by Arnon Chait, PhD, President and CEO, Cleveland Diagnostics
The landscape of cancer prevention, diagnosis, and treatment has changed immeasurably over the last half-century. While cancer remains a devastating health challenge for thousands, the outlook for those with the disease has improved overall, as the U.S. risk of cancer death declined for the 28th consecutive year as of 2022. The resources dedicated to the oncology field are a testament to the impact of cancer and the drive to eradicate it. Global funding for cancer research between 2016 and 2020 totaled roughly $24.5 billion, with efforts dedicated to diagnostics, screening, and monitoring representing about 13% of that amount.
Despite the impressive progress made in developing more effective cancer therapeutics, the value of early detection remains undeniable. Patients diagnosed earlier are more likely to survive cancer and tend to have better care experiences, lower treatment morbidity, and improved quality of life than those with later diagnoses. Approaches for presymptomatic screening and early detection of cancers are thus indispensable to improving patient outcomes and reducing the costs associated with cancer care.
Cancer screening has come a long way since the development and application of the Pap test for cervical cancer detection in 1923. Advances in imaging-based screening and the advent of molecular diagnostic approaches have opened new doors in how clinicians diagnose and understand patients’ unique cancer cases. While accurate and less invasive early detection tools are becoming available, they are not necessarily accessible to the vast majority of patients and providers.
In this article, I’ll review some important milestones and advances in cancer screening and detection methods, important factors to prioritize in the development of diagnostic tools, and how our work at Cleveland Diagnostics aims to address gaps in the field to create tests that are accurate, actionable and accessible.
The evolving diagnostic landscape
The advent and expansion of molecular diagnostic capabilities, which largely refer to DNA- and RNA-based assays as well as advanced proteomic approaches, has made a massive impact on oncology as a whole. One arm of this impact is in identifying and testing for hereditary markers of cancer risk, such as BRCA1/2 mutations in breast and ovarian cancer. Such results convey increased risk rather than the presence of disease but can guide those with cancer-associated mutations to pursue earlier and more aggressive screening approaches. In-depth molecular testing has also become a more integral part of cancer care. Identification of tumor-specific biomarkers has revolutionized treatment selection for patients with known cancers. By enabling the identification of actionable mutations, genetic testing of tumor samples can provide insight into which therapeutic approaches are most likely to yield a durable response and help clinicians understand cancer progression. Unfortunately, the discomfort, risk, and cost associated with invasive biopsies can limit the utility of repeated tumor analysis in treatment monitoring.
Minimally invasive “liquid biopsy” testing methods, which focus on circulating cancer biomarkers in the blood, have generated enthusiasm as a solution to this issue and as a potential avenue to early cancer detection in people not yet diagnosed with cancer. However, liquid biopsy still faces significant limitations. While the method can be more readily leveraged for assessing disease status and treatment effectiveness in hematological malignancies, solid tumors present additional complexities. Circulating tumor DNA (ctDNA), which is secreted into the bloodstream upon tumor cell apoptosis and is present in circulating tumor cells, is typically present at very low concentrations and may not even be shed from all early-stage cancers. One notable exception is in the case of colon cancer. Cells shed from the lining of the colon are present in stool and can thus be screened for DNA markers of cancer or precancerous lesions, a method now employed in the Cologuard test.
When used to conduct tumor-guided analysis in known cases of cancer, sensitive methods that can detect known variants even at low concentrations, such as digital PCR, are relatively accessible. To be realistically employed as a screening tool for early detection of nonspecified cancers, liquid biopsy requires the use of a very broad screening panel on a highly sensitive platform. Several blood-based multi-cancer early detection (MCED) tests have entered the market, which use cell-free DNA sequencing to detect cancer-associated methylation patterns. However, these require the use of advanced sequencing technology and remain cost-prohibitive for many patients, highlighting the need for more widely accessible early detection methods.
Rethinking blood-based cancer testing
DNA- and RNA-focused molecular diagnostic techniques have presented a potential means of circumventing unnecessary biopsies in cancer screening, but the high cost of implementation and operation begs the question: Is there a simpler way? Does improving early, noninvasive cancer detection have to require artificial intelligence-guided mammography or top-of-the-line sequencers? While these technologies are incredible and can meaningfully improve outcomes for many, they are cost-prohibitive and logistically inaccessible for many patients and institutions and will likely remain so for the foreseeable future.
Malignancies are not just defined by their genetic signatures— alterations in protein structure, glycosylation, protein-protein interactions, and more are also hallmarks of cancer. These cancer-associated modifications are more closely connected with the disease than the distant RNA or DNA, which represent molecular instructions that are not always being followed on the protein and thus disease level. Our work at Cleveland Diagnostics aims to leverage changes in protein structure to make cancer detection simpler, more direct, and more accessible. In diagnostic applications for large populations, the complexity and molecular heterogeneity of cancer requires us to step back from a reductionist to a more holistic approach to providing clinically actionable results.
Indeed, having a simple, resource-efficient way to assess malignant changes in protein structure is valuable for early detection. This was the driving force behind the solvent interaction analysis (SIA) testing platform. Structural changes to plasma proteins, including changes in glycosylation profiles, are well-established for many cancers, including breast, lung, and ovarian cancer. These cancer-specific structural isoforms of relevant proteins and changes in protein-protein interactions can be detected and separated using a simple aqueous 2-phase physicochemical system.
The IsoPSA test leverages this concept to provide more relevant insight into prostate cancer risk than an elevated prostate-specific antigen (PSA) level alone can provide. Traditionally, an elevated PSA will direct clinicians to perform a biopsy, but only 30-45% of men with serum PSA levels of 4-10 ng/mL will have prostate cancer diagnosed upon needle biopsy, and up to 75% of all biopsies are negative for high-grade disease. Biopsy is not only unpleasant or stressful for patients; it also carries the risk of infection and even life-threatening sepsis. IsoPSA testing bridges the gap between basic PSA screening and diagnosis of prostate cancer, helping providers understand if an elevated PSA level is indicative of meaningful disease risk and whether a biopsy is necessary. Similarly, mammograms are known to have limited accuracy in detecting malignancies, with roughly half of women undergoing annual mammograms receiving a false-positive result at some point. This translates to unnecessary anxiety, cost, and discomfort associated with biopsies and other tests. While AI-assisted mammography can make a significant impact in improving diagnostic accuracy, performing a simple blood test that detects a breast cancer-specific protein glycosylation signature or other cancer-related changes in protein structure following an inconclusive mammogram could be a simpler and more easily implemented way to know whether a biopsy is necessary.
Tests that can achieve this kind of insight in a basic clinical lab setting, without high costs or complex equipment, are necessary to increase access to cancer screening without introducing unnecessary and invasive downstream procedures. As we explore the use of the SIA platform in other cancers, our organization aims to move the field forward with informative screening methods that are financially and logistically accessible to all patients. To do so, we must leverage tools that are widely available to labs and don’t require a massive investment in equipment and expertise to examine heterogenous, complex diseases in a more holistic way.
Forging ahead in oncology diagnostics
The evolution of cancer screening and diagnostic tools has largely followed a “zooming in,” starting at the level of the tumor and cell and moving to the level of the genome and transcriptome. As our work has shown, new diagnostics don’t have to stay at this level– we can zoom back out to changes in protein structure, the final manifestation of a complex disease such as cancer– and what they can tell us. We can use methods and tools already present in even the most basic clinical labs to get these answers. In doing so, we can create a future where all patients, regardless of the resources in their community or family, can detect cancer at its earliest stages for the best possible outcomes.
About the author
Arnon Chait co-founded Cleveland Diagnostics with the Cleveland Clinic to bring early detection of cancer into everyday practice with advanced testing that is both simple and affordable. With a background in physics, engineering and biosciences, a career spanning NASA, academia and private industry, and a history of launching and leading groundbreaking ventures with sustained revenues, Arnon has a proven track record bringing innovation to market.