Evaluating multi-cancer early detection tests - an argument for the outcome of recurrence - updated stage

Sep 24, 2026

Multi-cancer early detection (MCED) tests are proposed to improve cancer diagnosis by enabling earlier detection and greater use of curative therapies. The NHS-Galleri trial evaluates an MCED test developed by GRAIL, using the absolute incidence of late-stage cancer as the primary endpoint. The authors argue this may not fully represent effects on cancer mortality because micro-metastatic disease and late recurrence can alter how trial outcomes translate into survival benefit.

LanguageEnglish

CategoryHealthcare

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Pages3

Reading Time8 min

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Evaluating MCED test outcomes

Rationale for using late-stage incidence as endpoint

Why recurrence and micro-metastatic disease may affect mortality impact

Implications for trial design and evidence generation

British Journal of Cancer [www.nature.com/bjc](www.nature.com/bjc) PERSPECTIVE Clinical Studies OPEN Evaluating multi-cancer early detection tests: an argument for the outcome of recurrence-updated stage Matthew E. J. Callister 1,2 ✉, Emma J. Crosbie 3, Philip A. J. Crosbie4 and Hilary A. Robbins5 © The Author(s) 2023 | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | The advent of multi-cancer early detection (MCED) tests has the potential to revolutionise the diagnosis of cancer, improving patient outcomes through early diagnosis and increased use of curative therapies. The ongoing NHS-Galleri trial is evaluating an MCED test developed by GRAIL, and is using as its primary endpoint the absolute incidence of late-stage cancer. Proponents of this outcome argue that if the test reduces the number of patients with advanced, incurable cancer, it can be reasonably assumed to be beneﬁtting patients by reducing cancer mortality. Here, we argue that this assumption may not always hold due to the phenomenon of micro-metastatic disease, and propose an adjustment to the trial outcome so that it may better reﬂect the expected effect of the test on cancer mortality. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | British Journal of Cancer (2023) 129:1209–1211; [https://doi.org/10.1038/s41416-023-02434-4](https://doi.org/10.1038/s41416-023-02434-4) | | | | | | | | | | | | | | | | The potential widespread roll-out of MCED tests in nationwide screening programmes will be expensive and could carry harms that differ from traditional single-cancer screening. It is therefore imperative that any roll-out is supported by robust evidence for the test’s clinical efﬁcacy and cost-effectiveness. The accepted gold-standard evidence for a cancer screening test is a randomised controlled trial demonstrating a reduction in cancerspeciﬁc mortality, as this avoids biases such as lead-time or overdiagnosis. However, trials powered for mortality outcomes need to be large, expensive, and can take a decade or more to report by which time the technology may be out of date. The recent advances in systemic anti-cancer treatment might exacerbate this problem, because if treatments are more effective at prolonging survival in patients with metastatic disease, then demonstrating a mortality beneﬁt will require even longer followup. This has led to increased interest in surrogate endpoints which ideally would yield robust evidence of beneﬁt over a much shorter follow-up period. This would have the dual advantage of allowing more rapid implementation to save lives, whilst also driving innovation by ensuring earlier return on investment for those developing new technologies. The NHS-Galleri trial is a randomized controlled trial being conducted in partnership with the English National Health Service. The primary endpoint is the absolute incidence of late stage cancer, with the study powered at 90% to detect a reduction in stage III and IV cancers for all sites combined after three rounds of screening compared to usual care [1] . This endpoint was selected because it is not inﬂuenced by overdiagnosis, as it is unaffected by diagnosis of indolent disease. The study has recruited at a remarkable rate, exceeding its target of 140,000 participants in only 10 months [2] . The speed of recruitment, which has taken place in over 150 community locations, highlights the advantages of undertaking trials of this size in the NHS, with its centralised population databases and well curated cancer registry data. The NHS in England has committed to purchase 1 million tests for use in the English population if “initial results are promising” although nospeciﬁcs have been provided for the criteria that will trigger this roll-out [2] . It will be important to collect detailed data on this initial

FAQs

What is the primary endpoint used in the NHS-Galleri MCED trial?

The trial’s primary endpoint is the absolute incidence of late-stage cancer after three rounds of screening compared with usual care.

Why do the authors question whether late-stage incidence reliably indicates mortality benefit?

They argue the assumption may fail when micro-metastatic disease is present, since recurrence risk can differ and may not be captured fully by the late-stage endpoint.

How does the GRAIL Galleri test detect cancer signals?

It uses methylation patterns of cell-free DNA released into blood by apoptosis or necrosis to detect a cancer signal.

Sep 24, 2026

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