A multi-cancer early detection (MCED) test: clinical update for GPs

Introduction

Cancer screening can be effective at early-stage detection, but, currently, only around 6% of cancers in the UK are screen-detected with programmes for cervical, colorectal, breast, and more recently targeted lung cancer screening.¹ Increasing areas of interest are cancer detection tests based on circulating tumour-derived DNA (ctDNA) and their potential role in cancer screening,² with multiple blood-based tests being developed.³ These are designed to detect potential cancer signals that could originate from more than one site, and are termed multi-cancer early detection (MCED) tests.

Multi-cancer early detection (MCED) tests: an evolving technology

CtDNA are extracellular fragments of tumour DNA released via cell death to body fluids such as blood and have been termed ‘liquid biopsies’.⁴ CtDNA-based tests aim to detect a potential cancer signal and some tests also predict the likely site or cancer signal of origin (CSO).³ Screening tests based upon the detection of ctDNA signals may be less likely to detect relatively indolent tumours (as they shed less DNA) potentially reducing risks of overdiagnosis, though more research is needed.⁵ Besides ctDNA, several MCED tests also utilise other biomarkers such as cell-free RNA, circulating tumour cells, extra-cellular vesicles, tumour-related proteins, and metabolites, which are at different stages of research. This article primarily focuses on the Galleri^® test, which is the most developed at present and is being trialled in the UK NHS.

The MCED Galleri^® test

In a two-step process, the test utilises targeted methylation of ctDNA to predict the presence or absence of a potential cancer signal and the likely CSO to guide the diagnostic referral pathway. The test can report one or two of up to 21 CSOs (Box 1) covering many tissue types and organs, with the aim to guide diagnostic investigations. The Galleri^® test is intended to complement existing screening programmes and is currently undergoing a large-scale randomised controlled trial (RCT), the NHS-Galleri trial set to report in 2026.⁶ Some GPs might have seen results from trial participants who are registered with their practices.

Box 1.

Twenty-one possible cancer signal origin (CSO) labels⁷

Anus

Bladder, urothelial tract

Bone and soft tissue

Breast

Cervix

Colon, rectum

Head and neck

Kidney

Liver, bile duct

Lung

Lymphoid lineage

Melanocytic lineage

Myeloid lineage

Neuroendocrine cells of lung or other organs

Ovary

Pancreas, gallbladder

Plasma cell lineage

Prostate

Stomach, oesophagus

Thyroid gland

Uterus

Current evidence for the Galleri^® test

The Circulating Cell-free Genome Atlas (CCGA) study⁷ was a prospective, multi-centre, case-control, observational study of 15 254 asymptomatic participants aged 20 years or older in North America. Overall sensitivity for cancer signal detection was 51.5%, which increased with stage: stage I: 16.8%, stage II: 40.4%, stage III: 77.0%, and stage IV: 90.1%. Therefore, an important limitation of the Galleri^® test from current data is less sensitivity for earlier-stage cancers. Furthermore, sensitivity also varies significantly between the possible CSO signals, from, for example, above 80% for oesophagus, ovary, and pancreas, and below 20% for prostate and kidney.⁷ The PATHFINDER study⁸ was a prospective study of 6662 asymptomatic participants aged 50 years and over in the US and concluded that the test has 88.0% CSO prediction accuracy.

NHS-Galleri trial

The NHS-Galleri trial (NCT05611632) is a pragmatic and prospective RCT that has enrolled over 140 000 asymptomatic participants aged 50–77 years in eight Cancer Alliance areas in England.⁶ The primary end-point is whether the test reduces the incidence of late-stage cancer in asymptomatic individuals when combined with existing NHS cancer screening programmes.⁸ All enrolled participants undergo a blood draw and are then randomised into intervention (receiving the test) or control (blood stored for future testing if necessary) arms. Participants are only unblinded if they have a ‘cancer signal detected’ test result (one or two CSO predictions may be reported) and are referred by the trial team to their local participating NHS trust via existing urgent suspected cancer (USC) referral (previous 2-week wait) pathways for investigations and diagnostic resolution. All other participants receive a letter saying that their blood has been received and that they should continue with ‘standard care’ in terms of established cancer screening and seeking help if symptomatic. For clinicians receiving Galleri trial USC referrals, there is additional information provided on the potential cancer signal (CSO) and agreed guidance for referrals, which links to existing NHS guidelines.⁹ Historically, USC referrals have been for symptomatic patients via their GP, and this is the first use of these pathways for screening in asymptomatic individuals. Some patients may have two potential CSOs reported, adding to the complexity, as these will both likely need diagnostic work-up. In some trial areas, there is a single point of access including potential for triage via rapid diagnostic centres (RDCs), which are being rolled out for people with non-specific symptoms.

Any screening test has a potential risk of unnecessary investigations and overdiagnosis,¹⁰ and it is therefore crucial to have evidence of benefit vs. risk before implementing a national screening programme,¹¹ including for MCEDs such as the Galleri^® test.¹²

Key messages for primary care

The published data surrounding the Galleri^® test suggest a positive predictive value (PPV) for cancer in the region of 40%, which is higher than for existing single cancer screening tests. The current National Institute for Health and Care Excellence USC referral guidance⁹ (for symptomatic patients) discusses a 3% PPV when considering referral for cancer testing, while the overall PPV (or conversion rate) for USC referrals is currently around 7%. In the UK, MCED tests are at present a part of research studies and not routine NHS care. In the NHS-Galleri trial, GPs are copied into correspondence for people with a ‘Cancer Signal Detected’ test result and are informed that the patient has been referred via the USC pathway with no actions for primary care. The NHS has developed guidance for NHS-Galleri trial referrals.

Patients may have questions about MCED tests (including Galleri^®), such as what the test result means, and how to access tests. Patients may have accessed commercial MCED tests overseas and requested guidance in rarer cases. There is a need for clear messaging, education, and guidance for patients and healthcare professionals. This includes reinforcing that these tests are currently still being evaluated and validated in large research studies and are not routine NHS care. MCED tests are screening and triage tests, that is, identifying a potential cancer signal, rather than diagnostic tests. Safety netting is crucial, with patients and clinicians not biased by a test result, and patients should be encouraged to attend existing screening programmes and seek medical advice if they develop new or worrying symptoms. In addition, for the best public health benefit, any future implementation strategy must focus on equal participation among all socioeconomic groups.¹³

In the future, MCEDs might be used to help direct investigations for symptomatic patients. SYMPLIFY¹⁴ was a multi-centre UK observational study of symptomatic patients referred via USC for non-specific, gynaecological, lung, or upper or lower gastrointestinal pathways with a final cohort of 5461 patients. The Galleri^® test yielded a PPV of 75.5%, negative predictive value (NPV) of 97.6%, sensitivity of 66.3%, and specificity of 98.4%. The test’s prediction of CSO, assessed retrospectively, was accurate in 85.2% of cases.

Conclusions

The area of MCED tests is rapidly evolving and will likely see more tests and clinical trials, although the future role of these tests, including Galleri^®, in the NHS within symptomatic and asymptomatic populations remains to be defined. It is important to note that, while these tests are not within routine use, GPs who have patients testing positive in the NHS-Galleri trial will be informed of USC referrals. GPs may also have patients asking questions about these tests, with a need for education and guidance to support patients and healthcare staff. The development of MCED tests poses opportunities and challenges for healthcare systems, including a need for rigorous evaluation, including any potential risk of overdiagnosis and health economic consequences.

Funding

Thomas Round is partly funded on the NHS-Galleri trial at King’s College London via GRAIL, LLC. Richard D Neal provides his services as Co-Chief Investigator to the NHS-Galleri trial through university consultancy funded by GRAIL, LLC, to the University of Exeter; both he and the University of Exeter financially benefit from this partnership

Provenance

Freely submitted; externally peer reviewed.

Contributors

Tanvi Save and Thomas Round conceived of the article and co-wrote the manuscript together.

Competing interests

Tanvi Save was an MPH student at King’s College London while completing this work and Thomas Round was her supervisor. Thomas Round is an Associate Editor of the BJGP.