Circulating tumor markers are not routinely used in patients with endometrial cancer (EC). This pilot study evaluated the role of monitoring new biomarkers DJ1 and L1CAM, in correlation with CA125 and HE4, for the effects of anticancer treatment and preoperative management in EC patients. Serial serum levels of DJ1, L1CAM, CA125 and HE4 were collected in 65 enrolled patients. Serum DJ1, L1CAM, CA125 and HE4 levels were significantly higher at the time of diagnosis compared to those measured during follow-up (FU). In patients with recurrent disease, serum DJ1, CA125 and HE4 levels were significantly higher at the time of recurrence compared to levels in disease-free patients. Serum L1CAM levels were also higher in patients with recurrence but without reaching statistical significance. While DJ1 levels were not affected by any of the observed patient-related characteristics, L1CAM levels were significantly higher in patients with age ≥60 years who were overweight. At the time of EC diagnosis, DJ1 and L1CAM serum levels did not correlate with stage, histological type or risk of recurrence. This is a preliminary description of the potential of serial DJ1 and L1CAM serum level measurement for monitoring the effects of treatment in EC patients.

Department of Internal Medicine Hematology and Oncology Masaryk University and University Hospital 625 00 Brno Czech Republic

Department of Laboratory Medicine Department of Laboratory Methods Masaryk University and University Hospital 625 00 Brno Czech Republic

Department of Laboratory Medicine Masaryk Memorial Cancer Institute 602 00 Brno Czech Republic

Department of Obstetrics and Gynecology Masaryk University and University Hospital 625 00 Brno Czech Republic

Department of Pathology Masaryk University and University Hospital 625 00 Brno Czech Republic

Faculty of Medicine Institute of Biostatistics and Analyses Masaryk University 625 00 Brno Czech Republic

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Bidart J.-M., Thuillier F., Augereau C., Chalas J., Daver A., Jacob N., Labrousse F., Voitot H. Kinetics of Serum Tumor Marker Concentrations and Usefulness in Clinical Monitoring. Clin. Chem. 1999;45:1695–1707. doi: 10.1093/clinchem/45.10.1695. PubMed DOI

Ayhan A., Reed N., Gultekin M., Dursun P., editors. Textbook of Gynaecological Oncology. Günes Publishing; Ankara, Turkey: 2017.

Bast J.R., Xu F.-J., Yu Y.-H., Barnhill S., Zhang Z., Mills G. CA 125: The past and the Future. Int. J. Biol. Mark. 1998;13:179–187. doi: 10.1177/172460089801300402. PubMed DOI

Sood A.K., Buller R.E., Burger R.A., Dawson J.D., Sorosky J.I., Berman M. Value of Preoperative CA 125 Level in the Management of Uterine Cancer and Prediction of Clinical Outcome. Obstet. Gynecol. 1997;90:441–447. doi: 10.1016/S0029-7844(97)00286-X. PubMed DOI

Reijnen C., Visser N.C., Kasius J.C., Boll D., Geomini P.M., Ngo H., Van Hamont D., Pijlman B.M., Vos M.C., Bulten J., et al. Improved preoperative risk stratification with CA-125 in low-grade endometrial cancer: A multicenter prospective cohort study. J. Gynecol. Oncol. 2019;30:e70. doi: 10.3802/jgo.2019.30.e70. PubMed DOI PMC

Fischerova D. Ultrasound scanning of the pelvis and abdomen for staging of gynecological tumors: A review. Ultrasound Obstet. Gynecol. 2011;38:246–266. doi: 10.1002/uog.10054. PubMed DOI

Kalogera E., Scholler N., Powless C., Weaver A., Drapkin R., Li J., Jiang S.-W., Podratz K., Urban N., Dowdy S.C. Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer. Gynecol. Oncol. 2012;124:270–275. doi: 10.1016/j.ygyno.2011.10.025. PubMed DOI PMC

Moore R.G., Brown A.K., Miller M.C., Badgwell D., Lu Z., Allard W.J., Granai C., Bast R., Lu K. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecol. Oncol. 2008;110:196–201. doi: 10.1016/j.ygyno.2008.04.002. PubMed DOI PMC

Lo S., Cheng D., Ng T., Wong L., Ngan H. Prognostic Significance of Tumour Markers in Endometrial Cancer. Tumor Biol. 1997;18:241–249. doi: 10.1159/000218037. PubMed DOI

Bignotti E., Ragnoli M., Zanotti L., Calza S., Falchetti M.L., Lonardi S., Bergamelli S., Bandiera E., Tassi R.A., Romani C., et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br. J. Cancer. 2011;104:1418–1425. doi: 10.1038/bjc.2011.109. PubMed DOI PMC

Zanotti L., Bignotti E., Calza S., Bandiera E., Ruggeri G., Galli C., Tognon G., Ragnoli M., Romani C., Tassi R.A., et al. Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. Clin. Chem. Lab. Med. 2012;50:2189–2198. doi: 10.1515/cclm-2011-0757. PubMed DOI

Brennan D.J., Hackethal A., Mann K.P., Mutz-Dehbalaie I., Fiegl H., Marth C., Obermair A. Serum HE4 detects recurrent endometrial cancer in patients undergoing routine clinical surveillance. BMC Cancer. 2015;15:33. doi: 10.1186/s12885-015-1028-0. PubMed DOI PMC

Abbink K., Zusterzeel P.L., Geurts-Moespot A.J., van Herwaarden A.E., Pijnenborg J.M., Sweep F., Massuger L.F. HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients. Tumor Biol. 2018;40:101042831875710. doi: 10.1177/1010428318757103. PubMed DOI

Morelli M., Scumaci D., Di Cello A., Venturella R., Donato G., Faniello M.C., Quaresima B., Cuda G., Zullo F., Costanzo F.S. DJ-1 in Endometrial Cancer: A Possible Biomarker to Improve Differential Diagnosis Between Subtypes. Int. J. Gynecol. Cancer. 2014;24:649–658. doi: 10.1097/IGC.0000000000000102. PubMed DOI

Di Cello A., Di Sanzo M., Perrone F.M., Santamaria G., Rania E., Angotti E., Venturella R., Mancuso S., Zullo F., Cuda G., et al. DJ-1 is a reliable serum biomarker for discriminating high-risk endometrial cancer. Tumor Biol. 2017;39:101042831770574. doi: 10.1177/1010428317705746. PubMed DOI

Benati M., Montagnana M., Danese E., Paviati E., Giudici S., Ruzzenente O., Franchi M., Lippi G. The clinical significance of DJ-1 and HE4 in patients with endometrial cancer. J. Clin. Lab. Anal. 2018;32:e22223. doi: 10.1002/jcla.22223. PubMed DOI PMC

Fogel M., Gutwein P., Mechtersheimer S., Riedle S., Stoeck A., Smirnov A., Edler L., Ben-Arie A., Huszar M., Altevogt P. L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. Lancet. 2003;362:869–875. doi: 10.1016/S0140-6736(03)14342-5. PubMed DOI

Van Gool I.C., Stelloo E., Nout R.A., Nijman H.W., Edmondson R., Church D.N., Mackay H.J., Leary A., Powell M.E., Mileshkin L., et al. Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer. Mod. Pathol. 2016;29:174–181. doi: 10.1038/modpathol.2015.147. PubMed DOI

Wojciechowski M., Głowacka E., Wilczyński M., Pękala-Wojciechowska A., Malinowski A. The sL1CAM in sera of patients with endometrial and ovarian cancers. Arch. Gynecol. Obstet. 2016;295:225–232. doi: 10.1007/s00404-016-4226-3. PubMed DOI PMC

Tangen I.L., Kopperud R.K., Visser N.C., Staff A.C., Tingulstad S., Marcickiewicz J., Amant F., Bjørge L., Pijnenborg J.M., Salvesen H.B., et al. Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients. Br. J. Cancer. 2017;117:840–847. doi: 10.1038/bjc.2017.235. PubMed DOI PMC

Frühauf F., Dvořák M., Haaková L., Hašlík L., Herboltová P., Chaloupková B., Kožnarová J., Kubešová B., Lukáčová I., Marek R., et al. Ultrasound staging of endometrial cancer—Recommended methodology of examination. Ceska Gynekol. 2014;79:466–476. PubMed

Sobin L.H., Gospodarowicz M.K., Wittekind C. TNM Classification of Malignant Tumours. Wiley; Somerset, UK: 2011.

Colombo N., Creutzberg C., Amant F., Bosse T., González-Martín A., Ledermann J., Marth C., Nout R., Querleu D., Mirza M.R., et al. ESMO–ESGO–ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up. Radiother. Oncol. 2015;117:559–581. doi: 10.1016/j.radonc.2015.11.013. PubMed DOI

Kurman R.J., International Agency for Research on Cancer; World Health Organization, editor. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. World Health Organization classification of tumours; International Agency for Research on Cancer; Lyon, France: 2014.

FIGO Committee on Gynecologic Oncology FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int. J. Gynecol. Obstet. 2014;125:97–98. doi: 10.1016/j.ijgo.2014.02.003. PubMed DOI

Diamandis E.P. Tumor Markers: Physiology, Pathobiology, Technology and Clinical Application. AACC Press; Washington, WA, USA: 2002.

Burke W.M., Orr J., Leitao M., Salom E., Gehrig P., Olawaiye A.B., Brewer M., Boruta D., Villella J., Herzog T., et al. Endometrial cancer: A review and current management strategies: Part I. Gynecol. Oncol. 2014;134:385–392. doi: 10.1016/j.ygyno.2014.05.018. PubMed DOI

Burke W.M., Orr J., Leitao M., Salom E., Gehrig P., Olawaiye A.B., Brewer M., Boruta D., Herzog T.J., Abu Shahin F. Endometrial cancer: A review and current management strategies: Part II. Gynecol. Oncol. 2014;134:393–402. doi: 10.1016/j.ygyno.2014.06.003. PubMed DOI

Salani R., Backes F.J., Fung M.F.K., Holschneider C.H., Parker L.P., Bristow R.E., Goff B.A. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am. J. Obstet. Gynecol. 2011;204:466–478. doi: 10.1016/j.ajog.2011.03.008. PubMed DOI

Patsner B., Orr J.W., Mann W.J. Use of serum CA 125 measurement in posttreatment surveillance of early-stage endometrial carcinoma. Am. J. Obstet. Gynecol. 1990;162:427–429. doi: 10.1016/0002-9378(90)90400-2. PubMed DOI

Rose P.G., Sommers R.M., Reale F.R., Hunter R.E., Fournier L., Nelson B.E. Serial serum CA 125 measurements for evaluation of recurrence in patients with endometrial carcinoma. Obstet. Gynecol. 1994;84:12–16. PubMed

Fung-Kee-Fung M., Dodge J., Elit L., Lukka H., Chambers A., Oliver T. Follow-up after primary therapy for endometrial cancer: A systematic review. Gynecol. Oncol. 2006;101:520–529. doi: 10.1016/j.ygyno.2006.02.011. PubMed DOI

Creutzberg C.L., van Putten W.L., Koper P.C., Lybeert M.L., Jobsen J.J., Wárlám-Rodenhuis C.C., De Winter K.A., Lutgens L.C., Bergh A.C.V.D., van der Steen-Banasik E., et al. Survival after relapse in patients with endometrial cancer: Results from a randomized trial. Gynecol. Oncol. 2003;89:201–209. doi: 10.1016/S0090-8258(03)00126-4. PubMed DOI

Smith C.J., Heeren M., Nicklin J.L., Perrin L., Land R., Crandon A.J., Obermair A. Efficacy of routine follow-up in patients with recurrent uterine cancer. Gynecol. Oncol. 2007;107:124–129. doi: 10.1016/j.ygyno.2007.06.002. PubMed DOI

Angioli R., Capriglione S., Scaletta G., Aloisi A., Miranda A., Nardone C.D.C., Terranova C., Plotti F. The role of HE4 in endometrial cancer recurrence: How to choose the optimal follow-up program. Tumor Biol. 2015;37:4973–4978. doi: 10.1007/s13277-015-4324-z. PubMed DOI

Coppolino G., Bolignano D., Rivoli L., Mazza G., Presta P., Fuiano G. Tumour Markers and Kidney Function: A Systematic Review. BioMed Res. Int. 2014;2014:1–9. doi: 10.1155/2014/647541. PubMed DOI PMC

Chovanec J., Selingerova I., Greplova K., Antonsen S.L., Nalezinska M., Høgdall C., Høgdall E., Søgaard-Andersen E., Jochumsen K., Fabian P., et al. Adjustment of serum HE4 to reduced glomerular filtration and its use in biomarker-based prediction of deep myometrial invasion in endometrial cancer. Oncotarget. 2017;8:108213–108222. doi: 10.18632/oncotarget.22599. PubMed DOI PMC

Saarelainen S.K., Peltonen N., Lehtimäki T., Perheentupa A., Vuento M.H., Mäenpää J.U. Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma. Am. J. Obstet. Gynecol. 2013;209:142.e1–142.e6. doi: 10.1016/j.ajog.2013.04.014. PubMed DOI

Reijnen C., Gogou E., Visser N.C.M., Engerud H., Ramjith J., Van Der Putten L.J.M., Van De Vijver K., Santacana M., Bronsert P., Bulten J., et al. Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: A development and validation study. PLoS Med. 2020;17:e1003111. doi: 10.1371/journal.pmed.1003111. PubMed DOI PMC

Kandoth C., Schultz N., Cherniack A.D., Akbani R., Liu Y., Shen H., Robertson A.G., Pashtan I., Shen R., Benz C.C., et al. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. doi: 10.1038/nature12113. PubMed DOI PMC

Murali R., Delair D.F., Bean S.M., Abu-Rustum N.R., Soslow R.A. Evolving Roles of Histologic Evaluation and Molecular/Genomic Profiling in the Management of Endometrial Cancer. J. Natl. Compr. Cancer Netw. 2018;16:201–209. doi: 10.6004/jnccn.2017.7066. PubMed DOI PMC

Urick M.E., Bell D.W. Clinical actionability of molecular targets in endometrial cancer. Nat. Rev. Cancer. 2019;19:510–521. doi: 10.1038/s41568-019-0177-x. PubMed DOI PMC

Concin N., Matias-Guiu X., Vergote I., Cibula D., Mirza M.R., Marnitz S., Ledermann J., Bosse T., Chargari C., Fagotti A., et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int. J. Gynecol. Cancer. 2021;31:12–39. doi: 10.1136/ijgc-2020-002230. PubMed DOI

Raffone A., Travaglino A., Gabrielli O., Micheli M., Zuccalà V., Bitonti G., Camastra C., Gargiulo V., Insabato L., Zullo F. Clinical features of ProMisE groups identify different phenotypes of patients with endometrial cancer. Arch. Gynecol. Obstet. 2021;303:1393–1400. doi: 10.1007/s00404-021-06028-4. PubMed DOI PMC

Santoro A., Angelico G., Travaglino A., Inzani F., Arciuolo D., Valente M., D’Alessandris N., Scaglione G., Fiorentino V., Raffone A., et al. New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines. Cancers. 2021;13:2623. doi: 10.3390/cancers13112623. PubMed DOI PMC

Troisi J., Raffone A., Travaglino A., Belli G., Belli C., Anand S., Giugliano L., Cavallo P., Scala G., Symes S., et al. Development and Validation of a Serum Metabolomic Signature for Endometrial Cancer Screening in Postmenopausal Women. JAMA Netw. Open. 2020;3:e2018327. doi: 10.1001/jamanetworkopen.2020.18327. PubMed DOI PMC

Raffone A., Troisi J., Boccia D., Travaglino A., Capuano G., Insabato L., Mollo A., Guida M., Zullo F. Metabolomics in endometrial cancer diagnosis: A systematic review. Acta Obstet. Gynecol. Scand. 2020;99:1135–1146. doi: 10.1111/aogs.13847. PubMed DOI