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DOI: 10.1055/a-2422-0354
Neue Tumormarker bei Hodentumoren – im hier und jetzt und in der Zukunft
New tumor markers for testicular cancer – in the here and now and in the futureZusammenfassung
Keimzelltumore sind die häufigsten Tumorentitäten bei jungen Männern. Seit der Einführung der platinbasierten Chemotherapie in den 1970er-Jahren können die meisten Patienten trotz der Aggressivität der Keimzelltumoren kurativ behandelt werden. Für Diagnostik, Therapiemonitoring und Nachsorge werden möglichst optimale Serumtumormarker benötigt, an die hohe Anforderungen gestellt werden. Die konventionellen Hodentumormarker humanes Choriongonadotropin (hCG), Alpha-Fetoprotein (AFP) und Laktatdehydrogenase (LDH) werden diesen Anforderungen nur mit einer unzureichenden Sensitivität gerecht (30–70%). Die in den letzten Jahrzehnten untersuchten Marker wie PLAP, CEA und NSE haben sich nicht durchgesetzt. Aktuell wird besonders die miRNA-371 erforscht. Gesicherte Erkenntnisse liegen vor für das initiale Staging mit deutlich besseren Spezifitäten der miRNA-371 im Vergleich zu den konventionellen Tumormarkern. Für weitere mögliche klinische Einsatzgebiete wie der Nachsorge, dem Therapiemonitoring oder bei Residualtumoren erfolgen weitere prospektive Studien, um auch hier das revolutionäre Potenzial der miRNA-371 zu untersuchen. Weiterhin wird aktuell an zirkulierenden Tumorzellen (CTCs) und zellfreier DNA (cfNA) in verschiedenen Anwendungsgebieten geforscht. In Bezug auf Keimzelltumore des Hodens stehen diese Analysen jedoch noch am Anfang, aber man erhofft sich hiervon eine weitere suffiziente Möglichkeit Serumtumormarker einzusetzen.
Abstract
Germ cell tumors of the testis are the most common tumor entities in young men. Since the introduction of platinum-based chemotherapy in the 1970s, most patients can be cured despite the aggressiveness of germ cell tumors. Optimal serum tumor markers are required for diagnostics, therapy monitoring and aftercare, and these are subject to high requirements. The conventional testicular tumor markers human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) only meet these requirements with insufficient sensitivity (30–70%). The markers investigated in recent decades, such as PLAP, CEA and NSE, have not become established. Currently, miRNA-371 is being researched in particular. Reliable findings are available for initial staging with significantly better specificities of miRNA-371 compared to conventional tumor markers. Further prospective studies are being conducted for other possible clinical applications, such as follow-up care, therapy monitoring or residual tumors, in order to investigate the revolutionary potential of miRNA-371 in these areas as well. Research is also currently being conducted on circulating tumor cells (CTCs) and cell-free DNA (cfNA) in various areas of application. With regard to germ cell tumors of the testis, however, these analyses are still in their infancy, but it is hoped that this will provide a further sufficient opportunity to use serum tumor markers.
Publication History
Received: 12 June 2024
Accepted after revision: 20 September 2024
Article published online:
23 October 2024
© 2024. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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Literatur
- 1 S3-Leitlinie Diagnostik, Therapie und Nachsorge der Keimzelltumoren des Hodens (Version 1.1, 2020).
- 2 Chovanec M, Cheng L. Advances in diagnosis and treatment of testicular cancer. BMJ 2022; 379: e070499
- 3 International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594-603
- 4 Kliesch S, Schmidt S, Wilborn D. et al. Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages. Urol Int 2021; 105: 169-180
- 5 Paffenholz P, Heidegger IM, Kuhr K. et al. Non-Guideline-concordant Treatment of Testicular Cancer Is Associated With Reduced Relapse-free Survival. Clin Genitourin Cancer 2018; 6: e243-e250
- 6 Berney DM, Cree I, Rao V. et al. An introduction to the WHO 5th edition 2022 classification of testicular tumours. Histopathology 2022; 81: 459-466
- 7 Fankhauser CD, Gerke TA, Roth L. et al. Pre-orchiectomy tumor marker levels should not be used for International Germ Cell Consensus Classification (IGCCCG) risk group assignment. J Cancer Res Clin Oncol 2019; 145: 781-785
- 8 Majewski M, Paffenholz P, Ruf C. et al. Misuse of tumor marker levels leads to an insufficient International Germ Cell Consensus Classification (IGCCCG) risk group assignment and impaired treatment. Cancer Med 2023; 12: 16829-16836
- 9 Lange PH, Winfield HN. Biological markers in urologic cancer. Cancer 1987; 60 (Suppl. 03) 464-472
- 10 Fizazi K, Culine S, Kramar A. et al. Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 2004; 22: 3868-3876
- 11 Sturgeon JF, Moore MJ, Kakiashvili DM. et al. Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the Princess Margaret Hospital's experience. Eur Urol 2011; 59: 556-562
- 12 Zondek B. Maligne Hodentumoren und Hypophysenvorderlappenhormone. Hormonale Diagnostik aus Harn, Hydrocelenflüssigkeit und Tumorgewebe. Klinische Wochenschr 1932; 11: 274-279
- 13 Javadpour N, McIntire KR, Waldmann TA. Immunochemical determination of human chorionic gonadotropin and alpha-fetoprotein in sera and tumors of patients with testicular cancer. Natl Cancer Inst Monogr 1978; 49: 209-213
- 14 Norgaard-Pedersen B, Schultz HP, Arends J. et al. Tumour markers in testicular germ cell tumours. Five-year experience from the DATECA Study 1976–1980. Acta Radiol Oncol 1984; 23: 287-294
- 15 Dieckmann KP, Simonsen-Richter H, Kulejewski M. et al. Serum Tumour Markers in Testicular Germ Cell Tumours: Frequencies of Elevated Levels and Extents of Marker Elevation Are Significantly Associated with Clinical Parameters and with Response to Treatment. Biomed Res Int 2019; 2019: 5030349
- 16 Egan J, Salari K. Biomarkers in Testicular Cancer: Classic Tumor Markers and Beyond. Urol Clin North Am 2023; 50: 133-143
- 17 Mir MC, Pavan N, Gonzalgo ML. Current Clinical Applications of Testicular Cancer Biomarkers. Urol Clin North Am 2016; 43: 119-125
- 18 Takizawa A, Kawai K, Kawahara T. et al. The usefulness of testosterone administration in identifying false-positive elevation of serum human chorionic gonadotropin in patients with germ cell tumor. J Cancer Res Clin Oncol 2018; 144: 109-115
- 19 Szymendera JJ, Zborzil J, Sikorowa L. et al. Evaluation of five tumor markers (AFP, CEA, hCG, hPL and SP1) in monitoring therapy and follow-up of patients with testicular germ cell tumors. Oncology 1983; 40: 1-10
- 20 Kuzmits R, Schernthaner G, Krisch K. Serum neuron-specific enolase. A marker for responses to therapy in seminoma. Cancer 1987; 60: 1017-1021
- 21 Lajer H, Daugaard G, Andersson AM. et al. Clinical use of serum TRA-1–60 as tumor marker in patients with germ cell cancer. Int J Cancer 2002; 100: 244-246
- 22 Neumann A, Keller T, Jocham D. et al. Human placental alkaline phosphatase (hPLAP) is the most frequently elevated serum marker in testicular cancer. Aktuelle Urol 2011; 42: 311-315
- 23 Nielsen OS, Munro AJ, Duncan W. et al. Is placental alkaline phosphatase (PLAP) a useful marker for seminoma?. Eur J Cancer 1990; 26: 1049-1054
- 24 Pottek T, Muller M, Blum T. et al. Tu-M2-PK in the blood of testicular and cubital veins in men with testicular cancer. Anticancer Res 2000; 20: 5029-5033
- 25 Lobo J, Gillis AJM, Jeronimo C. et al. Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic. Int J Mol Sci 2019; 20: 258
- 26 Eini R, Dorssers LC, Looijenga LH. Role of stem cell proteins and microRNAs in embryogenesis and germ cell cancer. Int J Dev Biol 2013; 57: 319-332
- 27 Suh MR, Lee Y, Kim JY. et al. Human embryonic stem cells express a unique set of microRNAs. Dev Biol 2004; 270: 488-498
- 28 Gillis AJ, Stoop HJ, Hersmus R. et al. High-throughput microRNAome analysis in human germ cell tumours. J Pathol 2007; 213: 319-328
- 29 Syring I, Bartels J, Holdenrieder S. et al. Circulating serum miRNA (miR-367–3p, miR-371a-3p, miR-372–3p and miR-373–3p) as biomarkers in patients with testicular germ cell cancer. J Urol 2015; 193: 331-337
- 30 Agthoven T van, Looijenga LHJ. Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test). Oncotarget 2017; 8: 58037-58049
- 31 Dieckmann KP, Radtke A, Spiekermann M. et al. Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours. Eur Urol 2017; 71: 213-220
- 32 Radtke A, Cremers JF, Kliesch S. et al. Can germ cell neoplasia in situ be diagnosed by measuring serum levels of microRNA371a-3p?. J Cancer Res Clin Oncol 2017; 143: 2383-2392
- 33 Nestler T, Schoch J, Belge G. et al. MicroRNA-371a-3p-The Novel Serum Biomarker in Testicular Germ Cell Tumors. Cancers (Basel) 2023; 15: 3944
- 34 Sharbidre KG, Lockhart ME. Imaging of scrotal masses. Abdom Radiol (NY) 2020; 45: 2087-2108
- 35 Belge G, Dumlupinar C, Nestler T. et al. Detection of Recurrence through microRNA-371a-3p Serum Levels in a Follow-up of Stage I Testicular Germ Cell Tumors in the DRKS-00019223 Study. Clin Cancer Res 2024; 30: 404-412
- 36 Lobo J, Leao R, Gillis AJM. et al. Utility of Serum miR-371a-3p in Predicting Relapse on Surveillance in Patients with Clinical Stage I Testicular Germ Cell Cancer. Eur Urol Oncol 2021; 4: 483-491
- 37 Radtke A, Hennig F, Ikogho R. et al. The Novel Biomarker of Germ Cell Tumours, Micro-RNA-371a-3p, Has a Very Rapid Decay in Patients with Clinical Stage 1. Urol Int 2018; 100: 470-475
- 38 Rosas Plaza X, Agthoven T van, Meijer C. et al. miR-371a-3p, miR-373-3p and miR-367-3p as Serum Biomarkers in Metastatic Testicular Germ Cell Cancers Before, During and After Chemotherapy. Cells 2019; 8: 1221
- 39 Umbreit EC, McIntosh AG, Suk-Ouichai C. et al. Intraoperative and early postoperative complications in postchemotherapy retroperitoneal lymphadenectomy among patients with germ cell tumors using validated grading classifications. Cancer 2020; 126: 4878-4885
- 40 Nestler T, Paffenholz P, Pfister D. et al. Adjunctive Surgery Is Often Without Oncological Benefit at Time of Postchemotherapy Retroperitoneal Lymph Node Dissection. J Urol 2024; 211: 426-435
- 41 Daneshmand S, Albers P, Fossa SD. et al. Contemporary management of postchemotherapy testis cancer. Eur Urol 2012; 62: 867-876
- 42 Paffenholz P, Nestler T, Hoier S. et al. External validation of 2 models to predict necrosis/fibrosis in postchemotherapy residual retroperitoneal masses of patients with advanced testicular cancer. Urol Oncol 2019; 37: 809 e9–e18
- 43 Dieckmann KP, Radtke A, Geczi L. et al. Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. J Clin Oncol 2019; 37: 1412-1423
- 44 Dieckmann KP, Grobelny F, Soave A. et al. Serum Levels of MicroRNA-371a-3p for Predicting the Histology of Postchemotherapy Residual Masses of Germ Cell Tumours. Eur Urol Focus 2024;
- 45 EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN: 978-94-92671-19-6
- 46 Corcoran RB, Chabner BA. Application of Cell-free DNA Analysis to Cancer Treatment. N Engl J Med 2018; 379: 1754-1765
- 47 Ellinger J, Wittkamp V, Albers P. et al. Cell-free circulating DNA: diagnostic value in patients with testicular germ cell cancer. J Urol 2009; 181: 363-371
- 48 Krasic J, Skara L, Bojanac AK. et al. The utility of cfDNA in TGCT patient management: a systematic review. Ther Adv Med Oncol 2022; 14 17588359221090365
- 49 Bettegowda C, Sausen M, Leary RJ. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6: 224ra24
- 50 Bart J, Groen HJ, Graaf WT van der. et al. An oncological view on the blood-testis barrier. Lancet Oncol 2002; 3: 357-363
- 51 Agashe R, Kurzrock R. Circulating Tumor Cells: From the Laboratory to the Cancer Clinic. Cancers (Basel) 2020; 12: 2361
- 52 Banko P, Lee SY, Nagygyorgy V. et al. Technologies for circulating tumor cell separation from whole blood. J Hematol Oncol 2019; 12: 48
- 53 Hao SJ, Wan Y, Xia YQ. et al. Size-based separation methods of circulating tumor cells. Adv Drug Deliv Rev 2018; 125: 3-20
- 54 Nikanjam M, Kato S, Kurzrock R. Liquid biopsy: current technology and clinical applications. J Hematol Oncol 2022; 15: 131
- 55 Su DW, Nieva J. Biophysical technologies for understanding circulating tumor cell biology and metastasis. Transl Lung Cancer Res 2017; 6: 473-485
- 56 Plaks V, Koopman CD, Werb Z. Cancer. Circulating tumor cells. Science 2013; 341: 1186-1188
- 57 Nastaly P, Ruf C, Becker P. et al. Circulating tumor cells in patients with testicular germ cell tumors. Clin Cancer Res 2014; 20: 3830-3841