{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T14:19:51Z","timestamp":1760710791356,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Ovarian cancer has a low incidence, but high mortality due to a habitual diagnosis in advanced cancer stages. Currently, used biomarkers have good sensitivity, but low specificity. Aim: To determine the usefulness of the biomarkers and algorithms used up to now in the screening, diagnosis, response to treatments and identification of recurrence in patients with ovarian masses. Methodology: Systematic search of publications in English in the Medline-PubMed database with the terms: \u201cbiomarkers\u201d, \u201ctumour\u201d, \u201ctumour biomarkers\u201d, \u201cmarker\u201d, \u201ctumour marker\u201d, \u201covarian cancer\u201d, \u201covarian\u201d, \u201cNeoplasms\u201d, \u201ccancer\u201d, CA-125 Antigen; Human Epididymis-specific Protein E4; Risk of Malignancy Index (RMI); Risk of Ovarian Malignancy Algorithm (ROMA); Ovarian Neoplasms. Original articles, clinical trials, reviews, systematic reviews and meta-analyses, published between January 2000 and November 2020, were selected to determine the usefulness (among others) of CA 125 and HE4 antigen in ovarian cancer. Results: Finally, 39 transcendental publications were selected to write this article to determine the usefulness of tumour markers and algorithms in ovarian cancer. Conclusions: The usefulness of the tumour markers antigen CA125 and antigen HE4 individually or as a basis for decision-making algorithms has low specificity; however, there is little evidence that confirms their usefulness as markers in ovarian cancer screening.<\/jats:p>","DOI":"10.3390\/jpm11111115","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:34Z","timestamp":1635805294000},"page":"1115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Biomarkers in Ovarian Pathology: From Screening to Diagnosis. Review of the Literature"],"prefix":"10.3390","volume":"11","author":[{"given":"Miguel \u00c1ngel","family":"Elorriaga","sequence":"first","affiliation":[{"name":"Servicio de Ginecolog\u00eda y Obstetricia, Hospital Universitario Cruces, Universidad del Pa\u00eds Vasco, EHU\u2014UPV, 48903 Baracaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Luis","family":"Neyro","sequence":"additional","affiliation":[{"name":"Servicio de Ginecolog\u00eda y Obstetricia, Hospital Universitario Cruces, Universidad del Pa\u00eds Vasco, EHU\u2014UPV, 48903 Baracaldo, Spain"},{"name":"Internacional de Climaterio y Menopausia, Universidad a Distancia de Madrid (UDIMA) y Universidad Veracruzana Lomas del Estadio S\/N, Col. Zona Universitaria C.P. 91090, Xalapa, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Mieza","sequence":"additional","affiliation":[{"name":"Servicio de Ginecolog\u00eda y Obstetricia, Hospital Universitario Cruces, Universidad del Pa\u00eds Vasco, EHU\u2014UPV, 48903 Baracaldo, Spain"},{"name":"Instituto Ginecol\u00f3gico Deusto, 48014 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2793-6592","authenticated-orcid":false,"given":"Ignacio","family":"Crist\u00f3bal","sequence":"additional","affiliation":[{"name":"Servicio de Obstetricia y Ginecolog\u00eda, Hospital Cl\u00ednico San Carlos, Universidad Francisco de Vitoria, 28223 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3723-8795","authenticated-orcid":false,"given":"Antoni","family":"Llueca","sequence":"additional","affiliation":[{"name":"Unidad de Referencia en Cirug\u00eda Oncol\u00f3gica Abdomino-P\u00e9lvica (UR-COAP), Hospital General Universitario de Castell\u00f3n, 12004 Castell\u00f3, Spain"},{"name":"Departamento de Medicina, University Jaume I (UJI), 12071 Castell\u00f3n, Spain"},{"name":"University Jaume I (UJI), Av de Vicent Sos Baynat s\/n, 12071 Castell\u00f3n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"ref_1","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Garshell, J., Neyman, N., Altekruse, S.F., Kosary, C.L., Yu, M., Ruhl, J., and Tatalovich, Z. (2013, October 25). SEER Cancer Statistics Review, 1975\u20132010, Available online: https:\/\/seer.cancer.gov\/archive\/csr\/1975_2010\/."},{"key":"ref_2","unstructured":"Hinojo, C., Jimeno, R., and De Juan, A. (2017). Prevenci\u00f3n de los tumores ginecol\u00f3gicos. Manual SEOM de Prevenci\u00f3n y Diagn\u00f3stico Precoz del C\u00e1ncer. Cap26, 210-8. Grupo de Trabajo SEOM de Prevenci\u00f3n y Diagn\u00f3stico Precoz del C\u00e1ncer, Sociedad Espa\u00f1ola de Oncolog\u00eda M\u00e9dica (SEOM)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.humpath.2011.03.003","article-title":"Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer\u2014Shifting the paradigm","volume":"42","author":"Kurman","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_4","unstructured":"Committee on the State of the Science in Ovarian Cancer Research, Board on Health Care Services, Institute of Medicine, and National Academies of Sciences, Engineering, and Medicine (2016). Ovarian Cancers: Evolving Paradigms in Research and Care, National Academies Press (US)."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Scully, R.E., Young, R.H., and Clement, P.B. (1998). Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. Atlas of Tumor Pathology, Third Series. Fascicle 23, Armed Forces Institute of Pathology.","DOI":"10.1097\/00004347-199907000-00019"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"b2700","DOI":"10.1136\/bmj.b2700","article-title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration","volume":"339","author":"Liberati","year":"2009","journal-title":"BMJ"},{"key":"ref_7","unstructured":"NCI (National Cancer Institute) (2021, January 11). NCI Dictionary of Cancer Terms. 2015. [16 September 2015], Available online: http:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Consensus Study Report (2007). IOM (Institute of Medicine). Cancer Biomarkers the Promises and Challenges of Improving Detection and Treatment, The National Academies Press.","DOI":"10.17226\/11892"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1172\/JCI110380","article-title":"Reactivity of a monoclonal antibody with human ovarian carcinoma","volume":"68","author":"Bast","year":"1981","journal-title":"J. Clin. Investig."},{"key":"ref_10","first-page":"6208522","article-title":"CA125 antigen levels in obstetric and gynecologic patients","volume":"64","author":"Niloff","year":"1984","journal-title":"Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0090-8258(85)90015-0","article-title":"Elevation of serum CA 125 prior to diagnosis of an epithelial ovarian carcinoma","volume":"22","author":"Bast","year":"1985","journal-title":"Gynecol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ygyno.2009.08.007","article-title":"CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis","volume":"115","author":"Boivin","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1476-4598-13-129","article-title":"MUC16 (CA125): Tumor biomarker to cancer therapy, a work in progress","volume":"13","author":"Felder","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4331\/wjbc.v5.i3.286","article-title":"In 2014, can we do better than CA125 in the early detection of ovarian cancer?","volume":"5","author":"Cohen","year":"2014","journal-title":"World J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0378-1119(99)00342-X","article-title":"Comparative hybridization of an array of 21 500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas","volume":"238","author":"Schummer","year":"1999","journal-title":"Gene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1136\/ijgc-00009577-200511001-00015","article-title":"New tumor markers: CA125 and beyond","volume":"15","author":"Bast","year":"2005","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1158\/1055-9965.EPI-14-0447","article-title":"HE4 Tissue Expression and Serum HE4 Levels in Healthy Individuals and Patients with Benign or Malignant Tumors: A Systematic Review","volume":"23","author":"Karlsen","year":"2014","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1515\/cclm-2012-0097","article-title":"Human epididymis protein 4 (HE4) in benign and malignant diseases","volume":"50","author":"Hertlein","year":"2012","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1136\/jclinpath-2012-201031","article-title":"Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: A systematic review","volume":"66","author":"Ferraro","year":"2013","journal-title":"J. Clin. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6127","DOI":"10.1007\/s13277-014-1811-6","article-title":"Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: A meta-analysis","volume":"35","author":"Wang","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3892\/mco.2014.279","article-title":"Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer: A meta-analysis","volume":"2","author":"Zhen","year":"2014","journal-title":"Mol. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cca.2014.11.013","article-title":"Development of a multimarker assay for differential diagnosis of benign and malignant pelvic masses","volume":"440","author":"Chen","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.ygyno.2007.10.017","article-title":"The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass","volume":"108","author":"Moore","year":"2008","journal-title":"Gynecol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13048-019-0503-7","article-title":"Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review","volume":"12","author":"Dochez","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ygyno.2017.08.020","article-title":"Combining a symptom index, CA125 and HE4 (triple screen) to detect ovarian cancer in women with a pelvic mass","volume":"147","author":"Goff","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.6061\/clinics\/2012(05)06","article-title":"A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses","volume":"67","author":"Anton","year":"2012","journal-title":"Clinics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ejca.2016.01.007","article-title":"Subjective assessment versus ultrasound models to diagnose ovarian cancer: A systematic review and meta-analysis","volume":"58","author":"Meys","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, F., Tie, R., Chang, K., Wang, F., Deng, S., Lu, W., Yu, L., and Chen, M. (2012). Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and ca125 in predicting epithelial ovarian cancer: A meta-analysis. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-258"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"336","DOI":"10.5001\/omj.2016.68","article-title":"Evaluation of HE4, CA-125, Risk of Ovarian Malignancy Algorithm (ROMA) and Risk of Malignancy Index (RMI) in the Preoperative Assessment of Patients with Adnexal Mass","volume":"31","author":"Ramadhan","year":"2016","journal-title":"Oman Med. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.chroma.2012.12.079","article-title":"Isomer-specific chromatographic profiling yields highly sensitive and specific potential N-glycan biomarkers for epithelial ovarian cancer","volume":"1279","author":"Hua","year":"2013","journal-title":"J. Chromatogr. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1001\/jama.2011.766","article-title":"Effect of Screening on Ovarian Cancer Mortality","volume":"305","author":"Buys","year":"2011","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/S0140-6736(15)01224-6","article-title":"Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial","volume":"387","author":"Jacobs","year":"2016","journal-title":"Lancet"},{"key":"ref_33","unstructured":"U.S. Food and Drug Administration (2021, January 11). The FDA Recommends against Using Screening Tests for Ovarian Cancer Screening: FDA Safety Communication, Available online: http:\/\/www.fda.gov\/MedicalDevices\/Safety\/AlertsandNotices\/ucm519413.htm."},{"key":"ref_34","unstructured":"Abcodia (2021, January 11). Abcodia Statement on the ROCA Test for Ovarian Cancer Screening. Available online: https:\/\/www.rocatest.com\/about-us\/news-events\/news-item\/abcodia-statement-roca-test-ovarian-cancer-screening\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/j.1525-1438.2007.01035.x","article-title":"A randomized study of screening for ovarian cancer: A multicenter study in Japan","volume":"18","author":"Kobayashi","year":"2008","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1097\/IGC.0b013e318251cc3f","article-title":"Ovarian Cancer Screening in the High-Risk Population\u2014The UK Familial Ovarian Cancer Screening Study (UKFOCSS)","volume":"22","author":"Rosenthal","year":"2012","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1373\/clinchem.2008.105601","article-title":"National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers","volume":"54","author":"Sturgeon","year":"2008","journal-title":"Clin. Chem."},{"key":"ref_38","first-page":"665","article-title":"Tercer Consenso Nacional de C\u00e1ncer de Ovario 2011.Grupo de Investigaci\u00f3n en C\u00e1ncer de Ovario y Tumores Ginecol\u00f3gicos de M\u00e9xico \u201cGICOM\u201d","volume":"63","year":"2011","journal-title":"Rev. Investig. Clin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/j.1471-0528.1990.tb02448.x","article-title":"A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer","volume":"97","author":"Jacobs","year":"1990","journal-title":"BJOG: Int. J. Obstet. Gynaecol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/00006250-199903000-00028","article-title":"The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals","volume":"93","author":"Tingulstad","year":"1999","journal-title":"Obstet. Gynecol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ygyno.2008.08.031","article-title":"A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass","volume":"112","author":"Moore","year":"2009","journal-title":"Gynecol. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/01.coc.0000231364.89294.13","article-title":"Epithelial Ovarian Cancer and Low Malignant Potential (LMP) Tumors Associated with a Lower Incidence of Second Primary Breast Cancer","volume":"30","author":"Hunter","year":"2007","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_43","unstructured":"(2021, January 12). Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/510k-program-evaluating-substantial-equivalence-premarket-notifications-510k."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ygyno.2012.11.022","article-title":"Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay","volume":"128","author":"Bristow","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/3098542","article-title":"Evaluation of Prognostic and Predictive Significance of Circulating MicroRNAs in Ovarian Cancer Patients","volume":"2017","author":"Halvorsen","year":"2017","journal-title":"Dis. Mark."},{"key":"ref_46","unstructured":"(2021, January 12). Available online: https:\/\/edrn.nci.nih.gov\/."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.ygyno.2019.04.006","article-title":"Multiple biomarker algorithms to predict epithelial ovarian cancer in women with a pelvic mass: Can additional makers improve performance?","volume":"154","author":"Moore","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"vi24","DOI":"10.1093\/annonc\/mdt333","article-title":"Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"24","author":"Ledermann","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/IGC.0b013e318199009c","article-title":"The Fallopian Tube: Primary Site of Most Pelvic High-grade Serous Carcinomas","volume":"19","author":"Salvador","year":"2009","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_50","unstructured":"Curtis, R.E., Freedman, D.M., Ron, E., Ries, L.A.G., Hacker, D.G., Edwards, B.K., Tucker, M.A., and Fraumeni, J.F. (2021, January 12). New Malignancies Following Cancer of the Uterine Corpus and Ovary, New Malignancies Among Cancer Survivors: SEER Cancer Registries, Available online: http:\/\/seer.cancer.gov\/archive\/publications\/mpmono\/MPMonograph_complete.pdf."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/oxfordjournals.humrep.a136832","article-title":"The CA 125 tumour-associated antigen: A review of the literature","volume":"4","author":"Jacobs","year":"1989","journal-title":"Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1158\/1055-9965.EPI-20-1057","article-title":"Biomarkers and Strategies for Early Detection of Ovarian Cancer","volume":"29","author":"Bast","year":"2020","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"831","DOI":"10.7326\/0003-4819-158-11-201306040-00008","article-title":"Influence of study features and methods on overdiagnosis estimates in breast and prostate cancer screening","volume":"158","author":"Etzioni","year":"2013","journal-title":"Ann. Intern. Medicine."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-3-030-34025-4_18","article-title":"Ovarian Cancer Biomarkers: Moving Forward in Early Detection","volume":"1219","year":"2020","journal-title":"Adv. Exp. Med. Biol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/11\/1115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:22:43Z","timestamp":1760167363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/11\/1115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,29]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jpm11111115"],"URL":"https:\/\/doi.org\/10.3390\/jpm11111115","relation":{},"ISSN":["2075-4426"],"issn-type":[{"type":"electronic","value":"2075-4426"}],"subject":[],"published":{"date-parts":[[2021,10,29]]}}}