAGomes) in plasma and urine doubled stage I sensitivity reported by genomics biomarkers and preferentially detected poor prognosis any-type cancer with a simple IVD-ready assay.

Microbiome entered in 2022 the Hallmarks of Cancer. Yet, mostly gut microbiome is considered at this stage. In our presentation, we will discuss the importance of newly discovered tissue and circulating microbiomes in early cancer detection as well as MRD or relapse monitoring. We will also cover the potential to greatly improve treatment or drug clinical trials with this new set of microbial biomarkers easily accessible in blood.

Exosomes are excellent vehicles of circulating biomarkers characterized by an intrinsic multiplex capacity: different hallmarks of cancer can be combined in a single vesicle. Exosomes reflect the phenotype of parental cells and reveal disease onset in early phases. The use of cancer metabolic markers displayed on tumor exosomes from plasma as baits for selective enrichment of tumor markers (including genomic ones) and early-stage multi-cancer detection with high specificity and sensitivity will be presented. Such an approach can be synergistic or even alternative to other hyper-technological cancer screening approaches, being original, simple, and accurate while delivering viable health economics.

The potential of blood tests for multi-cancer early detection (MCED) to reduce cancer mortality has elicited both optimism and concern about their generalized applicability. The varied needs of different cancers for biomarker-based blood tests will be discussed.  An important need for cancers for which screening is currently an option is a personalized risk profile based on a combination of biomarkers and subject characteristics that would allow tailoring of screening according to risk. For other less common cancers for which screening in a general population setting is not practical, blood based tests would offer the opportunity to identify individuals at sufficiently high risk to initiate surveillance. An additional benefit of risk assessment is the potential for intervention to prevent or intercept cancer at early developmental stages.

Cell-free DNA (cfDNA) consists of small nucleic acid fragments entering the bloodstream during apoptosis or necrosis. cfDNA fragmentation patterns detected by low-coverage whole-genome sequencing can be used to detect the presence of circulating tumor DNA (ctDNA) in a background of cfDNA mostly derived from hematologic cells. This presentation will describe the development of a blood-based, whole-genome, next-generation sequencing (NGS) test to detect early stages of cancer.

Technological innovation in healthcare now offers a new framing of preemptive health and medicine. Harbinger Health’s platform is an example of preemptive assessment of diseases. The preemptive approach will likely offer new values and diagnostic pathways in early cancer surveillance and long-term clinical outcomes.

Blood-based multi-cancer early detection (MCED) tests leveraging cell-free DNA offer an opportunity to extend the benefits of cancer screening to a broader set of cancer types, including those that do not have recommended screening tests, and which are responsible for approximately 70% of cancer deaths. A methylation-based MCED detects a common cancer signal across a large number of cancer types, generates a single low false positive rate, and predicts the cancer signal origin to direct the downstream diagnostic work-up. The performance of this methylation-based MCED, the underlying biology of the signal that results in a balance of detecting more aggressive cancers while minimizing the risk of overdiagnosis, and the potential population impact of implementing MCEDs in conjunction with standard-of-care cancer screening will be discussed. 

A more accessible and economic way to sequence the human genome has created the potential to benefit millions of cancer patients by turning genomic information into action with simple blood tests. Now, we are on the cusp of bringing to market high-performing blood tests to detect cancer at its earliest stage. But with progress comes challenges with widespread clinical adoption of innovative and life-saving technologies. This presentation provides a unique perspective on how a simple blood test to detect cancer early will transform cancer care, only if we ensure patients can access it. 

Detecting cancer early is like listening for a whisper in a crowded room - you need to separate a faint signal from considerable background noise. Details of how our highly sensitive PCR and NGS platforms detect minute cancer epigenetic signals will be presented. Highly sensitive tests for lung cancer have the potential to increase screening compliance and drive more patients to treatment when it has the greatest chance of providing long-term benefits.