Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a 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. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This 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. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial.

We report the design of the NHS-Galleri trial (ISRCTN91431511), aiming to establish whether a multi-cancer early detection (MCED) test that screens asymptomatic individuals for cancer can reduce late-stage cancer incidence. This randomised controlled trial has invited approximately 1.5 million persons and enrolled over 140,000 from the general population of England (50-77 years; ≥3 years without cancer diagnosis or treatment; not undergoing investigation for suspected cancer). Blood is being collected at up to three annual visits. Following baseline blood collection, participants are randomised 1:1 to the intervention (blood tested by MCED test) or control (blood stored) arm. Only participants in the intervention arm with a cancer signal detected have results returned and are referred for urgent investigations and potential treatment. Remaining participants in both arms stay blinded and return for their next visit. Participants are encouraged to continue other NHS cancer screening programmes and seek help for new or unusual symptoms. The primary objective is to demonstrate a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention versus control arm 3-4 years after randomisation. NHS-Galleri will help determine the clinical utility of population screening with an MCED test.

Addressing the growing international challenge of cancer: a multinational perspective.

Leaders in cancer research and policy from 15 economically diverse countries met at the U.S. National Institutes of Health in November 2012 to discuss opportunities to reduce cancer incidence and mortality, improve cancer care, and increase our understanding of disease pathophysiology. Here, we present recommendations that the participants believe will enable faster progress in addressing the growing international challenge of cancer.