Multi-cancer early detection (MCED) tests and the SPOT-MAS breakthroughSeptember 16, 2024
Lung cancer mortality rates remain alarmingly high despite advancements in early detection methods. Many current screening tests, such as colonoscopy or annual CT scans, are invasive and complex, limiting their accessibility and uptake. In fact, the annual CT scan for lung cancer screening has a low compliance rate of only 40%. Furthermore, most existing screening methods target only a single type of cancer, resulting in high false-positive rates when conducted sequentially.
This issue highlights an urgent need for innovative solutions, such as multi-cancer early detection (MCED) tests, which are designed to screen multiple types of cancers simultaneously. Dr Tran Le Son (pix), Principal Investigator of the Oncology Division at Gene Solutions, discussed this challenge at the National Cancer Congress Malaysia, emphasizing the potential of these new approaches to revolutionize cancer screening. The false positives dilemma in current screening methods According to Dr Tran, "Let's take an example of a 60-year-old male or female who belongs to a high-risk population. If they undergo multiple cancer screening tests, the false-positive rate can be as high as 30%. This often leads to over-diagnosis and over-treatment, causing anxiety for patients and increasing the burden on healthcare systems." This issue is exacerbated when screening is conducted for several cancers one after another, leading to the accumulation of false positives. While screening is crucial for cancers like breast, cervical, colorectal, lung, and prostate, these account for only 40% of newly diagnosed cancers each year and less than 30% of cancer-related deaths. Unmet needs for a multi-cancer detection (MCED) test The remaining 60% of cancer types lack standard, widely accessible screening tests. These cancers, which often present no clear symptoms in their early stages, are frequently diagnosed too late, leading to poor prognosis and high mortality rates. If detected early, five-year survival rates for many of these cancers could be increased fourfold. A key question arises: How can we develop a screening program for these underdiagnosed cancer types that currently lack widespread screening? A single-organ screening for these cancers would be inefficient due to their low prevalence. For example, colorectal cancer requires screening of 167 people to detect a single case, while esophageal cancer requires screening of over 1,000 people for one detection. The case for multi-cancer early detection (MCED) tests The development of MCED tests addresses these challenges by aggregating the prevalence of multiple cancer types. For instance, if a multi-cancer screening test is designed to detect several types of gastrointestinal cancers, only 33 participants would need to be screened to find one positive case. This highlights the clinical significance of MCED tests, which can complement existing single-cancer screenings to enhance the overall effectiveness of early detection efforts. Liquid biopsy: A new frontier in multi-cancer early detection One of the most promising methods for developing MCED tests is liquid biopsy. Over the past five years, liquid biopsy has emerged as a potential game-changer in multi-cancer detection. These tests work by detecting circulating tumor DNA (ctDNA) in the bloodstream. Tumor cells shed ctDNA during apoptosis or necrosis, making it detectable in blood samples. Dr Tran explained that recent research shows tumor cells can actively secrete DNA into the bloodstream. "The key challenge," he said, "is distinguishing ctDNA from other cell-free DNA, which is shed by normal cells. However, ctDNA carries distinct genetic and epigenetic markers, such as point mutations, DNA rearrangements, and methylation changes, which make it possible to identify cancerous cells." Compared to conventional screening methods, liquid biopsy offers several advantages. It is minimally invasive, requires only a blood sample, and can detect multiple cancers at once. Moreover, ctDNA is considered a cancer-specific biomarker, allowing for earlier detection of tumors than many traditional methods. Current landscape of multi-cancer early detection (MCED) tests Several MCED tests are currently in development, and some have already completed clinical trials: CancerSEEK: Detects eight types of cancers, including ovarian, liver, stomach, pancreatic, esophageal, colon, lung, and breast cancers. It uses mutations in 16 cancer genes and biochemical markers. Sensitivity ranges from 33% to 98%, with a specificity of 99%. The DETECT-A study validated its use. PANSEER: Targets five cancer types—stomach, esophageal, colorectal, lung, and liver. It relies on methylation variations across 447 genomic regions, with a sensitivity of 88% and specificity of 96%. OverC: Focuses on esophageal, liver, lung, ovarian, and pancreatic cancers. Its methylation-based approach has a sensitivity of 80% and specificity of 98%. Galleri: A groundbreaking test that detects over 50 types of cancers using methylation variations in tumor DNA, with a sensitivity of 51.5% and specificity of 99.5%. Galleri has been hailed as one of the best inventions of 2022 by the New York Times and has already completed its clinical validation trials. The development of SPOT-MAS Despite the promise of current MCED tests, they remain prohibitively expensive, especially for low- and middle-income countries. For example, the Galleri test is commercialized in the United States at a cost of $950 per test, making it inaccessible for widespread use. To address this gap, researchers have developed a new MCED test called SPOT-MAS (Screening for the Presence of Tumor by Metabolism and Size). The SPOT-MAS test is designed to be more cost-effective by using both targeted and generalized sequencing to analyze multiple ctDNA signatures. These include methylation patterns from 22 chromosomes, fragment length profiles, DNA copy number alterations, and end motifs. By combining multiple ctDNA signatures and leveraging advanced machine learning algorithms, SPOT-MAS increases detection sensitivity while maintaining low sequencing depth, making it more affordable. The test requires only a single blood draw and a single library reaction, maximizing cost-effectiveness. Validation and future directions for SPOT-MAS The SPOT-MAS test has gone through three important phases of development. During its initial phase, researchers used large databases containing over 20,000 cancer cases to select cancer-specific signatures for the machine learning algorithm. In subsequent analytical validation studies (K-DISCOVERY A and K-DISCOVERY B), SPOT-MAS demonstrated its ability to detect 10 types of cancers, including seven that lack standard-of-care screening. Clinical validation studies, such as the K-DETEK study, involved over 10,000 asymptomatic participants from 75 hospitals, making it one of the largest cancer detection studies in Asia. The results were promising: 28% of the true positive cases were cancers lacking standard screening methods. The SPOT-MAS test also demonstrated its ability to predict tumor tissue origins with an accuracy of more than 80%, helping clinicians guide diagnostic workups. The development of MCED tests, particularly those based on liquid biopsy like SPOT-MAS, marks a significant advancement in the field of cancer screening. These tests are minimally invasive, detect multiple cancer types simultaneously, and can identify cancers at their early stages, offering hope for reducing cancer mortality rates. While challenges remain, such as cost and accessibility, ongoing research and clinical trials will help determine the broader applicability of these tests and refine their use in healthcare systems worldwide. |
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