LBA100 Background: MCED blood tests can detect a shared cancer signal from circulating cell-free DNA. NHS-Galleri (NCT05611632) is a randomised controlled trial in England of 142,924 enrolled participants evaluating the clinical utility of an MCED test (Galleri) for annual screening of asymptomatic individuals aged 50–79 yrs. Methods: Peripheral blood samples were taken at up to 3 annual visits (Y0, Y1, Y2). After the Y0 blood draw, participants were randomised 1:1 to the intervention (I; blood tested by MCED test) or control (C; blood not tested) arms. I arm participants with a cancer signal detected MCED test result were referred into the NHS for diagnostic workup via appropriate urgent suspected cancer pathways. As agreed with NHS England, clinical utility was assessed by reduction in late stage (Stage III/IV [primary objective] and Stage IV [key secondary objective]) cancer incidence in I vs C arm ~3 yrs after the last participant’s randomisation. Results: Trial arms were well balanced. The primary endpoint of statistically significant Stage III/IV reduction in 12 prespecified cancers was not met (706 vs 688; incidence rate ratio [IRR] 1.03; Table). In these 12 cancers, Stage III/IV decreased from the prevalence screening round (IRR 1.19) to incidence rounds (0.95; 0.88). A 14% reduction in Stage IV cancers (342 vs 397) was observed after 3 yrs of screening (Y0: 9%; Y1: 22%; Y2: 26%). Stage I/II cancers increased by 16% (647 vs 559; relative risk [RR] 1.16 [1.03, 1.30]) after 3 yrs of screening. Similarly, Stage I-III cancers increased by 19% (1007 vs 846; RR 1.19 [1.09, 1.30]). Across all cancer types, 3637 and 3400 were diagnosed in I and C arms, respectively, over 3 yrs of screening. MCED quadrupled the number of screen-detected cancers (1173 vs 290). MCED reduced clinically-detected cancers by 21% (2464 vs 3110) and emergency presentations by 21% (225 vs 286). Aggregate test performance (99.55% specificity, 52.0% positive predictive value, 92.5% top-two and 87.0% top-one cancer signal origin accuracy) was consistent with prior studies and real-world evidence. There were 381 and 333 related adverse events (AEs) in I and C arms, respectively, and no related serious AEs. Conclusions: Although the primary endpoint was not met, adding annual MCED testing to standard-of-care cancer screening substantially increased screen-detected cancers and reduced Stage IV cancers and emergency presentations. This evidence combined with the favourable safety profile and robust performance suggests that integrating MCED into population screening programs may help reduce late stage cancer burden. Clinical trial information: NCT05611632 . Late-stage IRR (I/C) of 12 prespecified cancers. Stage III/IV Stage IV Y0 1.19 (95% CI: 0.98, 1.43) 0.91 (0.71, 1.18) Y1 0.95 (0.77, 1.17) 0.78 (0.57, 1.06) Y2 0.88 (0.73, 1.07) 0.74 (0.57, 0.95) Overall 1.03 (0.92, 1.14)p=0.6324 0.86 (0.744, 0.998)

Background:The observational SYMPLIFY study reported the accuracy of a multi-cancer early detection (MCED) test in a referred symptomatic population. We explore how the MCED test may contribute to a faster or more efficient diagnosis if acted upon. Methods:We reviewed all cancers diagnosed in SYMPLIFY (ISRCTN10226380) using data collected at study sites plus two years of cancer registry data. All cancer diagnoses were classified based on the congruence between the participant's symptoms, diagnostic referral pathway, MCED test cancer signal origin (CSO) prediction, cancer site, and time to diagnosis. Findings:There were 533 cancers diagnosed among 5461 (9.8%) evaluable participants in SYMPLIFY during the 2-year follow-up period. Among the 79 participants with an apparent false positive test result in the original SYMPLIFY study, 28 (35%) were diagnosed with cancer based on cancer registry data, increasing the MCED PPV to 84.2% (80.1-87.6). In aggregate, only one of the 28 additional patients had a cancer diagnosed that was incongruent with a predicted MCED CSO. Among the 5014 patients with an apparent true negative MCED test result, 113 (2%) received a subsequent cancer diagnosis. In 101 (19%) of the 533 cancers diagnosed, the MCED test result might have contributed to a more efficient diagnosis had it been used to inform the clinical work-up. Conversely, 49 (9%) cancers might have taken longer to diagnose if the MCED test result alone had been used in the diagnostic process, directing investigations based upon an incorrect CSO prediction. Interpretation:These exploratory findings demonstrate a substantially higher rate of cancer diagnoses in symptomatic participants originally classified with a false positive MCED test result than those originally classified as true negative. We show how MCED tests have the potential to assist clinical decision making, which may in turn lead to a timelier cancer diagnosis for one fifth of cancers diagnosed. Funding:GRAIL Bio UK, Ltd. NIHR.

BACKGROUND:Cancer places a high burden on society and health-care systems. Cancer research requires high-quality data, which is resource-intensive to obtain. Using administrative datasets such as cancer registries could improve the efficiency of cancer studies if data were valid and timely. We aimed to compare the validity and timeliness of diagnostic cancer data on-site during the SYMPLIFY study to that obtained from the cancer registries of England and Wales. METHODS:Cancer data were collected from 5461 participants across 44 hospital sites during a prospective observational study in England and Wales, SYMPLIFY (ISRCTN10226380). Linked cancer data were obtained from Digital Health and Care Wales (DHCW), the Welsh Cancer Intelligence and Surveillance Unit (WCISU), and the English National Cancer Registration Dataset (NCRD) and Rapid Cancer Registration Dataset (RCRD), regularly between April, 2022, and September, 2023. The primary objectives of the study were to evaluate the validity (via assessment of the proportion of completed data fields and concordance with SYMPLIFY sites), and timeliness of the data in all datasets, for all cancers diagnosed within 9 months of study enrolment. Data fields investigated were cancer site via International Classification of Disease, 10th Revision (ICD-10) code; cancer morphology via International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) morphology histology code and broad morphological grouping; overall stage; and TNM classification. FINDINGS:For data collected between April, 2022, and September, 2023, completeness at the last data cut available for each dataset ranged from 84% to 100% for ICD-O-3 morphology, from 43% to 100% for overall stage, and from 74% to 83% for TNM stage. The concordance between SYMPLIFY data and NCRD was 96% (95% CI 92-98) for ICD-10, 60% (53-66) for ICD-O-3 morphology, 83% (78-88) for ICD-O-3 broad morphology groupings, 73% (67-78) for stage, and 51% (44-59) for TNM; and with WCISU was 89% (95% CI 81-94) for ICD-10, 63% (53-73) for ICD-O-3 morphology, 80% (70-87) for ICD-O-3 broad morphology groupings, 83% (74-90) for overall stage, and 49% (38-61) for TNM stage. Concordance between SYMPLIFY and RCRD was 95% (95% CI 92-98) for ICD-10, 67% (60-74) for ICD-O-3 morphology, 85% (79-90) for ICD-O-3 broad morphology groupings, and 73% (65-80) for overall stage; and between SYMPLIFY and DHCW was 96% (91-99) for ICD-10, 74% (64-83) for ICD-O-3 morphology, 84% (75-91) for ICD-O-3 broad morphology groupings, and 87% (74-95) for stage. The SYMPLIFY dataset reached completion at 12 months post-enrolment in November, 2022, compared with 13 months for NCRD in December, 2023. RCRD and DHCW reached completion at 13 months and 15 months post-enrolment, in December, 2022, and February, 2023, respectively. INTERPRETATION:We report similar completeness of data fields, concordance, and timeliness between on-site and centrally collected cancer outcomes data. Our findings suggest that central registry data can help alleviate the resource burden in clinical trials and improve cancer research. Cancer registries might need additional resources to provide data for registry-based trials at scale. FUNDING:GRAIL Bio UK.

1501 Background: Delays in cancer diagnosis can lead to increased mortality, leading to specialized diagnostic pathways for symptomatic patients when cancer is suspected. Identification of circulating tumour DNA can stratify individuals into those more or less likely to have cancer and predict the cancer origin. This could both expedite cancer diagnosis and reduce harm and inefficient investigation in those who do not have cancer. We evaluated the performance of a next-generation sequencing MCED test (GRAIL, LLC) using cell-free DNA (cfDNA) isolated from whole blood in symptomatic patients referred to cancer diagnostic clinics by their primary care physician. Methods: Patients referred for urgent imaging, endoscopy or other diagnostic modalities to investigate symptoms suspicious for cancer were invited to take part. Participants with non-specific symptoms or being tested for lung, gynaecological, upper gastrointestinal (GI) or lower GI cancers gave a blood sample on the day they attended for urgent standard of care investigations. cfDNA was isolated from blood samples and stored until the MCED test was performed in batches, blinded to clinical outcome. The test’s predictions (cancer signal detected yes/no; predicted signal origin) were compared with the diagnosis obtained by standard care to establish the positive and negative predictive value (PPV & NPV), sensitivity and specificity across the whole study population, by referral pathway, and by presenting symptom. In addition, sensitivity was analysed by cancer site and stage. Results: 6238 participants were recruited over 5 months from the 5 clinical pathways at 44 hospital sites in England and Wales. 5461 individuals had an MCED test result and diagnostic outcome and were evaluable. Mean age was 62.1 years (SD, 13.8), 3609 (66.1%) female, 2533 (46.4%) current or former smokers. 368 (6.7%) evaluable patients had a cancer diagnosed. The MCED test detected a cancer signal in 323 cases, 244 in whom cancer was diagnosed and 79 where it was not, yielding a PPV of 75.5% (95% CI 70.5-80.1%), NPV 97.6% (97.1-98.0%), sensitivity 66.3% (61.2-71.1%), and specificity 98.4% (98.1-98.8%). Sensitivity increased with increasing age and cancer stage, from 24.2% (16.0-34.1%) in Stage I to 95.3% (88.5-98.7%) in Stage IV. Sensitivity 80.4% (66.1-90.6%) and NPV 99.1% (98.2-99.6%) were highest for patients referred with symptoms qualifying for the upper GI pathway. Conclusions: This is the first large-scale prospective evaluation of an MCED test in a symptomatic population. These data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms with low, but higher than background, probability of being due to cancer. Study data are also being used to enhance the negative predictive value of the current MCED classifier for a symptomatic population. Clinical trial information: ISRCTN10226380 .

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 & BULL;7%] with a cancer diagnosis and 5093 [93 & BULL;3%] without a cancer diagnosis). The median age of participants was 61 & BULL;9 years (IQR 53 & BULL;4-73 & BULL;0), 3609 (66 & BULL;1%) were female and 1852 (33 & BULL;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 & BULL;5% (95% CI 70 & BULL;5-80 & BULL;1), negative predictive value of 97 & BULL;6% (97 & BULL;1-98 & BULL;0), sensitivity of 66 & BULL;3% (61 & BULL;2-71 & BULL;1), and specificity of 98 & BULL;4% (98 & BULL;1-98 & BULL;8). Sensitivity increased with increasing age and cancer stage, from 24 & BULL;2% (95% CI 16 & BULL;0-34 & BULL;1) in stage I to 95 & BULL;3% (88 & BULL;5-98 & BULL;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 & BULL;2% (95% CI 79 & BULL;8-89 & BULL;3) of cases. Sensitivity 80 & BULL;4% (95% CI 66 & BULL;1-90 & BULL;6) and negative predictive value 99 & BULL;1% (98 & BULL;2-99 & BULL;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.

TPS6606 Background: Cancer is a leading cause of premature death globally. Early detection can reduce cancer mortality by reducing the number of cancers diagnosed at a late stage. A blood-based MCED test (Galleri) was developed that can detect cancer signals and predict cancer origin with a single blood draw. The NHS-Galleri trial is a randomized controlled trial (RCT) assessing the clinical utility of this MCED test in a targeted screening population alongside current screening programs. Screening adherence is lower among certain individuals (eg, those with lower socioeconomic status), despite healthcare being free at the point of access in England. NHS-Galleri utilizes innovative strategies to optimize equity in study recruitment, with the goal of enrolling a representative sample. Methods: This pragmatic, blinded RCT is currently enrolling 140,000 asymptomatic participants by inviting ̃1.3 million residents aged 50-77 in select postcodes of England via the NHS DigiTrials service. Regions were selected to include areas of high cancer mortality, socioeconomic deprivation, and ethnic diversity; eligible participants will be identified from these regions. A variety of methods are employed to enroll a representative study population (defined as including a reasonable number of participants from all socioeconomic statuses and all major ethnic minority groups). These methods include the use of mobile phlebotomy clinics that facilitate access in economically deprived areas, monitoring of participant representativeness by postcode with dynamic adjustment of enrollment, providing interpreters and wheelchair accessibility, and targeted local campaigns. Blood will be collected at 3 annual visits (baseline, year 1, year 2) unless cancer is diagnosed. After baseline blood collection, participants will be randomized 1:1 to the intervention (blood sample analyzed by the MCED test) or control (blood sample stored for potential future MCED testing) arm. Only participants in the intervention arm with “cancer signal detected” will have results returned and be referred for investigations and possible treatment. Participants in the intervention arm without “cancer signal detected” and all in the control arm will remain blinded and return for annual visits. All participants will be reminded to continue guideline-based screening and report unusual/concerning symptoms to a doctor. The primary study objective is a significant reduction in the absolute numbers of stage III & IV cancers diagnosed in the intervention versus control arm 3.5 years after randomization. Cancer-specific mortality will be assessed during trial follow-up. Exploratory endpoints include assessing the primary objective by participant age, gender, socioeconomic status, and ethnicity. Clinical trial information: ISRCTN91431511.

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.

I write in response to some of the key points raised in Barclay and Bradley’s editorial regarding the partnership between Grail and NHS England.1 Grail’s multi-cancer early detection (MCED) test represents one of the first examples of an innovation developed by a private company but intended for public health uptake. Adding MCED to ongoing single cancer screening could dramatically improve …

Cancer is the leading cause of death in the UK and lung cancer kills more people than any other cancer, accounting for 35 620 (21%) of all cancer deaths in 2016. 1 Cancer Research UKLung cancer statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancerDate accessed: July 3, 2018 Google Scholar Survival for lung cancer has historically been worse in the UK than in comparator countries. 2 Walters S Maringe C Coleman MP et al. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004–2007. Thorax. 2013; 68: 551-564 Crossref PubMed Scopus (2) Google Scholar Robust evidence 3 Royal College of PhysiciansNational Lung Cancer AuditNational Lung Cancer Audit Annual report 2017 (for the audit period 2016). https://www.hqip.org.uk/wp-content/uploads/2018/03/NLCA2017AnnualReport_web_FINAL.pdfDate: 2018 Date accessed: July 3, 2018 Google Scholar , 4 Møller H Coupland VH Tataru D et al. Geographical variations in the use of active cancer treatments are associated with survival of lung cancer patients in England. Thorax. 2018; 73: 530-537 Crossref PubMed Scopus (20) Google Scholar suggests that the two major explanatory factors are late diagnosis and wide geographical variation within the UK in the proportion of people receiving potentially curative treatment. Late diagnosis is not confined to the UK, but a high proportion of patients are diagnosed at a late stage 2 Walters S Maringe C Coleman MP et al. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004–2007. Thorax. 2013; 68: 551-564 Crossref PubMed Scopus (2) Google Scholar and the majority of excess lung cancer deaths occur in the first year after diagnosis. 5 Holmberg L Sandin F Bray F et al. National comparisons of lung cancer survival in England, Norway and Sweden 2001–2004: differences occur early in follow-up. Thorax. 2010; 65: 436-441 Crossref PubMed Scopus (79) Google Scholar Patients diagnosed with the earliest stage of non-small-cell lung cancer have a much better prognosis than those diagnosed at later stages, with more than 90% of individuals surviving 5 years from diagnosis in some studies (appendix), but data 3 Royal College of PhysiciansNational Lung Cancer AuditNational Lung Cancer Audit Annual report 2017 (for the audit period 2016). https://www.hqip.org.uk/wp-content/uploads/2018/03/NLCA2017AnnualReport_web_FINAL.pdfDate: 2018 Date accessed: July 3, 2018 Google Scholar for England and Wales show that 60% of patients have incurable disease by the time they receive specialist care. Cancers need to be diagnosed at an earlier stage, and patients require rapid diagnosis and definitive treatment, since the volume doubling time is between 88 and 200 days in many patients (appendix), which means that disease stage shifts can occur during the typical interval between first symptom onset and treatment. A delay of weeks in commencing treatment can be of substantial detriment to survival; in a previous study, 6 Yang CJ Wang H Kumar A et al. Impact of timing of lobectomy on survival for clinical stage IA lung squamous cell carcinoma. Chest. 2017; 152: 1239-1250 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar 5-year survival was found to be significantly worse in patients for whom surgery was delayed for more than 38 days and progressively worsened with incrasing time to surgery.

Cancer and other non-communicable diseases (NCDs) enjoy an unprecedented global profile, yet of the 4 billion people living in cities today, few of them have access to high-quality cancer treatment outside of high-income countries.

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.