The Limits of the Galleri Approach and the Strengths of Biologically Grounded Liquid Biopsy
Dr Letizia Gulino
Head of Science and Technology – RMDM
The recent failure of the large-scale study evaluating the Galleri blood test represents an important inflection point after years of intense enthusiasm surrounding the concept of a single blood test capable of detecting more than fifty cancers. The outcome underscores a fundamental reality: the biology of cancer detection is more complex than early expectations suggested.
Importantly, the disappointing performance of one multi-cancer detection approach should not be interpreted as a failure of liquid biopsy as a scientific field. On the contrary, liquid biopsy remains a conceptually sound and clinically promising strategy, grounded in well-established biological mechanisms rather than purely statistical screening paradigms.
Several leading experts have openly questioned the performance of the Galleri test. Richard Houlston of the Institute of Cancer Research in the United Kingdom described the assay as “simply not a very good test,” a view widely reported in The New York Times. Similarly, Richard Sullivan of the Institute of Cancer Policy at King’s College London argued in the British Medical Journal that, given the unfavourable signals from earlier studies, the rationale for undertaking the large trial was already uncertain. The negative primary outcome of the study now reinforces these concerns.
Sullivan further cautioned that portraying the trial as successful despite the absence of statistical significance risks misrepresenting the evidence and undermining scientific integrity. Framing negative or inconclusive results as positive findings not only distorts scientific interpretation but may also erode public trust in biomedical innovation and research.
Nevertheless, the limitations observed in the Galleri trial should not be generalised to the broader domain of blood-based cancer diagnostics. As Peter Lichter has emphasised, the biological constraints encountered by mutation-based pan-cancer detection strategies reflect the intrinsic heterogeneity of tumor biology rather than a fundamental limitation of liquid biopsy itself.
Tumors differ substantially in the quantity and type of biological material they release into circulation. Some malignancies shed detectable genetic material readily, generating strong circulating signals, whereas others release very little or highly fragmented material. As a result, universal mutation-based screening panels face inherent sensitivity challenges, particularly when applied across diverse tumor entities.
These biological realities highlight an important conceptual distinction: while broad mutation-based pan-cancer screening approaches encounter significant limitations due to tumor heterogeneity and low circulating DNA abundance, liquid biopsy strategies based on functional tumor biology may offer a more robust alternative.
PanTum Detect exemplifies such an alternative approach. Rather than attempting to catalogue a wide spectrum of tumor-specific mutations, the test focuses on two functionally relevant biomarkers that reflect core hallmarks of malignant transformation.
TKTL1 is a regulator of metabolic reprogramming associated with altered glucose metabolism, increased glycolytic activity, and tumor progression. As such, it captures metabolic adaptations that are central to cancer cell biology.
Apo10 is linked to dysregulated apoptosis and abnormal tumor-associated cellular turnover, reflecting a pathological imbalance between cell survival and programmed cell death within transformed tissues.
PanTum Detect is based on EDIM (Epitope Detection in Monocytes) technology. In contrast to approaches that rely exclusively on free circulating tumor DNA, EDIM exploits the biological role of circulating immune cells, particularly monocytes and macrophages, which actively phagocytose tumor-derived material.
These immune cells effectively concentrate tumor-associated proteins within their intracellular compartments. The internalised biomarkers can subsequently be analysed, creating a form of natural biological signal amplification.
This strategy enables the detection of tumor-associated activity even in situations where circulating tumor DNA is scarce or difficult to identify, thereby addressing one of the major limitations of mutation-based liquid biopsy approaches.
PanTum Detect is characterised by several key features:
- Functional assessment of metabolic reprogramming and apoptosis dysregulation
- Immune-mediated amplification of tumor-derived biological signals
- Applicability across multiple tumor entities without reliance on tumor-specific mutation panels
- A biologically grounded multi-tumor detection strategy rather than a purely statistical pattern-recognition model
In this context, the shortcomings observed in broad ctDNA-based multi-cancer tests highlight a crucial distinction. The challenges associated with universal mutation-based screening models do not invalidate the concept of liquid biopsy. Rather, they illustrate the intrinsic biological constraints faced by mutation-driven pan-cancer detection strategies.
PanTum Detect operates on a fundamentally different principle. Instead of attempting to identify every possible tumor mutation, it captures the functional consequences of malignant transformation through metabolic and apoptosis-related biomarkers, amplified through interaction with the immune system.
From a scientific standpoint, the future of multi-tumor detection is likely to depend on mechanistically defined, biologically stratified diagnostic strategies, rather than on screening models that rely primarily on broad statistical correlations across heterogeneous tumor types.
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