Multi-Cancer Early Detection (MCED) Blood Tests: Promise and Current Limitations

Multi-cancer early detection (MCED) blood tests are under development to identify early signs of numerous cancer types from a single blood sample. While proponents suggest they offer advancements in early diagnosis, a recent randomized controlled trial (RCT) for the Galleri test indicated it did not meet its primary objective of reducing advanced-stage cancer diagnoses. Experts highlight current limitations, including the potential for missed cancers, false positive results, and an unproven long-term impact on mortality rates in healthy populations.

Introduction to Multi-Cancer Early Detection (MCED) Tests

MCED tests are designed to detect early signs of various cancers by analyzing biological markers in bodily fluids. This innovative technology, known as 'liquid biopsy,' often scrutinizes DNA fragments shed by cancer cells (circulating tumor DNA, ctDNA) or epigenetic changes like DNA methylation patterns. Approximately 40 such tests are currently in development or on sale globally. However, few have undergone randomized controlled trials (RCTs), which are considered the gold standard, and none have yet received regulatory approval.

Cancer remains a leading cause of death worldwide. Early detection is generally linked to less invasive treatments and significantly improved survival rates. While existing screening programs, such as mammography and colonoscopy, are effective, they have limitations in uptake and coverage for many cancer types.

Trial Results and Early Findings

Grail's Galleri test recently released details from the first RCT of an MCED test, conducted in partnership with the UK National Health Service (NHS). The trial's primary objective was to assess whether the Galleri test could reduce advanced-stage cancer diagnoses when used in conjunction with existing screening programs. The results indicated that the test did not meet this primary objective.

Separately, a large UK study further underscored the challenges, finding that a multi-cancer blood test missed most cancers that participants later developed.

Current Challenges and Limitations

The science behind detecting early-stage cancer presents significant challenges. For instance, tumor DNA concentration in the blood can be incredibly low, potentially as little as 0.006% of free-floating DNA.

Evaluations of MCED tests often focus on metrics such as sensitivity (the proportion of people with cancer who receive a positive result) and specificity (the proportion of people without cancer correctly identified as negative). Systematic reviews show mixed results: while specificity is generally high (96–99.5%), sensitivity remains variable, ranging from 30–80%. For example, one study involving the CancerSEEK test detected only 26 out of 96 diagnosed cancers in women aged 65–75, though it accurately identified 98.9% of those without the disease as negative.

Current limitations for MCED tests include:

• Risk of False Negatives: A negative test result could provide individuals with false reassurance, potentially leading them to delay seeking medical attention for emergent symptoms that could indicate cancer.
• Risk of False Positives: Positive test results that do not indicate cancer can lead to significant anxiety for individuals. These may also result in subsequent invasive follow-up procedures that prove unnecessary, potentially increasing demands on already stretched healthcare systems.
• Unproven Mortality Impact: Unlike established screening methods that have demonstrated their ability to reduce cancer deaths over decades, the long-term impact of MCED blood tests on mortality rates in healthy populations remains unproven.
• Resource Allocation Concerns: The high development and potential purchase costs of these tests raise questions about resource allocation. If widely adopted without clear evidence of clinical efficacy, this could divert funds from proven public health measures, such as prompt diagnosis, smoking cessation initiatives, and existing effective screening programs.

Some researchers have expressed caution regarding the promotion of these tests based on current data, highlighting concerns about their ability to detect many early cancers and whether the benefits currently outweigh the potential downsides.

Potential and Future Applications

Despite current limitations, the underlying scientific principles of liquid biopsy are advancing rapidly. The technology is already utilized to monitor cancer progression and guide treatment for individuals with diagnosed cancers.

MCED tests may offer future benefits for specific high-risk groups, such as individuals with strong family histories of cancer or inherited genetic mutations. For these groups, they could potentially detect tumors earlier than conventional methods. The technology also demonstrates utility in monitoring cancer recurrence after treatment and assisting in the selection of personalized treatments based on a patient's unique cancer biology.

Guidance for Individuals and Broader Context

When considering new cancer blood tests, individuals are advised to:

• Understand the objectives and current knowledge base of any clinical trial they are invited to join.
• For privately offered tests, inquire about the interpretation of results, post-test support, and the likelihood of the test meaningfully altering care.
• Recognize that new blood tests should not replace established health practices. Persistent symptoms, such as a new lump, unexplained bleeding, a prolonged cough, weight loss, or changes in bowel habits lasting several weeks, warrant a consultation with a medical professional, even if a previous test result was normal.

Historically, improved cancer outcomes have resulted from a combination of enhanced treatments, earlier diagnoses, and robust public health initiatives. While new technologies, including MCED tests, are expected to contribute to future advancements, they are not considered a singular solution.