Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging

Frank M Sullivan, Frances S Mair, William Anderson, Pauline Armory, Andrew Briggs, Cindy Chew, Alistair Dorward, John Haughney, Fiona Hogarth, Denise Kendrick, Roberta Littleford, Alex McConnachie, Colin McCowan, Nicola McMeekin, Manish Patel, Petra Rauchhaus, Lewis Ritchie, Chris Robertson, John Robertson, Jose Robles-Zurita, Joseph Sarvesvaran, Herbert Sewell, Michael Sproule, Thomas Taylor, Agnes Tello, Shaun Treweek, Kavita Vedhara, Stuart Schembri, Early Diagnosis of Lung Cancer Scotland (ECLS) Team, Frank M Sullivan, Frances S Mair, William Anderson, Pauline Armory, Andrew Briggs, Cindy Chew, Alistair Dorward, John Haughney, Fiona Hogarth, Denise Kendrick, Roberta Littleford, Alex McConnachie, Colin McCowan, Nicola McMeekin, Manish Patel, Petra Rauchhaus, Lewis Ritchie, Chris Robertson, John Robertson, Jose Robles-Zurita, Joseph Sarvesvaran, Herbert Sewell, Michael Sproule, Thomas Taylor, Agnes Tello, Shaun Treweek, Kavita Vedhara, Stuart Schembri, Early Diagnosis of Lung Cancer Scotland (ECLS) Team

Abstract

The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT.

Trial registration: ClinicalTrials.gov NCT01925625.

Conflict of interest statement

Conflict of interest: F.M. Sullivan reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: F.S. Mair reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: W. Anderson has nothing to disclose. Conflict of interest: P. Armory reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: A. Briggs reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: C. Chew has nothing to disclose. Conflict of interest: A. Dorward has nothing to disclose. Conflict of interest: J. Haughney has nothing to disclose. Conflict of interest: F. Hogarth reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and from Oncimmune, during the conduct of the study. Conflict of interest: D. Kendrick has nothing to disclose. Conflict of interest: R. Littleford reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: A. McConnachie reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: C. McCowan has nothing to disclose. Conflict of interest: N. McMeekin reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: M. Patel has nothing to disclose. Conflict of interest: P. Rauchhaus reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: L. Ritchie has nothing to disclose. Conflict of interest: C. Robertson reports personal fees and other funding from Oncimmune, outside the study. Conflict of interest: J. Robertson reports other funding from Oncimmune, during the conduct of the study; and other funding from Oncimmune, outside the study. J. Robertson was a founder of Oncimmune, a company spun out from the University of Nottingham based on his academic research. Between 2003 and 2013 he was Chief Scientific Officer of Oncimmune and a Director of the company. During this time, he was responsible for the original drafting of the ECLS protocol. Since 2013 he has had no involvement in the science or management of the company. He has been and remains a shareholder in the company. Conflict of interest: J. Robles-Zurita reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: J. Sarvesvaran has nothing to disclose. Conflict of interest: H. Sewell reports other funding from Oncimmune, outside the submitted work; and was an external member of the Oncimmune Scientific Advisory Board from 2006 to 2013. Conflict of interest: M. Sproule has nothing to disclose. Conflict of interest: T. Taylor reports grants, nonfinancial support and other funding from Oncimmune, grants and personal fees from the Chief Scientist Office for Scotland, and grants and nonfinancial support from the Scottish Government, outside the submitted work. Conflict of interest: A. Tello reports grants from Oncimmune, during the conduct of the study. Conflict of interest: S. Treweek reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: K. Vedhara has nothing to disclose. Conflict of interest: S. Schembri reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study; and nonfinancial support from GlaxoSmithKline and AstraZeneca, outside the submitted work.

Copyright ©ERS 2021.

Figures

FIGURE 1
FIGURE 1
CONSORT flowchart. CT: computed tomography.
FIGURE 2
FIGURE 2
Primary outcome: diagnosis of stage III/IV/unspecified lung cancer 2 years after randomisation in the intervention and control arms.
FIGURE 3
FIGURE 3
Secondary outcomes: mortality 2 years after randomisation in the intervention and control arms.

References

    1. Allemani C, Matsuda T, Di Carlo V, et al. . Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018; 391: 1023–1075. doi:10.1016/S0140-6736(17)33326-3
    1. The National Lung Screening Trial Research Team Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409. doi:10.1056/NEJMoa1102873
    1. The National Lung Screening Trial Research Team Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial. J Thorac Oncol 2019; 14: 1732–1742. doi:10.1016/j.jtho.2019.05.044
    1. de Koning HJ, van der Aalst CM, de Jong PA, et al. . Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med 2020; 382: 503–513. doi:10.1056/NEJMoa1911793
    1. Infante M, Cavuto S, Lutman F, et al. . Long-term follow-up results of the DANTE trial, a randomized study of lung cancer screening with spiral computed tomography. Ann Oncol 2019; 30: 1162–1169. doi:10.1093/annonc/mdz117
    1. Pastorino U, Silva M, Sestini S, et al. . Prolonged lung cancer screening reduced 10-year mortality in the MILD trial. Ann Oncol 2019; 30: 1162–1169. doi:10.1093/annonc/mdz117
    1. Huang KL, Wang SY, Lu WC, et al. . Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis. BMC Pulm Med 2019; 19: 126. doi:10.1186/s12890-019-0883-x
    1. Becker N, Motsch E, Trotter A, et al. . Lung cancer mortality reduction by LDCT screening – results from the randomized German LUSI trial. Int J Cancer 2019; 1513: 1503–1513. doi:10.1002/ijc.32486
    1. Wille MMW, Dirksen A, Ashraf H, et al. . Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling. Am J Respir Crit Care Med 2016; 193: 542–551. doi:10.1164/rccm.201505-1040OC
    1. Han D, Heuvelmans MA, Vliegenthart R, et al. . An update on the European lung cancer screening trials and comparison of lung cancer screening recommendations in Europe. J Thorac Imaging 2019; 34: 65–71. doi:10.1097/RTI.0000000000000367
    1. Oudkerk M, Devaraj A, Vliegenthart R, et al. . European position statement on lung cancer screening. Lancet Oncol 2017; 18: e754–e766. doi:10.1016/S1470-2045(17)30861-6
    1. Li Y, Karjalainen A, Koskinen H, et al. . p53 autoantibodies predict subsequent development of cancer. Int J Cancer 2005; 114: 157–160. doi:10.1002/ijc.20715
    1. Robertson JFR, Chapman C, Cheung K-L, et al. . Autoantibodies in early breast cancer. J Clin Oncol 2005; 23: 549–549. doi:10.1200/jco.2005.23.16_suppl.549
    1. Chapman CJ, Healey GF, Murray A, et al. . EarlyCDT-Lung test: improved clinical utility through additional autoantibody assays. Tumor Biol 2012; 33: 1319–1326. doi:10.1007/s13277-012-0379-2
    1. Jett JR, Peek LJ, Fredericks L, et al. . Audit of the autoantibody test, EarlyCDT-Lung, in 1600 patients: an evaluation of its performance in routine clinical practice. Lung Cancer 2014; 83: 51–55. doi:10.1016/j.lungcan.2013.10.008
    1. Sullivan FM, Farmer E, Mair FS, et al. . Detection in blood of autoantibodies to tumour antigens as a case-finding method in lung cancer using the EarlyCDT-Lung Test (ECLS): study protocol for a randomized controlled trial. BMC Cancer 2017; 17: 187. doi:10.1186/s12885-017-3175-y
    1. Health Research Authority UK Policy Framework for Health and Social Care Research 2017. Date last accessed: September 26, 2019.
    1. Weller D, Vedsted P, Rubin G, et al. . The Aarhus statement: improving design and reporting of studies on early cancer diagnosis. Br J Cancer 2012; 106: 1262–1267. doi:10.1038/bjc.2012.68
    1. Schulz KF, Altman DG, Moher D, et al. . CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332. doi:10.1136/bmj.c332
    1. MacMahon H, Naidich DP, Goo JM, et al. . Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology 2017; 284: 228–243. doi:10.1148/radiol.2017161659
    1. National Institute for Health and Care Excellence Suspected Cancer: Recognition and Referral. NICE Guideline NG12. London, NICE, 2015.
    1. Young B, Vedhara K, Kendrick D, et al. . Determinants of motivation to quit in smokers screened for the early detection of lung cancer: a qualitative study. BMC Public Health 2018; 18: 1276. doi:10.1186/s12889-018-6211-1
    1. Clark ME, Bedford LE, Young B, et al. . Lung cancer CT screening: psychological responses in the presence and absence of pulmonary nodules. Lung Cancer 2018; 124: 160–167. doi:10.1016/j.lungcan.2018.08.001
    1. Information Services Division Scotland Scottish Cancer Registry (SMR06) 2019. Date last accessed: November19, 2019.
    1. World Health Organization International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) 2015. Date last accessed: July 23, 2019.
    1. Swensen SJ, Jett JR, Hartman TE, et al. . CT screening for lung cancer: five-year prospective experience. Radiology 2005; 235: 259–265. doi:10.1148/radiol.2351041662
    1. Sharpe KH, McMahon AD, Raab GM, et al. . Association between socioeconomic factors and cancer risk: a population cohort study in Scotland (1991–2006). PLoS One 2014; 9: e89513. doi:10.1371/journal.pone.0089513
    1. Kinsinger LS, Anderson C, Kim J, et al. . Implementation of lung cancer screening in the Veterans Health Administration. JAMA Intern Med 2017; 177: 399. doi:10.1001/jamainternmed.2016.9022
    1. Pinsky P, Miller A, Kramer B, et al. . Evidence of a healthy volunteer effect in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Epidemiol 2007; 165: 874–881. doi:10.1093/aje/kwk075
    1. Tammemägi MC, Katki HA, Hocking WG, et al. . Selection criteria for lung-cancer screening. N Engl J Med 2013; 368: 728–736. doi:10.1056/NEJMoa1211776
    1. Schreuder A, Schaefer-Prokop CM, Scholten ET, et al. . Lung cancer risk to personalise annual and biennial follow-up computed tomography screening. Thorax 2018; 73: 626–633. doi:10.1136/thoraxjnl-2017-211107
    1. Cooper GC, Harvie MN, French DP. Do negative screening test results cause false reassurance? A systematic review. Br J Health Psychol 2017; 22: 958–977. doi:10.1111/bjhp.12265
    1. Edelsberg J, Weycker D, Atwood M, et al. . Cost-effectiveness of an autoantibody test (EarlyCDT-Lung) as an aid to early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules. PLoS One 2018; 13: e0197826. doi:10.1371/journal.pone.0197826
    1. Zaenker P, Gray ES, Ziman MR. Autoantibody production in cancer – the humoral immune response toward autologous antigens in cancer patients. Autoimmun Rev 2016; 15: 477–483. doi:10.1016/j.autrev.2016.01.017
    1. Massion PP, Healey GF, Peek LJ, et al. . Autoantibody signature enhances the positive predictive power of computed tomography and nodule-based risk models for detection of lung cancer. J Thorac Oncol 2017; 12: 578–584. doi:10.1016/j.jtho.2016.08.143
    1. McKinney SM, Sieniek M, Godbole V, et al. . International evaluation of an AI system for breast cancer screening. Nature 2020; 577: 89–94. doi:10.1038/s41586-019-1799-6
    1. Balata H, Evison M, Sharman A, et al. . CT screening for lung cancer: are we ready to implement in Europe? Lung Cancer 2019; 134: 25–33. doi:10.1016/j.lungcan.2019.05.028

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren