Blood-based cancer screening

The advent of blood-based cancer screening has brought hope and excitement to the medical community, particularly in the field of colorectal cancer (CRC). Groundbreaking advancements in laboratory science and data analytics have catalyzed the development of circulating cell-free DNA (cfDNA) assays that promise a less invasive, potentially more accessible approach to cancer detection. However, as these innovative tests begin to gain traction, particularly in the United States, it is imperative to assess their efficacy, cost-effectiveness, and impact on overall screening outcomes.

Colorectal cancer remains a significant global health challenge, accounting for a substantial burden of cancer-related morbidity and mortality. Traditional screening methods, such as fecal immunochemical testing (FIT) and sigmoidoscopy, have demonstrated remarkable success in reducing CRC incidence and mortality through the early detection of precancerous lesions and curable-stage cancers. These methods—validated through rigorous randomized controlled trials—represent the gold standard of CRC screening. The ability to detect and remove advanced precancerous lesions before they progress to cancer is a hallmark of FIT-based screening programs, which are widely implemented worldwide.

In this context, novel cfDNA-based blood tests for CRC detection are emerging as an alternative screening modality. Initial regulatory approvals for these tests in the United States have set the stage for their potential expansion to other countries. However, these tests must be evaluated against established benchmarks of screening effectiveness. One widely used FIT, the OC-Sensor, achieves sensitivities of 74% for CRC and 23% for advanced precancerous lesions, with a specificity of 94% at a 20 μg hemoglobin/g feces threshold. Comparatively, the first-generation cfDNA blood test shows an 83% sensitivity for CRC detection, 55% sensitivity for stage 1 CRC, and a modest 13% sensitivity for advanced precancerous lesions, with a specificity of 90%. While these figures are promising, they highlight a critical gap: the markedly lower sensitivity of cfDNA tests for detecting precancerous lesions, which undermines their preventive potential.

The programmatic nature of CRC screening adds another layer of complexity to the comparison between FIT and cfDNA tests. FIT is typically performed annually or biennially, while current guidelines in the United States recommend triennial testing with cfDNA assays. This disparity in screening intervals raises questions about the cumulative effectiveness of cfDNA testing. For example, decision analytic models predict that annual FIT or decennial colonoscopy could reduce CRC incidence and mortality by over 70%. In contrast, triennial cfDNA testing is estimated to achieve reductions of 42% in incidence and 56% in mortality. These differences emphasize the importance of both test sensitivity and screening frequency in determining long-term outcomes.

The accessibility and acceptability of screening methods significantly influence participation rates, a crucial determinant of programmatic effectiveness. Blood tests may appeal to individuals who are reluctant to complete stool-based tests or undergo colonoscopy. By integrating CRC screening into routine blood work, cfDNA tests could potentially increase screening uptake among underserved populations. However, this potential benefit is tempered by the risk that individuals currently adhering to effective FIT-based or colonoscopy-based programs might switch to less effective cfDNA testing, inadvertently increasing CRC mortality. Model simulations suggest that for cfDNA testing to match the effectiveness of FIT, it would require a 35% higher uptake among currently unscreened individuals.

Cost considerations further complicate the adoption of cfDNA-based CRC screening. In the United States, the list price of the first-generation cfDNA test is $1,450, compared to $20 for FIT. This significant cost differential limits the feasibility of widespread cfDNA testing, particularly in low- and middle-income countries. Moreover, reducing the screening interval to increase cfDNA’s efficacy is not cost-effective at current pricing levels. Addressing the affordability of cfDNA tests will be essential for their integration into global CRC screening programs.

A pivotal challenge for cfDNA tests lies in their ability to detect advanced precancerous lesions, which are critical targets for CRC prevention. Decision models underscore that enhancing the sensitivity of blood tests for these lesions would yield greater reductions in CRC incidence and mortality than improving CRC detection alone. As such, future iterations of cfDNA assays must prioritize advancements in this area to fulfill their preventive promise.

Another concern with cfDNA-based screening is its limited organ specificity. Unlike stool-based tests, which focus solely on the colorectum, blood tests may yield ambiguous results, prompting extensive diagnostic evaluations. This lack of specificity could lead to unnecessary procedures and patient anxiety, detracting from the overall benefits of screening. The potential for false positives and diagnostic odysseys underscores the need for robust education and shared decision-making between patients and clinicians.

The introduction of cfDNA-based CRC screening tests represents a significant milestone in cancer diagnostics. However, their current performance characteristics suggest they are best suited for individuals who would otherwise remain unscreened. For the broader population, FIT and colonoscopy remain the more effective options for reducing CRC incidence and mortality. Enthusiasm for novel technologies must be tempered by rigorous evaluation of their efficacy, safety, and cost-effectiveness. Substantial improvements in cfDNA test sensitivity for early-stage CRC and precancerous lesions, coupled with competitive pricing, could herald a new era in CRC screening. Until then, the integration of cfDNA tests into existing programs must be approached with caution, ensuring that innovations enhance—rather than compromise—the effectiveness of CRC prevention efforts.

Subject of Research: Cancer screening technologies, with a focus on blood-based tests for colorectal cancer.

Article Title: Can molecular cancer signals circulating in blood help us prevent cancer-related deaths?

News Publication Date: 2025-01-12

Article Doi References: https://doi.org/10.1016/S0140-6736(24)02708-9

Keywords: colorectal cancer, cancer screening, blood-based tests, circulating cell-free DNA, faecal immunochemical testing, cost-effectiveness, advanced precancerous lesions, cancer prevention.