TY - JOUR
T1 - Tumor-associated autoantibodies as early detection markers for ovarian cancer? A prospective evaluation
AU - Kaaks, Rudolf
AU - Fortner, Renée Turzanski
AU - Hüsing, Anika
AU - Barrdahl, Myrto
AU - Hopper, Marika
AU - Johnson, Theron
AU - Tjønneland, Anne
AU - Hansen, Louise
AU - Overvad, Kim
AU - Fournier, Agnès
AU - Boutron-Ruault, Marie Christine
AU - Kvaskoff, Marina
AU - Dossus, Laure
AU - Johansson, Mattias
AU - Boeing, Heiner
AU - Trichopoulou, Antonia
AU - Benetou, Vassiliki
AU - La Vecchia, Carlo
AU - Sieri, Sabina
AU - Mattiello, Amalia
AU - Palli, Domenico
AU - Tumino, Rosario
AU - Matullo, Giuseppe
AU - Onland-Moret, N. Charlotte
AU - Gram, Inger T.
AU - Weiderpass, Elisabete
AU - Sánchez, Maria Jose
AU - Navarro Sanchez, Carmen
AU - Duell, Eric J.
AU - Ardanaz, Eva
AU - Larranaga, Nerea
AU - Lundin, Eva
AU - Idahl, Annika
AU - Jirström, Karin
AU - Nodin, Björn
AU - Travis, Ruth C.
AU - Riboli, Elio
AU - Merritt, Melissa
AU - Aune, Dagfinn
AU - Terry, Kathryn
AU - Cramer, Daniel W.
AU - Anderson, Karen
N1 - Funding Information:
This study was funded by National Institutes of Health, grants NCI Early Detection Research Network, U01 CA117374 (K.S.A.) and R01 CA 158119 (D.W.C.). For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php
Funding Information:
Key words: early detection, antibodies, prospective validation Abbreviations: AAbs: autoantibodies; AUC: area under curve; CA125: cancer antigen 125; CRP: C-reactive protein; ECL: electrochemo-luminiscence; EPIC: European Prospective Investigation into Cancer and Nutrition; FPR: false-positive detection rate; HRT: hormone replacement therapy; MSD: Meso Scale Discovery; OC: oral contraceptives; PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RAPID: Rapid Antigenic Protein In situ Display; RLU: relative light unit; ROC: receiver operating characteristic; ROCA: Risk of Ovarian Cancer Algorithm; TVUS: trans-vaginal ultrasonography; UKCTOCS: United Kingdom Collaborative Trial on Ovarian Cancer Screening Additional Supporting Information may be found in the online version of this article. Conflicts of Interest: Karen Anderson declares consultancies to PROVISTA Diagnostics. Grant sponsor: National Institutes of Health; Grant numbers: U01 CA117374, R01 CA 158119; Grant sponsor: European Commission (DG-SANCO); Grant sponsor: International Agency for Research on Cancer; Grant sponsor: Danish Cancer Society (Denmark); Grant sponsor: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santéet de la Recherche Médicale (INSERM) (France); Grant sponsor: German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Grant sponsor: Hellenic Health Foundation (Greece); Grant sponsor: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Grant sponsor: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR); Grant sponsor: LK Research Funds; Grant sponsor: Dutch Prevention Funds; Grant sponsor: Dutch ZON (Zorg Onderzoek Nederland); Grant sponsor: World Cancer Research Fund (WCRF); Grant sponsor: Statistics Netherlands (The Netherlands); Grant sponsor: RIVM (National Institute for Public Health and the Environment, Bilthoven, the Netherlands); Grant number: ERC-2009-AdG 232997; Grant sponsor: Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Grant sponsor: Health Research Fund (FIS); Grant numbers: PI13/00061, PI13/01162; Grant sponsor: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (Spain); Grant number: RD06/0020; Grant sponsor: Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and V€asterbotten (Sweden); Grant sponsor: Cancer Research UK; Grant numbers: 14136, C570/A16491, C8221/A19170; Grant sponsor: Medical Research Council (United Kingdom); Grant numbers: 1000143, MR/M012190/1 DOI: 10.1002/ijc.31335 History: Received 3 Nov 2017; Accepted 1 Feb 2018; Online 1 Feb 2018 Correspondence to: Rudolf Kaaks, German Cancer Research Center, Division of Cancer Epidemiology, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Fax: 149-6221-42-2203, E-mail: r.kaaks@dkfz.de
Publisher Copyright:
© 2018 UICC
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08–0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10–0.44] for P53 (0.33 [0.11–0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01–0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.
AB - Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08–0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10–0.44] for P53 (0.33 [0.11–0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01–0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.
KW - antibodies
KW - early detection
KW - prospective validation
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U2 - 10.1002/ijc.31335
DO - 10.1002/ijc.31335
M3 - Article
C2 - 29473162
AN - SCOPUS:85043348365
SN - 0020-7136
VL - 143
SP - 515
EP - 526
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -