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Molekulares Tumorboard – Urothelkarzinom

  • M. C. HupeEmail author
  • G. Gakis
  • R. Seiler
Leitthema
  • 6 Downloads

Zusammenfassung

Hintergrund

Molekulare Tumorboards (MTB) finden immer mehr Einzug in den klinischen Alltag. Es gibt viele molekulare Alterationen beim Urothelkarzinom, die für potentielle Empfehlungen seitens eines MTB genutzt werden könnten.

Ziel der Arbeit

Es werden verschiedene molekulare Alterationen und deren Korrelation mit klinischen Endpunkten aufgezeigt sowie konkrete Fragestellungen an ein „MTB Urothelkarzinom“ herausgearbeitet.

Material und Methoden

Dieses ist ein deskriptiver Review mittels Literaturrecherche in PubMed.

Ergebnisse

Aufgrund der heterogenen molekularen Alterationen beim Urothelkarzinom fokussiert sich die aktuelle Biomarkerforschung nicht auf singuläre Biomarker, sondern auf Biomarkerpanels oder Classifier. Identifizierte molekulare Subtypen des Urothelkarzinoms werden aktuell mit verschiedenen Endpunkten korreliert. Zirkulierende Tumorzellen oder Tumor-DNA sind ebenso Gegenstand der aktuellen Biomarkerforschung beim Urothelkarzinom. Neben dem Therapieansprechen und der Prognose sind beim Urothelkarzinom auch molekulare Marker zur Optimierung des klinischen Stagings vor etwaiger radikaler Zystektomie oder zur Selektion für eine neoadjuvante Chemotherapie von Interesse. Mit Erdafitinib ist seit kurzem nun die erste auf eine molekulare Alteration (FGFR-Alteration, „fibroblast growth factor receptor“) zielgerichtete Substanz beim Urothelkarzinom zugelassen (in den USA).

Diskussion

Es fehlt bei den vielen identifizierten Biomarkern eine unabhängige Validierung für eine Implementierung in den Alltag. Zudem gibt es beim Urothelkarzinom im Gegensatz zu manch anderen Karzinomen keine einzelne Treibermutation, die die Entwicklung von Biomarkern und zielgerichteten Therapien einfacher gestaltet.

Schlüsselwörter

Prädiktionsmarker Biomarker, Tumor Alterationen, molekulare Prognosemarker 

Abkürzungen

CSS

Krebsspezifisches Überleben

LK

Lymphknoten

MIBC

Muskelinvasives Blasenkarzinom

MTB

Molekulares Tumorboard

NAC

Neoadjuvante Chemotherapie

OS

Gesamtüberleben

RC

Radikale Zystektomie

RFS

Rezidivfreies Überleben

TMT

Trimodale Therapie

Molecular tumor board—urothelial cancer

Abstract

Background

Molecular tumor boards (MTB) are becoming more common. There are several molecular alterations in urothelial cancer a molecular tumor board can potentially rely on.

Objectives

The aim is to specify molecular alterations and their correlations with different clinical endpoints and to highlight potential questions addressed to a MTB for urothelial cancer.

Materials and methods

Descriptive review of the literature based on PubMed.

Results

The landscape of molecular alterations in urothelial cancer is heterogeneous. Thus, recent biomarker research has been focusing on biomarker panels and classifiers instead of single biomarkers. Recently, molecular subtypes of urothelial cancer have been identified and correlated with different clinical endpoints. Furthermore, circulating tumor cells and tumor DNA are under investigation as potential biomarkers. In addition to treatment response and prognosis, molecular markers are also needed to improve clinical staging prior to radical cystectomy or for proper patient selection for neoadjuvant chemotherapy. Erdafitinib is the first targeted therapy (fibroblast growth factor receptor [FGFR] alteration) in urothelial cancer that was recently approved (in the USA).

Conclusions

Due to the lack of external validation, none of the identified biomarkers is currently established in clinical routine. In addition, there is no single driver mutation in urothelial cancer that facilitates the development of biomarkers and targeted therapies.

Keywords

Predictive marker Biomarkers, cancer Alteration, molecular Prognostic marker 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

R. Seiler: Mitbeteiligung an Patent eines Genomic Classifiers (Hauptinhaber: GenomeDx Biosciences, Vancouver, BC). M.C. Hupe und G. Gakis geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Al-Ahmadie HA, Iyer G, Janakiraman M, Lin O, Heguy A, Tickoo SK, Fine SW, Gopalan A, Chen YB, Balar A, Riches J, Bochner B, Dalbagni G, Bajorin DF, Reuter VE, Milowsky MI, Solit DB (2011) Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma. J Pathol 224:270–279CrossRefGoogle Scholar
  2. 2.
    Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF, KEYNOTE-045 Investigators (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015–1026CrossRefGoogle Scholar
  3. 3.
    Birkenkamp-Demtröder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Høyer S, Lamy P, Agerbæk M, Jensen JB, Dyrskjøt L (2018) Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis. Eur Urol 73:535–540CrossRefGoogle Scholar
  4. 4.
    Bryce AH, Egan JB, Borad MJ, Stewart AK, Nowakowski GS, Chanan-Khan A, Patnaik MM, Ansell SM, Banck MS, Robinson SI, Mansfield AS, Klee EW, Oliver GR, McCormick JB, Huneke NE, Tagtow CM, Jenkins RB, Rumilla KM, Kerr SE, Kocher JA, Beck SA, Fernandez-Zapico ME, Farrugia G, Lazaridis KN, McWilliams RR (2017) Experience with precision genomics and tumor board, indicates frequent target identification, but barriers to delivery. Oncotarget 8:27145–27154CrossRefGoogle Scholar
  5. 5.
    Christensen E, Nordentoft I, Vang S, Birkenkamp-Demtröder K, Jensen JB, Agerbæk M, Pedersen JS, Dyrskjøt L (2018) Optimized targeted sequencing of cell-free plasma DNA from bladder cancer patients. Sci Rep 8:1917CrossRefGoogle Scholar
  6. 6.
    Culp SH, Dickstein RJ, Grossman HB, Pretzsch SM, Porten S, Daneshmand S, Cai J, Groshen S, Siefker-Radtke A, Millikan RE, Czerniak B, Navai N, Wszolek MF, Kamat AM, Dinney CP (2014) Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 191:40–47CrossRefGoogle Scholar
  7. 7.
    Downes MR, Weening B, van Rhijn BW, Have CL, Treurniet KM, van der Kwast TH (2017) Analysis of papillary urothelial carcinomas of the bladder with grade heterogeneity: Supportive evidence for an early role of CDKN2A deletions in the FGFR3 pathway. Histopathology 70:281–289CrossRefGoogle Scholar
  8. 8.
    Eckstein M, Wirtz RM, Gross-Weege M, Breyer J, Otto W, Stoehr R, Sikic D, Keck B, Eidt S, Burger M, Bolenz C, Nitschke K, Porubsky S, Hartmann A, Erben P (2018) mRNA-expression of KRT5 and KRT20 defines distinct prognostic subgroups of muscle-invasive urothelial bladder cancer correlating with histological variants. Int J Mol Sci.  https://doi.org/10.3390/ijms19113396 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Efstathiou JA, Mouw KW, Gibb EA, Liu Y, Wu CL, Drumm MR, da Costa JB, du Plessis M, Wang NQ, Davicioni E, Feng FY, Seiler R, Black PC, Shipley WU, Miyamoto DT (2019) Impact of immune and stromal infiltration on outcomes following bladder-sparing trimodality therapy for muscle-invasive bladder cancer. Eur Urol.  https://doi.org/10.1016/j.eururo.2019.01.011 CrossRefPubMedGoogle Scholar
  10. 10.
    Gesellschaft der epidemiologischen Krebsregister e. V. (GEKID), Zentrums für Krebsregisterdaten (ZfKD) (2017) Krebs in Deutschland für 2013/2014 Bd. 11. Robert-Koch-Institut, Berlin, S 104–107Google Scholar
  11. 11.
    Harada S, Arend R, Dai Q, Levesque JA, Winokur TS, Guo R, Heslin MJ, Nabell L, Nabors LB, Limdi NA, Roth KA, Partridge EE, Siegal GP, Yang ES (2017) Implementation and utilization of the molecular tumor board to guide precision medicine. Oncotarget 8(34):57845–57854CrossRefGoogle Scholar
  12. 12.
    de Jong JJ, Stoop H, Nieboer D, Boormans JL, van Leenders GJLH (2018) Concordance of PD-L1 expression in matched urothelial bladder cancer specimens. Histopathology 73:983–989CrossRefGoogle Scholar
  13. 13.
    van Kessel KE, van de Werken HJ, Lurkin I, Ziel-van der Made AC, Zwarthoff EC, Boormans JL (2017) A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable. PLoS ONE 12:e174039.  https://doi.org/10.1371/journal.pone.0174039 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kim SH, Ryu H, Ock CY, Suh KJ, Lee JY, Kim JW, Lee JO, Kim JW, Kim YJ, Lee KW, Bang SM, Kim JH, Lee JS, Ahn JB, Kim KJ, Rha SY (2018) BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression. Int J Mol Sci.  https://doi.org/10.3390/ijms19103164 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Knepper TC, Bell GC, Hicks JK, Padron E, Teer JK, Vo TT, Gillis NK, Mason NT, McLeod HL, Walko CM (2017) Key lessons learned from Moffitt’s molecular tumor board: The clinical genomics action committee experience. Oncologist 22:144–151CrossRefGoogle Scholar
  16. 16.
    Kriegmair MC, Wirtz RM, Worst TS, Breyer J, Ritter M, Keck B, Boehmer C, Otto W, Eckstein M, Weis CA, Hartmann A, Bolenz C, Erben P (2018) Prognostic value of molecular breast cancer subtypes based on Her2, ESR1, PGR and Ki67 mRNA-expression in muscle invasive bladder cancer. Transl Oncol 11:467–476CrossRefGoogle Scholar
  17. 17.
    Kundra V, Silverman PM (2003) Imaging in oncology from the University of Texas M. D. Anderson Cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am J Roentgenol 180:1045–1054CrossRefGoogle Scholar
  18. 18.
    Lotan Y, Boorjian SA, Zhang J, Bivalacqua TJ, Porten SP, Lerner SP, Wheeler TM, Hutchinson R, Francis F, Du Plessis M, Davicioni E, Svatek R, Black P, Gibb EA (2019) Molecular subtyping reveals luminal bladder tumors have lower rates of pathological upstaging at radical cystectomy. Eur Urol Suppl 18:e634–e635CrossRefGoogle Scholar
  19. 19.
    Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE (2003) Radical cystectomy for bladder cancer today—A homogeneous series without neoadjuvant therapy. J Clin Oncol 21:690–696CrossRefGoogle Scholar
  20. 20.
    Mitra AP (2016) Molecular substratification of bladder cancer: Moving towards Individualized patient management. Ther Adv Urol 8:215–233CrossRefGoogle Scholar
  21. 21.
    Mitra AP, Lam LL, Ghadessi M, Erho N, Vergara IA, Alshalalfa M, Buerki C, Haddad Z, Sierocinski T, Triche TJ, Skinner EC, Davicioni E, Daneshmand S, Black PC (2014) Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer. J Natl Cancer Inst.  https://doi.org/10.1093/jnci/dju290 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Patel KM, van der Vos KE, Smith CG, Mouliere F, Tsui D, Morris J, Chandrananda D, Marass F, van den Broek D, Neal DE, Gnanapragasam VJ, Forshew T, van Rhijn BW, Massie CE, Rosenfeld N, van der Heijden MS (2017) Association of plasma and urinary mutant DNA with clinical outcomes in muscle invasive bladder cancer. Sci Rep 7:5554CrossRefGoogle Scholar
  23. 23.
    Rebouissou S, Hérault A, Letouzé E, Neuzillet Y, Laplanche A, Ofualuka K, Maillé P, Leroy K, Riou A, Lepage ML, Vordos D, de la Taille A, Denoux Y, Sibony M, Guyon F, Lebret T, Benhamou S, Allory Y, Radvanyi F (2012) CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J Pathol 227:315–324CrossRefGoogle Scholar
  24. 24.
    Rinaldetti S, Wirtz RM, Worst TS, Eckstein M, Weiss CA, Breyer J, Otto W, Bolenz C, Hartmann A, Erben P (2017) FOXM1 predicts overall and disease specific survival in muscle-invasive urothelial carcinoma and presents a differential expression between bladder cancer subtypes. Oncotarget 8:47595–47606CrossRefGoogle Scholar
  25. 25.
    Rink M, Chun FK, Dahlem R, Soave A, Minner S, Hansen J, Stoupiec M, Coith C, Kluth LA, Ahyai SA, Friedrich MG, Shariat SF, Fisch M, Pantel K, Riethdorf S (2012) Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: A prospective study. Eur Urol 61:810–817CrossRefGoogle Scholar
  26. 26.
    Rosenberg JE, Carroll PR, Small EJ (2005) Update on chemotherapy for advanced bladder cancer. J Urol 174:14–20CrossRefGoogle Scholar
  27. 27.
    Seiler R, Ashab HAD, Erho N, van Rhijn BWG, Winters B, Douglas J, Van Kessel KE, Fransen van de Putte EE, Sommerlad M, Wang NQ, Choeurng V, Gibb EA, Palmer-Aronsten B, Lam LL, Buerki C, Davicioni E, Sjödahl G, Kardos J, Hoadley KA, Lerner SP, McConkey DJ, Choi W, Kim WY, Kiss B, Thalmann GN, Todenhöfer T, Crabb SJ, North S, Zwarthoff EC, Boormans JL, Wright J, Dall’Era M, van der Heijden MS, Black PC (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72:544–554CrossRefGoogle Scholar
  28. 28.
    Seiler R, Lam LL, Erho N, Takhar M, Mitra AP, Buerki C, Davicioni E, Skinner EC, Daneshmand S, Black PC (2016) Prediction of lymph node metastasis in patients with bladder cancer using whole transcriptome gene expression signatures. J Urol 196:1036–1041CrossRefGoogle Scholar
  29. 29.
    Siefker-Radtke AO, Necchi A, Rosenbaum E, Culine S, Burgess EF, O’Donnell PH, Tagawa ST, Zakharia Y, OHagan A, Avadhani AN, Zhong B, Santiago-Walker AE, Roccia T, Loriot Y (2018) Efficacy of programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors in patients with FGFR mutations and gene fusions: Results from a data analysis of an ongoing phase 2 study of erdafitinib (JNJ-42756493) in patients (pts) with advanced urothelial cancer (UC). J Clin Oncol 36(6_suppl):450–450CrossRefGoogle Scholar
  30. 30.
    Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, Moskaluk CA, Fradet Y, Lehmann J, Stöckle M, Hartmann A, Lee JK, Theodorescu D (2011) A 20-gene model for molecular nodal staging of bladder cancer: Development and prospective assessment. Lancet Oncol 12:137–143CrossRefGoogle Scholar
  31. 31.
    Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG (2001) Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666–675CrossRefGoogle Scholar
  32. 32.
    Vandekerkhove G, Todenhöfer T, Annala M, Struss WJ, Wong A, Beja K, Ritch E, Brahmbhatt S, Volik SV, Hennenlotter J, Nykter M, Chi KN, North S, Stenzl A, Collins CC, Eigl BJ, Black PC, Wyatt AW (2017) Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin Cancer Res 23:6487–6497CrossRefGoogle Scholar
  33. 33.
    Volkmer JP, Sahoo D, Chin RK, Ho PL, Tang C, Kurtova AV, Willingham SB, Pazhanisamy SK, Contreras-Trujillo H, Storm TA, Lotan Y, Beck AH, Chung BI, Alizadeh AA, Godoy G, Lerner SP, van de Rijn M, Shortliffe LD, Weissman IL, Chan KS (2012) Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A 109:2078–2083CrossRefGoogle Scholar
  34. 34.
    Witjes JA, Bruins M, Cathomas R, Comperat E, Cowan NC, Gakis G, Hernandez V, Lorch A, Ribal MJ, Thalmann GN, van der Heijden AG, Veskimäe E (2019) European Association of Urology Guidelines on Muscle-invasive and Metastastic Bladder Cancer. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/. Zugegriffen: 29. März 2019Google Scholar
  35. 35.
    Worst TS, Weis CA, Stöhr R, Bertz S, Eckstein M, Otto W, Breyer J, Hartmann A, Bolenz C, Wirtz RM, Erben P (2018) CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making. Sci Rep 8:14383CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Klinik für UrologieUniversitätsklinikum Schleswig-Holstein, Campus LübeckLübeckDeutschland
  2. 2.Klinik und Poliklinik für Urologie und KinderurologieUniversitätsklinikum WürzburgWürzburgDeutschland
  3. 3.Departement für UrologieInselspital BernBernSchweiz

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