Advances in biomarker discovery and radiological techniques for early detection of ovarian cancer: A comprehensive review

Ahmed Mufleh Alenazi; Abdulmohsen Khalaf Ali Alkhalaf; Sulaiman Ali Sulaiman Alkhateeb; Bushra Mana Alshammari; Dima Ahmed Alharbi; Abdulaziz Alangari; Shatha Alkahtani; Ola Yousef Fadan; Ahmed Mufleh Alenazi; Nouf Hamed Alanazi; Mohanad Abdulraouf Seraj; Fatimah Khalid Alkhunaizi; Dalal Mussad Albugami; Ahlam Nazeh Alenezi

doi:10.53730/ijhs.v6nS10.15008

Authors

Ahmed Mufleh Alenazi KSA, National Guard Health Affairs
Abdulmohsen Khalaf Ali Alkhalaf KSA, National Guard Health Affairs
Sulaiman Ali Sulaiman Alkhateeb KSA, National Guard Health Affairs
Bushra Mana Alshammari KSA, National Guard Health Affairs
Dima Ahmed Alharbi KSA, National Guard Health Affairs
Abdulaziz Alangari KSA, National Guard Health Affairs
Shatha Alkahtani KSA, National Guard Health Affairs
Ola Yousef Fadan KSA, National Guard Health Affairs
Ahmed Mufleh Alenazi KSA, National Guard Health Affairs
Nouf Hamed Alanazi KSA, National Guard Health Affairs
Mohanad Abdulraouf Seraj KSA, National Guard Health Affairs
Fatimah Khalid Alkhunaizi KSA, National Guard Health Affairs
Dalal Mussad Albugami KSA, National Guard Health Affairs
Ahlam Nazeh Alenezi KSA, National Guard Health Affairs

Keywords:

ovarian cancer, biomarkers, early detection, CA125, HE4, ROCA, multivariate assays, circulating tumor DNA, microRNA, radiological imaging

Abstract

Aim: This review investigates recent advances in biomarker discovery and radiological techniques for the early detection of ovarian cancer, emphasizing the significance of early diagnosis in improving patient outcomes. Methods: A comprehensive literature review was conducted, focusing on various biomarkers, including CA125, HE4, and emerging candidates such as circulating tumor DNA and microRNA, alongside radiological imaging techniques such as ultrasound and MRI. The sensitivity and specificity of these biomarkers and imaging modalities were analyzed through clinical studies and trials. Results: Current biomarkers like CA125 and HE4 demonstrate varied sensitivities and specificities, with CA125 having low sensitivity in early stages but higher specificity. Radiological techniques provide crucial complementary information, enhancing diagnostic accuracy. Novel approaches, such as the Risk of Ovarian Cancer Algorithm (ROCA) and multivariate index assays like OVA1 and ROMA, show promise in enhancing diagnostic accuracy. Additionally, potential biomarkers, including glycoforms of CA125, autoantibodies, and methylation changes, have emerged as significant candidates for further research. Conclusion: While significant progress has been made in biomarker and radiological technique development for ovarian cancer, challenges persist in achieving the ideal sensitivity and specificity for early detection.

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References

Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 2021, 71, 209–249.

Jayson, G.C.; Kohn, E.C.; Kitchener, H.C.; Ledermann, J.A. Ovarian cancer. Lancet 2014, 384, 1376–1388.

Hinchcliff, E.; Westin, S.N.; Herzog, T.J. State of the science: Contemporary front-line treatment of advanced ovarian cancer. Gynecol. Oncol. 2022, 166, 18–24.

Bartoletti, M.; Musacchio, L.; Giannone, G.; Tuninetti, V.; Bergamini, A.; Scambia, G.; Lorusso, D.; Valabrega, G.; Mangili, G.; Puglisi, F.; et al. Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors. Cancer Treat. Rev. 2021, 101, 102298.

Pierce, S.R.; Clark, L.H. Current first-line therapy for ovarian cancer: A comprehensive review. Obstet. Gynecol. Surv. 2017, 33, 792–793.

Qiao, L.; Chen, X.; Xi, X.; Chen, X.; Zhang, P.; Dong, H.; Wu, X.; Chen, X. Correlation analysis and clinical significance of CA125, HE4, DDI, and FDP in type II epithelial ovarian cancer. Medicine 2020, 99, e23329.

Zapardiel, I.; Diestro, M.D.; Aletti, G. Conservative treatment of early stage ovarian cancer: Oncological and fertility outcomes. Eur. J. Surg. Oncol. 2014, 40, 387–393.

Colombo, N.; Sessa, C.; Bois, A.D.; Ledermann, J.; McCluggage, W.G.; McNeish, I.; Morice, P.; Pignata, S.; Ray-Coquard, I.; Vergote, I.; et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann. Oncol. 2019, 30, 672–705.

Havrilesky, L.J.; Sanders, G.D.; Kulasingam, S.; Myers, E.R. Reducing ovarian cancer mortality through screening: Is it possible, and can we afford it? Gynecol. Oncol. 2008, 111, 179–187

Braat, D.D.M. Diagnosis and management of ovarian disorders. Eur. J. Obstet. Gynecol. Reprod. Biol. 1997, 72, 217.

Campbell, S.; Gentry-Maharaj, A. The role of transvaginal ultrasound in screening for ovarian cancer. Climacteric 2018, 21, 221–226.

Mathis, J.; Jellouli, M.A.; Sabiani, L.; Fest, J.; Blache, G.; Mathevet, P. Ovarian cancer screening in the general population. Horm. Mol. Biol. Clin. Investig. 2020, 41, 350–353.

Felder, M.; Kapur, A.; Gonzalez-Bosquet, J.; Horibata, S.; Heintz, J.; Albrecht, R.; Fass, L.; Kaur, J.; Hu, K.; Shojaei, H.; et al. MUC16 (CA125): Tumor biomarker to cancer therapy, a work in progress. Mol. Cancer 2014, 13, 129.

Høgdall, E.V.S.; Christensen, L.; Kjaer, S.K.; Blaakaer, J.; Kjærbye-Thygesen, A.; Gayther, S.; Jacobs, I.J.; Høgdall, C.K. CA125 expression pattern, prognosis and correlation with serum CA125 in ovarian tumor patients. From The Danish “MALOVA” Ovarian Cancer Study. Gynecol. Oncol. 2007, 104, 508–515.

Sturgeon, C.M.; Duffy, M.J.; Walker, G. The National Institute for Health and Clinical Excellence (NICE) guidelines for early detection of ovarian cancer: The pivotal role of the clinical laboratory. Ann. Clin. Biochem. 2011, 48, 295–299.

Mukama, T.; Fortner, R.T.; Katzke, V.; Hynes, L.C.; Petrera, A.; Hauck, S.M.; Johnson, T.; Schulze, M.; Schiborn, C.; Rostgaard-Hansen, A.L.; et al. Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer. Br. J. Cancer. 2022, 126, 1301–1309.

Funston, G.; Mounce, L.T.A.; Price, S.; Rous, B.; Crosbie, E.J.; Hamilton, W.; Walter, F.M. CA125 test result, test-to-diagnosis interval, and stage in ovarian cancer at diagnosis: A retrospective cohort study using electronic health records. Br. J. Gen. Pract. 2021, 71, E465–E472.

Ghaemmaghami, F.; Akhavan, S. Is postoperative CA125 level in patients with epithelial ovarian cancer reliable to guess the optimality of surgery? Eur. J. Gynaecol. Oncol. 2011, 32, 192–195.

Gu, Z.; He, Y.; Zhang, Y.; Chen, M.; Song, K.; Huang, Y.; Li, Q.; Di, W. Postprandial increase in serum CA125 as a surrogate biomarker for early diagnosis of ovarian cancer. J. Transl. Med. 2018, 16, 114.

Chan, K.K.L.; Chen, C.A.; Nam, J.H.; Ochiai, K.; Wilailak, S.; Choon, A.T.; Sabaratnam, S.; Hebbar, S.; Sickan, J.; Schodin, B.A.; et al. The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass. Gynecol. Oncol. 2013, 128, 239–244.

Partridge, E.; Kreimer, A.R.; Greenlee, R.T.; Williams, C.; Xu, J.L.; Church, T.R.; Kessel, B.; Johnson, C.C.; Weissfeld, J.L.; Isaacs, C.; et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet. Gynecol. 2009, 113, 775–782.

Qing, X.; Liu, L.; Mao, X. A clinical diagnostic value analysis of serum CA125, CA199, and HE4 in women with early ovarian cancer : Systematic review and meta-analysis. Comput. Math. Methods Med. 2022, 2022, 9339325

Bressan, A.; Bozzo, F.; Maggi, C.A.; Binaschi, M. OC125, M11 and OV197 epitopes are not uniformly distributed in the tandem-repeat region of CA125 and require the entire SEA domain. Dis. Markers. 2013, 34, 257–267.

Weiland, F.; Fritz, K.; Oehler, M.K.; Hoffmann, P. Methods for identification of CA125 from ovarian cancer ascites by high resolution mass spectrometry. Int. J. Mol. Sci. 2012, 13, 9942–9958.

Wang, Y.-S.; Ren, S.-F.; Jiang, W.; Lu, J.-Q.; Zhang, X.-Y.; Li, X.-P.; Cao, R.; Xu, C.-J. CA125-Tn ELISA assay improves specificity of pre-operative diagnosis of ovarian cancer among patients with elevated serum CA125 levels. Ann. Transl. Med. 2021, 9, 788.

Schuster-Little, N.; Fritz-Klaus, R.; Etzel, M.; Patankar, N.; Javeri, S.; Patankar, M.S.; Whelan, R.J. Affinity-free enrichment and mass spectrometry analysis of the ovarian cancer biomarker CA125 (MUC16) from patient-derived ascites. Analyst 2021, 146, 85–94.

Li, S.; Hu, C.; Chen, C.; Zhang, J.; Bai, Y.; Tan, C.S.; Ni, G.; He, F.; Li, W.; Ming, D. Molybdenum disulfide supported on metal-organic frameworks as an ultrasensitive layer for the electrochemical detection of the ovarian cancer biomarker CA125. ACS Appl. Bio Mater. 2021, 4, 5494–5502

Chen, Z.; Liang, Q.; Zeng, H.; Zhao, Q.; Guo, Z.; Zhong, R.; Xie, M.; Cai, X.; Su, J.; He, Z.; et al. Exosomal CA125 as A promising biomarker for ovarian cancer diagnosis. J. Cancer. 2020, 11, 6445–6453.

McLemore, M.R.; Aouizerat, B. Introducing the MUC16 gene: Implications for prevention and early detection in epithelial ovarian cancer. Biol. Res. Nurs. 2005, 6, 262–267.

Jankovic, M.M.; Milutinovic, B.S. Glycoforms of CA125 antigen as a possible cancer marker. Cancer Biomark. 2008, 4, 35–42.

Saldova, R.; Wormald, M.R.; Dwek, R.A.; Rudd, P.M. Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to disease pathogenesis. Dis. Markers. 2008, 25, 219–232

Salminen, L.; Nadeem, N.; Rolfsen, A.L.; Dørum, A.; Laajala, T.D.; Grènman, S.; Hietanen, S.; Heinosalo, T.; Perheentupa, A.; Poutanen, M.; et al. Exploratory analysis of CA125-MGL and -STn glycoforms in the differential diagnostics of pelvic masses. J. Appl. Lab. Med. 2020, 5, 263–272.

Bayoumy, S.; Hyytiä, H.; Leivo, J.; Talha, S.M.; Huhtinen, K.; Poutanen, M.; Hynninen, J.; Perheentupa, A.; Lamminmäki, U.; Gidwani, K.; et al. Glycovariant-based lateral flow immunoassay to detect ovarian cancer–associated serum CA125. Commun. Biol. 2020, 3, 460.

Jain, S.; Nadeem, N.; Ulfenborg, B.; Mäkelä, M.; Ruma, S.A.; Terävä, J.; Huhtinen, K.; Leivo, J.; Kristjansdottir, B.; Pettersson, K.; et al. Diagnostic potential of nanoparticle aided assays for MUC16 and MUC1 glycovariants in ovarian cancer. Int. J. Cancer 2022, 151, 1175–1184.

Gidwani, K.; Nadeem, N.; Huhtinen, K.; Kekki, H.; Heinosalo, T.; Hynninen, J.; Perheentupa, A.; Poutanen, M.; Carpen, O.; Pettersson, K.; et al. Europium nanoparticle-based sialyl-Tn monoclonal antibody discriminates epithelial ovarian cancer-associated CA125 from benign sources. J. Appl. Lab. Med. 2019, 4, 299–310.

Yoshikawa, T.; Takano, M.; Kita, T.; Kudoh, K.; Sasaki, N.; Kato, M.; Watanabe, A.; Miyamoto, M.; Goto, T.; Furuya, K. Normal serum CA125 half-life and normal serum nadir CA125 level in patients with ovarian cancers. Eur. J. Gynaecol. Oncol. 2012, 33, 269–273.

Gentry-Maharaj, A.; Blyuss, O.; Ryan, A.; Burnell, M.; Karpinskyj, C.; Gunu, R.; Kalsi, J.K.; Dawnay, A.; Marino, I.P.; Manchanda, R.; et al. Multi-marker longitudinal algorithms incorporating HE4 and CA125 in ovarian cancer screening of postmenopausal women. Cancers 2020, 12, 1931.

Skates, S.J. Ovarian cancer screening: Development of the risk of ovarian cancer algorithm (ROCA) and ROCA screening trials. Int. J. Gynecol. Cancer. 2012, 22 (Suppl. 1), S24–S26.

Lu, K.H.; Skates, S.; Hernandez, M.A.; Bedi, D.; Bevers, T.; Leeds, L.; Moore, R.; Granai, C.; Harris, S.; Newland, W.; et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer 2013, 119, 3454–3461

Menon, U.; Gentry-Maharaj, A.; Burnell, M.; Singh, N.; Ryan, A.; Karpinskyj, C.; Carlino, G.; Taylor, J.; Massingham, S.K.; Raikou, M.; et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet 2021, 397, 2182–2193.

James, N.E.; Chichester, C.; Ribeiro, J.R. Beyond the biomarker: Understanding the diverse roles of human epididymis protein 4 in the pathogenesis of epithelial ovarian cancer. Front. Oncol. 2018, 8, 124.

Jiang, S.-W.; Chen, H.; Dowdy, S.; Fu, A.; Attewell, J.; Kalogera, E.; Drapkin, R.; Podratz, K.; Broaddus, R.; Li, J. HE4 transcription- and splice variants-specific expression in endometrial cancer and correlation with patient survival. Int. J. Mol. Sci. 2013, 14, 22655–22677.

Bingle, L.; Cross, S.S.; High, A.S.; Wallace, W.A.; Rassl, D.; Yuan, G.; Hellstrom, I.; Campos, M.A.; Bingle, C.D. WFDC2 (HE4): A potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir. Res. 2006, 7, 61.

Rowswell-Turner, R.B.; Singh, R.K.; Urh, A.; Yano, N.; Kim, K.K.; Khazan, N.; Pandita, R.; Sivagnanalingam, U.; Hovanesian, V.; James, N.E.; et al. HE4 overexpression by ovarian cancer promotes a suppressive tumor immune microenvironment and enhanced tumor and macrophage PD-L1 expression. J. Immunol. 2021, 206, 2478–2488.

Li, J.; Dowdy, S.; Tipton, T.; Podratz, K.; Lu, W.-G.; Xie, X.; Jiang, S.-W. HE4 as a biomarker for ovarian and endometrial cancer management. Expert Rev. Mol. Diagn. 2009, 9, 555–566.

Kim, B.; Park, Y.; Kim, B.; Ahn, H.J.; Lee, K.A.; Chung, J.E.; Han, S.W. Diagnostic performance of CA 125, HE4, and risk of ovarian malignancy algorithm for ovarian cancer. J. Clin. Lab. Anal. 2019, 33, e22624.

Huang, J.; Chen, J.; Huang, Q. Diagnostic value of HE4 in ovarian cancer: A meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2018, 231, 35–42.

Scaletta, G.; Plotti, F.; Luvero, D.; Capriglione, S.; Montera, R.; Miranda, A.; Lopez, S.; Terranova, C.; Nardone, C.d.; Angioli, R. The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: A systematic review. Expert Rev. Anticancer Ther. 2017, 17, 827–839.

Hamed, E.O.; Ahmed, H.; Sedeek, O.B.; Mohammed, A.M.; Abd-Alla, A.A.; Ghaffar, H.M.A. Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn. Pathol. 2013, 8, 1.

Barr, C.E.; Funston, G.; Jeevan, D.; Sundar, S.; Mounce, L.T.A.; Crosbie, E.J. The performance of HE4 alone and in combination with CA125 for the detection of ovarian cancer in an enriched primary care population. Cancers 2022, 14, 2124

Lycke, M.; Ulfenborg, B.; Lauesgaard, J.M.; Kristjansdottir, B.; Sundfeldt, K. Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics. Clin. Chem. Lab. Med. 2021, 59, 1954–1962

Jacobs, I.; Oram, D.; Fairbanks, J.; Turner, J.; Frost, C.; Grudzinskas, J.G. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br. J. Obstet. Gynaecol. 1990, 97, 922–929.

Geomini, P.; Kruitwagen, R.; Bremer, G.L.; Cnossen, J.; Mol, B.W.J. The accuracy of risk scores in predicting ovarian malignancy: A systematic review. Obstet. Gynecol. 2009, 113, 384–394.

Tingulstad, S.; Hagen, B.; Skjeldestad, F.E.; Onsrud, M.; Kiserud, T.; Halvorsen, T.; Nustad, K. Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br. J. Obstet. Gynaecol. 1996, 103, 826–831.

Tingulstad, S.; Hagen, B.; Skjeldestad, F.E.; Halvorsen, T.; Nustad, K.; Onsrud, M. The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals. Obstet. Gynecol. 1999, 93, 448–452.

Yamamoto, Y.; Yamada, R.; Oguri, H.; Maeda, N.; Fukaya, T. Comparison of four malignancy risk indices in the preoperative evaluation of patients with pelvic masses. Eur. J. Obstet. Gynecol. Reprod. Biol. 2009, 144, 163–167.]

Ovarian Cancer: The Recognition and Initial Management of Ovarian Cancer; National Collaborating Centre for Cancer (UK): Cardiff, UK, 2011.

Hada, A.; Han, L.-P.; Chen, Y.; Hu, Q.-H.; Yuan, Y.; Liu, L. Comparison of the predictive performance of risk of malignancy indexes 1–4, HE4 and risk of malignancy algorithm in the triage of adnexal masses. J. Ovarian Res. 2020, 13, 46.

Bristow, R.E.; Smith, A.; Zhang, Z.; Chan, D.W.; Crutcher, G.; Fung, E.T.; Munroe, D.G. Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol. Oncol. 2013, 128, 252–259.

Dunton, C.J.; Hutchcraft, M.L.; Bullock, R.G.; Northrop, L.E.; Ueland, F.R. Salvaging detection of early-stage ovarian malignancies when ca125 is not informative. Diagnostics 2021, 11, 1440

Ueland, F.R.; Desimone, C.P.; Seamon, L.G.; Miller, R.A.; Goodrich, S.; Podzielinski, I.; Sokoll, L.; Smith, A.; van Nagell, J.R.; Zhang, Z. Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstet. Gynecol. 2011, 117, 1289–1297.

Longoria, T.C.; Ueland, F.R.; Zhang, Z.; Chan, D.W.; Smith, A.; Fung, E.T.; Munroe, D.G.; Bristow, R.E. Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer. Am. J. Obstet. Gynecol. 2014, 210, 78.e1–78.e9.

Moore, R.G.; McMeekin, D.S.; Brown, A.K.; DiSilvestro, P.; Miller, M.C.; Allard, W.J.; Gajewski, W.; Kurman, R.; Bast, R.C.; Skates, S.J. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol. Oncol. 2009, 112, 40–46.

Wang, H.; Liu, P.; Xu, H.; Dai, H. Early diagonosis of ovarian cancer: Serum HE4, CA125 and ROMA model. Am. J. Transl. Res. 2021, 13, 14141–14148.

Cui, R.; Wang, Y.; Li, Y.; Li, Y. Clinical value of ROMA index in diagnosis of ovarian cancer: Meta-analysis. Cancer Manag. Res. 2019, 11, 2545–2551.

Suri, A.; Perumal, V.; Ammalli, P.; Suryan, V.; Bansal, S.K. Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: A meta-analysis. Sci. Rep. 2021, 11, 17308.

Oranratanaphan, S.; Wanishpongpan, S.; Termrungruanglert, W.; Triratanachat, S. Assessment of diagnostic values among CA-125, RMI, HE4, and ROMA for cancer prediction in women with nonfunctional ovarian cysts. Obstet. Gynecol. Int. 2018, 2018, 7821574.

Jacob, F.; Meier, M.; Caduff, R.; Goldstein, D.; Pochechueva, T.; Hacker, N.; Fink, D.; Heinzelmann-Schwarz, V. No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. Gynecol. Oncol. 2011, 121, 487–491.

Grenache, D.G.; Heichman, K.A.; Werner, T.L.; Vucetic, Z. Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. Clin. Chim. Acta 2015, 438, 358–363

Ngu, S.F.; Chai, Y.K.; Choi, K.M.; Leung, T.W.; Li, J.; Kwok, G.S.T.; Chu, M.M.Y.; Tse, K.Y.; Cheung, V.Y.T.; Ngan, H.Y.S.; et al. Diagnostic performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and expert ultrasound assessment in a pelvic mass classified as inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules. Cancers 2022, 14, 810.

Timmerman, D.; Planchamp, F.; Bourne, T.; Landolfo, C.; Bois, A.D.; Chiva, L.; Cibula, D.; Concin, N.; Fischerova, D.; Froyman, W.; et al. ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors. Int. J. Gynecol. Cancer. 2021, 31, 961–982.

van Calster, B.; Valentin, L.; Froyman, W.; Landolfo, C.; Ceusters, J.; Testa, A.C.; Wynants, L.; Sladkevicius, P.; van Holsbeke, C.; Domali, E.; et al. Validation of models to diagnose ovarian cancer in patients managed surgically or conservatively: Multicentre cohort study. BMJ 2020, 370, m2614.

Nawaz, F.Z.; Kipreos, E.T. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends Endocrinol. Metab. 2022, 33, 159–174.

Parker, N.; Turk, M.J.; Westrick, E.; Lewis, J.D.; Low, P.S.; Leamon, C.P. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal. Biochem. 2005, 338, 284–293.

Köbel, M.; Madore, J.; Ramus, S.J.; Clarke, B.A.; Pharoah, P.D.P.; Deen, S.; Bowtell, D.D.; Odunsi, K.; Menon, U.; Morrison, C.; et al. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: Implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br. J. Cancer. 2014, 111, 2297–2307

Leung, F.; Dimitromanolakis, A.; Kobayashi, H.; Diamandis, E.P.; Kulasingam, V. Folate-receptor 1 (FOLR1) protein is elevated in the serum of ovarian cancer patients. Clin. Biochem. 2013, 46, 1462–1468.

Kurosaki, A.; Hasegawa, K.; Kato, T.; Abe, K.; Hanaoka, T.; Miyara, A.; O’Shannessy, D.J.; Somers, E.B.; Yasuda, M.; Sekino, T.; et al. Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression. Int. J. Cancer. 2016, 138, 1994–2002.

Li, M.; Men, X.; Zhang, X. Diagnostic value of carbohydrate antigen 72-4 combined with carbohydrate antigen 15.3 in ovarian cancer, cervical cancer and endometrial cancer. J. BU ON 2020, 25, 1918–1927.

Anastasi, E.; Manganaro, L.; Granato, T.; Panici, P.B.; Frati, L.; Porpora, M.G. Is CA72-4 a useful biomarker in differential diagnosis between ovarian endometrioma and epithelial ovarian cancer? Dis. Markers. 2013, 35, 331–335.

Shin, K.H.; Kim, H.H.; Kwon, B.S.; Suh, D.S.; Joo, J.K.; Kim, K.H. Clinical usefulness of cancer antigen (CA) 125, human epididymis 4, and CA72-4 levels and risk of ovarian malignancy algorithm values for diagnosing ovarian tumors in Korean patients with and without endometriosis. Ann. Lab. Med. 2020, 40, 40–47.

Granato, T.; Midulla, C.; Longo, F.; Colaprisca, B.; Frati, L.; Anastasi, E. Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2012, 33, 1335–1339.

Xin, B.; Ji, K.Q.; Liu, Y.S.; Zhao, X.D. NFAT overexpression correlates with CA72-4 and poor prognosis of ovarian clear-cell carcinoma subtype. Reprod. Sci. 2021, 28, 745–756.

Negishi, Y.; Iwabuchi, H.; Sakunaga, H.; Sakamoto, M.; Okabe, K.; Sato, H.; Asano, G. Serum and tissue measurements of CA72-4 in ovarian cancer patients. Gynecol. Oncol. 1993, 48, 148–154.

Terry, K.L.; Schock, H.; Fortner, R.T.; Hüsing, A.; Raina, N.; Yamamoto, H.S.; Vitonis, A.F.; Johnson, T.; Overvad, K.; Tjønneland, A. S Mesrine, ovarian cancer in the European EPIC cohort. Clin. Cancer Res. 2017, 22, 4664–4675.

Zheng, X.; Chen, S.; Li, L.; Liu, X.; Liu, X.; Dai, S.; Zhang, P.; Lu, H.; Lin, Z.; Yu, Y.; et al. Evaluation of HE4 and TTR for diagnosis of ovarian cancer : Comparison with CA-125. J. Gynecol. Obstet. Hum. Reprod. 2018, 47, 227–230.

Kozak, K.R.; Su, F.; Whitelegge, J.P.; Faull, K. Characterization of serum biomarkers for detection of early stage ovarian cancer. Proteomics 2005, 125, 4589–4596.

Scholz, C.; Heublein, S.; Lenhard, M.; Friese, K.; Mayr, D.; Jeschke, U. Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients. BMC Res. Notes 2012, 5, 551.

Diamandis, E.P.; Borgoño, C.A.; Scorilas, A.; Harbeck, N.; Dorn, J.; Schmitt, M. Human kallikrein 11: An indicator of favorable prognosis in ovarian cancer patients. Clin. Biochem. 2004, 37, 823–829.

Karlsen, M.A.; Høgdall, E.V.S.; Christensen, I.J.; Borgfeldt, C.; Kalapotharakos, G.; Zdrazilova-Dubska, L.; Chovanec, J.; Lok, C.A.R.; Stiekema, A.; Mutz-Dehbalaie, I.; et al. A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer—An international multicenter study in women with an ovarian mass. Gynecol. Oncol. 2015, 138, 640–646.

Minar, L.; Felsinger, M.; Cermakova, Z.; Zlamal, F.; Bienertova-Vasku, J. Comparison of the Copenhagen Index versus ROMA for the preoperative assessment of women with ovarian tumors. Int. J. Gynecol. Obstet. 2018, 140, 241–246.

Tran, D.T.; Vo, V.K.; Le, M.T.; Chuang, L.; Nguyen, V.Q.H. Copenhagen Index versus ROMA in preoperative ovarian malignancy risk stratification: Result from the first Vietnamese prospective cohort study. Gynecol. Oncol. 2021, 162, 113–119.

Carreras-Dieguez, N.; Glickman, A.; Munmany, M.; Casanovas, G.; Agustí, N.; Díaz-Feijoo, B.; Saco, A.; Sánchez, B.; Gaba, L.; Angeles, M.A.; et al. Comparison of HE4, CA125, ROMA and CPH-I for preoperative assessment of adnexal tumors. Diagnostics 2022, 12, 226.

Zhu, C.; Zhang, N.; Zhong, A.; Xiao, K.; Lu, R.; Guo, L. A combined strategy of TK1, HE4 and CA125 shows better diagnostic performance than risk of ovarian malignancy algorithm (ROMA) in ovarian carcinoma. Clin. Chim. Acta 2022, 524, 43–50.

Hasenburg, A.; Eichkorn, D.; Vosshagen, F.; Obermayr, E.; Geroldinger, A.; Zeillinger, R.; Bossart, M. Biomarker-based early detection of epithelial ovarian cancer based on a five-protein signature in patient’s plasma—A prospective trial. BMC Cancer 2021, 21, 1–8.

Lokman, N.A.; Ricciardelli, C.; Stephens, A.N.; Jobling, T.W.; Hoffmann, P.; Oehler, M.K. Diagnostic value of plasma annexin a2 in early-stage high-grade serous ovarian cancer. Diagnostics 2021, 11, 69.

Russell, M.R.; Graham, C.; D’Amato, A.; Gentry-Maharaj, A.; Ryan, A.; Kalsi, J.K.; Ainley, C.; Whetton, A.D.; Menon, U.; Jacobs, I.; et al. A combined biomarker panel shows improved sensitivity for the early detection of ovarian cancer allowing the identification of the most aggressive type II tumours. Br. J. Cancer 2017, 117, 666–674.

Whitwell, H.J.; Worthington, J.; Blyuss, O.; Gentry-Maharaj, A.; Ryan, A.; Gunu, R.; Kalsi, J.; Menon, U.; Jacobs, I.; Zaikin, A.; et al. Improved early detection of ovarian cancer using longitudinal multimarker models. Br. J. Cancer 2020, 122, 847–856

Katchman, B.A.; Chowell, D.; Wallstrom, G.; Vitonis, A.F.; LaBaer, J.; Cramer, D.W.; Anderson, K.S. Autoantibody biomarkers for the detection of serous ovarian cancer. Gynecol. Oncol. 2017, 146, 129–136.

Anderson, K.S.; Cramer, D.W.; Sibani, S.; Wallstrom, G.; Wong, J.; Park, J.; Qiu, J.; Vitonis, A.; LaBaer, J. Autoantibody signature for the serologic detection of ovarian cancer. J. Proteome Res. 2015, 14, 578–586.

Silwal-Pandit, L.; Langerød, A.; Børresen-Dale, A.-L. Irminger-Finger BARD1 autoantibody blood test for early detection of ovarian cancer. Cold Spring Harb. Perspect. Med. 2017, 7, a026252.

Yang, W.L.; Gentry-Maharaj, A.; Simmons, A.; Ryan, A.; Fourkala, E.O.; Lu, Z.; Baggerly, K.A.; Zhao, Y.; Lu, K.H.; Bowtell, D.; et al. Elevation of TP53 autoantibody before CA125 in preclinical invasive epithelial ovarian cancer. Clin. Cancer Res. 2017, 23, 5912–5922.

Ma, Y.; Wang, X.; Qiu, C.; Qin, J.; Wang, K.; Sun, G.; Jiang, D.; Li, J.; Wang, L.; Shi, J.; et al. Using protein microarray to identify and evaluate autoantibodies to tumor-associated antigens in ovarian cancer. Cancer Sci. 2021, 112, 537–549.

Wang, P.; Qin, J.; Ye, H.; Li, L.; Wang, X.; Zhang, J. Using a panel of multiple tumor-associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer. J. Cell. Biochem. 2019, 120, 3091–3100.

Liu, W.; de la Torre, I.G.; Gutiérrez-Rivera, M.C.; Wang, B.; Liu, Y.; Dai, L.; Qian, W.; Zhang, J.Y. Detection of autoantibodies to multiple tumor-associated antigens (TAAs) in the immunodiagnosis of breast cancer. Tumor Biol. 2015, 36, 1307–1312.

Duan, Y.; Cui, C.; Qiu, C.; Sun, G.; Wang, X.; Wang, P.; Ye, H.; Dai, L.; Shi, J. Serum Autoantibodies against LRDD, STC1, and FOXA1 as Biomarkers in the Detection of Ovarian Cancer. Dis. Markers 2022, 2022, 6657820.

Pilyugin, M.; Ratajska, M.; Stukan, M.; Concin, N.; Zeillinger, R.; Irminger-Finger, I. BARD1 autoantibody blood test for early detection of ovarian cancer. Genes 2021, 12, 969.

Qiu, C.; Duan, Y.; Wang, B.; Shi, J.; Wang, P.; Ye, H.; Dai, L.; Zhang, J.; Wang, X. Serum Anti-PDLIM1 autoantibody as diagnostic marker in ovarian cancer. Front. Immunol. 2021, 12, 698312.

Pessoa, L.S.; Heringer, M.; Ferrer, V.P. ctDNA as a cancer biomarker: A broad overview. Crit. Rev. Oncol. Hematol. 2020, 155, 103109.

Lu, Y.; Li, L. The prognostic value of circulating tumor DNA in ovarian cancer: A meta-analysis. Technol. Cancer Res. Treat. 2021, 20, 1–12.

Li, B.; Pu, K.; Ge, L.; Wu, X. Diagnostic significance assessment of the circulating cell-free DNA in ovarian cancer: An updated meta-analysis. Gene 2019, 714, 143993.

Wise, D.R.; Thompson, C.B. Glutamine addiction: A new therapeutic target in cancer. Trends Biochem. Sci. 2010, 35, 427–433.

Morgan, S.R.; Whiteley, J.; Donald, E.; Smith, J.; Eisenberg, M.T.; Kallam, E.; Kam-Morgan, L. Comparison of KRAS mutation assessment in tumor DNA and circulating free DNA in plasma and serum samples. Clin. Med. Insights Pathol. 2012, 15–22.

Gong, G.; Lin, T.; Yuan, Y. Integrated analysis of gene expression and DNA methylation profiles in ovarian cancer. J. Ovarian Res. 2020, 13, 30.

Singh, A.; Gupta, S.; Badarukhiya, J.A.; Sachan, M. Detection of aberrant methylation of HOXA9 and HIC1 through multiplex MethyLight assay in serum DNA for the early detection of epithelial ovarian cancer. Int. J. Cancer 2020, 147, 1740–1752.

Melnikov, A.; Scholtens, D.; Godwin, A.; Levenson, V. Differential methylation profile of ovarian cancer in tissues and plasma. J. Mol. Diagn. 2009, 11, 60–65.

Singh, A.; Gupta, S.; Sachan, M. Evaluation of the diagnostic potential of candidate hypermethylated genes in epithelial ovarian cancer in North Indian Population. Front. Mol. Biosci. 2021, 8, 719056.

Flores, C.P.; García-Vázquez, R.; Rincón, D.G.; Ruiz-García, E.; de la Vega, H.A.; Marchat, L.A.; Vera, Y.M.S.; López-Camarillo, C. MicroRNAs driving invasion and metastasis in ovarian cancer: Opportunities for translational medicine (Review). Int. J. Oncol. 2017, 50, 1461–1476.

Maeda, K.; Sasaki, H.; Ueda, S.; Miyamoto, S.; Terada, S.; Konishi, H.; Kogata, Y.; Ashihara, K.; Fujiwara, S.; Tanaka, Y.; et al. Serum exosomal microRNA-34a as a potential biomarker in epithelial ovarian cancer. J. Ovarian Res. 2020, 13, 47.

Teng, Y.; Su, X.; Zhang, X.; Zhang, Y.; Li, C.; Niu, W.; Liu, C.; Qu, K. miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): Evidence based on miRNA meta-signature and clinical investigations. Oncotarget 2016, 7, 81621–81633.

Zhu, Z.; Chen, Z.; Wang, M.; Zhang, M.; Chen, Y.; Yang, X.; Zhou, C.; Liu, Y.; Hong, L.; Zhang, L. Detection of plasma exosomal miRNA-205 as a biomarker for early diagnosis and an adjuvant indicator of ovarian cancer staging. J. Ovarian Res. 2022, 15, 27.