is a prospective, randomised, controlled trial to assess the performance and clinical utility of a multi-cancer early detection test (GalleriTM) for population screening in the United Kingdom (UK) when added to standard of care
Galleri test
is a new biomarker technology for early cancer detection that has been developed by GRAIL, Inc in the US as a cancer screening test to complement existing screening programmes
recognises methylation patterns in cell-free DNA (cfDNA) isolated from peripheral whole blood
the detection of a methylation pattern associated with cancer is returned as a 'Cancer Signal Detected' result
if no cancer is detected, the test will return a 'Cancer Signal Not Detected' result
when a cancer signal is detected, the report will include one or two predicted 'Cancer Signal Origin' (CSO)
21 possible CSOs are reported based on 24 cancer classes, representing more than 50 different cancers
the CSO cannot be used to confirm a cancer diagnosis but can be used to inform the diagnostic pathway
the Galleri test does not determine an individual's genetic risk for cancer
trial is designed to establish if screening with the Galleri test reduces the incidence of late stage cancer when used in an asymptomatic population in combination with existing NHS cancer screening programmes
trial is managed by the Cancer Research UK & King's College London (KCL) Cancer Prevention Trials Unit (CPTU) on behalf of GRAIL Bio UK Ltd. (GRAIL) and NHS England (NHSE)
trial aims to enrol 140,000 participants, 15-20,000 people from each participating Cancer Alliance
NHS-Galleri trial, participants must be:
age 50-77 years old;
registered at a postcode within a participating Cancer Alliance; and
not diagnosed with cancer in the past 3 years or currently under diagnostic follow up/treatment for cancer
is a randomised double blind trial - i.e. 50% of the trial participants will not have the Galleri test
in the intervention arm, all samples will be tested. In the control arm, samples will be stored for future analysis
participants in the intervention arm with a 'Cancer Signal Detected' result will be referred directly to the two-week wait cancer referral pathway for follow up diagnostic testing as agreed by NHSE. GPs will be informed if their patient receives a 'Cancer Signal Detected' result
How good is the Galleri test at detecting cancer?
in the study by Lui et al
stage I-III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for approximately 63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types
a 'Cancer Signal Detected' result is not a diagnosis of cancer and diagnostic follow up is needed to confirm whether a participant has cancer
in clinical studies, the test was found to be highly specific, with a low false positive rate of 0.5% (Beer et al., 2021; Klein et al., 2021)
Lui et al reported that specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]
the positive predictive value (PPV) for a positive Galleri test is about 40% - i.e. in about 40% of participants with a 'Cancer Signal Detected' result, a cancer diagnosis was confirmed (Beer et al., 2021)
thus in the Galleri trial about 60% of patients with a positive test will not have cancer
by contrast, the PPVs for United States Preventive Services Task Force (USPSTF) recommended screening for breast, colorectal (stool-based), and lung cancer (in the USPSTF-recommended high-risk population) range from 3.7% to 4.4% i.e. for every one person with cancer correctly detected, there would be between 22 and 27 people incorrectly identified as having cancer (4,5,6)
if a cancer signal is detected, one or two CSOs are reported
if pathway specific diagnostic investigations have been carried out for the first indicated CSO and no cancer is found, then the second CSO site should be investigated
interim results from the PATHFINDER study (prospective cohort, n = 6629) (NCT04241796) indicate that the proportion of correctly predicted first or second CSO among true positive cases is high, at 96.3% (95% CI: 81.7-99.8) (Beer et al., 2021)
in the study by Lui et al TOO (tissue of origin) was predicted in 96% of samples with cancer-like signal; of those, the tissue of origin(TOO) localization was accurate in 93% - therefore the tissue of origin was identified and correct in 0.96 x 0.93 cases - i.e. in approximately 90% of patients who had cancer
Klein EA, Donald R, Cohn A, Tummala M, Lapham R, Cosgrove D, Chung G, Clement J, Gao J, Hunkapiller N, Jamshidi A, Kurtzman KN, Seiden MV, Swanton C and Liu MC, 2021, Clinical Validation of a Targeted Methylation Based Multi-Cancer Early Detection Test. American Association for Cancer Research (AACR) Annual Meeting, 10-15 April and 17-21 May, virtual conference
Lui MC et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. Jun;31(6):745-759. doi: 10.1016/j.annonc.2020.02.011. Epub 2020 Mar 30.
Lehman CD, Arao RF, Sprague BL, et al. National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology. 2017;283(1): 49e58.
U. S. Food and Drug Administration. Cologuard Summary of Safety and Effectiveness Data (Premarket Approval Application P130017). 2014. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf13/P13 0017B.pdf.
The National Lung Screening Trial Research Team. Results of initial lowdose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21):1980e1991.
GP Information Sheet NHS-Galleri Trial (August 2021).
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