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SYMPLIFY - evaluation of methylation-based multicancer early detection (MCED) diagnostic test

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

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SYMPLIFY - evaluation of methylation-based multicancer early detection (MCED) diagnostic test

  • blood-based multicancer early detection (MCED) tests measure cancer biomarkers, such as genetic and epigenetic changes in circulating tumour DNA or proteins produced by cancer cells
    • tests have primarily been used for screening in asymptomatic populations or in detecting recurrence following cancer treatment
    • SYMPLIFY investigated the performance of a targeted methylation-based MCED test in symptomatic patients referred from primary care for urgent cancer investigation

  • multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales
    • participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation
    • participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test
    • Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome
    • MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution

  • results:
    • MCED detected a cancer signal in 323 cases, 244 of whom had a cancer diagnosed
    • overall sensitivity of the MCED test in identifying the presence or absence of cancer across all 368 cancers was 66.3%, the specificity was 98.4%, the positive predictive value was 75.5%, and the negative predictive value was 97.6%
    • overall accuracy of the top cancer signal origin prediction in cases for which a cancer signal was detected was 85.2%, ranging from 71.7% for cancers diagnosed by the lung pathway to 93.8% for the lower gastrointestinal pathway

  • conclusion:
    • first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care


  1. Nicholson BD, Oke J, Virdee PS, Harris DA, O'Doherty C, Park JE, Hamady Z, Sehgal V, Millar A, Medley L, Tonner S, Vargova M, Engonidou L, Riahi K, Luan Y, Hiom S, Kumar H, Nandani H, Kurtzman KN, Yu LM, Freestone C, Pearson S, Hobbs FR, Perera R, Middleton MR. Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study. Lancet Oncol. 2023 Jul;24(7):733-743. doi: 10.1016/S1470-2045(23)00277-2. Epub 2023 Jun 20. PMID: 37352875.

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