Skip to main content
SpringerLink
Log in

Therapieprädiktive Biomarker des Harnblasenkarzinoms

Predictive biomarkers in bladder cancer

  • Hauptreferate: Hauptprogramm der DGP
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

In den letzten Jahren hat es beim fortgeschrittenen Urothelkarzinom der Harnblase bezüglich der therapeutischen Möglichkeiten deutliche Fortschritte gegeben.

Ziel der Arbeit

Ziel der Arbeit ist es, einen Überblick über den aktuellen Stand und zukünftige Entwicklungen der therapeutischen Möglichkeiten zu geben. Dabei liegt der Schwerpunkt auf der Diskussion gewebebasierter therapieprädiktiver Marker, deren Erhebung eine Domäne der (Molekular‑)Pathologie ist und damit die Rolle der Pathologie als Fach insgesamt stärkt.

Material und Methoden

Es wurden die aktuelle (Studien‑)Datenlage, Literatur sowie eigene Erfahrungen berücksichtigt und in die Teilbereiche der Therapieprädiktion einer platinhaltigen Chemotherapie, Immuntherapie und weiterer Therapieansätze zusammengefasst.

Ergebnisse und Diskussion

Die molekularen Subtypen zeigen in der Therapieprädiktion sowohl der platinhaltigen Chemotherapie wie auch der Immuntherapie eine klare Wertigkeit, wobei es zur genauen Definition noch weiterer Arbeiten und Klärung bedarf. Als weitere Marker des Chemotherapieerfolgs zeigen Genveränderungen in den DNA-Schäden-Reparaturenzymen (DDR), ERCC2 und ERBB2 sowie die Expressionsunterschiede von EMMPRIN, Survivin und HMGA2 vielversprechende Ergebnisse. Bei der Prädiktion eines Immuntherapieerfolgs betrifft dieses vor allem die Evaluation der Tumormutationslast („tumor mutational burden“, TMB), Tumor-Neoantigenlast („tumor neoantigen burden“, TNB), APOBEC-Signaturen (MSig1; 3A/3B) und CD8-positiven T‑Effektorzell-Signatur. Beim Einsatz des in dieser Indikation noch nicht in Deutschland zugelassenen FGFR(„fibroblast growth factor receptor“)-Inhibitors Erdafitinib ist die Evaluation von spezifischen FGFR-Mutationen und/oder Fusionen per companion-diagnostic-Test in den USA verpflichtend.

Abstract

Background

In the last few years, significant progress has been achieved in the therapeutic options for advanced urothelial bladder cancer.

Objectives

The aim of this work was to give an overview of the status and future perspective of the therapeutic options in this setting. Its focus is on the discussion of tissue-based therapy-predictive markers, which are evaluated through (molecular) pathology and thereby strengthening the role of pathology itself.

Materials and methods

Current (clinical study) data, the literature, and our own expertise were considered and summarized in the areas of therapy prediction of platinum-based chemotherapy, immunotherapy, and other therapeutic approaches.

Results and conclusions

Molecular subtypes exhibit a predictive value both in platinum-based chemotherapy as well as in immunotherapy. However, further work is required to elucidate the predictive role of molecular subtypes in both settings. Changes in the DNA damage repair enzyme (DDR) genes, ERCC2, and ERBB2 as well as differences in the expression of EMMPRIN, survivin, and HMGA2 show promising results as further markers of chemotherapy efficacy. In the prediction of immunotherapy success, this mainly relates to the evaluation of the tumor mutation burden (TMB), tumor neoantigen burden (TNB), APOBEC signatures (MSig1; 3A/3B), and CD8-positive T‑effector cell signature. When using the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib, which has not yet been approved in Germany, the evaluation of specific FGFR mutations and/or gene fusions by a companion diagnostic test is mandatory in the USA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Als AB, Dyrskjot L, Von Der Maase H et al (2007) Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res 13:4407–4414

    CAS  PubMed  Google Scholar 

  2. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (2016) S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms, Langversion 1.1. AWMF-Registrierungsnummer 032/038OL. AWMF, DKG, DKH, Berlin, S 49–52

    Google Scholar 

  3. Balar AV, Galsky MD, Rosenberg JE et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389:67–76

    CAS  PubMed  Google Scholar 

  4. Barnes B, Bertz J, Buttmann-Schweiger N et al (2017) Bericht zum Krebsgeschehen in Deutschland 2016. RKI, Berlin

    Google Scholar 

  5. Bertz S, Hartmann A, Knuchel-Clarke R et al (2016) Specific types of bladder cancer. Pathologe 37:40–51

    CAS  PubMed  Google Scholar 

  6. Blaveri E, Simko JP, Korkola JE et al (2005) Bladder cancer outcome and subtype classification by gene expression. Clin Cancer Res 11:4044–4055

    CAS  PubMed  Google Scholar 

  7. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322

    Google Scholar 

  8. Chalmers ZR, Connelly CF, Fabrizio D et al (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9:34

    PubMed  PubMed Central  Google Scholar 

  9. Choi W, Porten S, Kim S et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Choudhury A, Nelson LD, Teo MT et al (2010) MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res 70:7017–7026

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Damrauer JS, Hoadley KA, Chism DD et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A 111:3110–3115

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Dyrskjot L, Thykjaer T, Kruhoffer M et al (2003) Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 33:90–96

    CAS  PubMed  Google Scholar 

  13. Groenendijk FH, De Jong J, Van De Fransen Putte EE et al (2016) ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol 69:384–388

    CAS  PubMed  Google Scholar 

  14. Hedegaard J, Lamy P, Nordentoft I et al (2016) Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30:27–42

    CAS  PubMed  Google Scholar 

  15. Heide T, Maurer A, Eipel M et al (2019) Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy. J Pathol 248:230–242

    CAS  PubMed  Google Scholar 

  16. Hoffmann AC, Wild P, Leicht C et al (2010) MDR1 and ERCC1 expression predict outcome of patients with locally advanced bladder cancer receiving adjuvant chemotherapy. Neoplasia 12:628–636

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kamoun A, De Reyniès A, Allory Y et al (2019) The consensus molecular classification of muscle-invasive bladder cancer. bioRxiv. https://doi.org/10.1101/488460

    Article  Google Scholar 

  18. Kim J, Kwiatkowski D, Mcconkey DJ et al (2019) The cancer genome atlas expression subtypes stratify response to checkpoint inhibition in advanced urothelial cancer and identify a subset of patients with high survival probability. Eur Urol 75:961–964

    CAS  PubMed  Google Scholar 

  19. Kollberg P, Chebil G, Eriksson P et al (2019) Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival. Urol Oncol. https://doi.org/10.1016/j.urolonc.2019.04.010

    Article  PubMed  Google Scholar 

  20. Krafft U, Tschirdewahn S, Hess J et al (2019) Validation of survivin and HMGA2 as biomarkers for cisplatin resistance in bladder cancer. Urol Oncol. https://doi.org/10.1016/j.urolonc.2019.04.015

    Article  PubMed  Google Scholar 

  21. Lawrence MS, Stojanov P, Polak P et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Linder BJ, Boorjian SA, Cheville JC et al (2013) The impact of histological reclassification during pathology re-review—evidence of a Will Rogers effect in bladder cancer? J Urol 190:1692–1696

    PubMed  Google Scholar 

  23. Lindgren D, Frigyesi A, Gudjonsson S et al (2010) Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 70:3463–3472

    CAS  PubMed  Google Scholar 

  24. Liu D, Plimack ER, Hoffman-Censits J et al (2016) Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol 2:1094–1096

    PubMed  PubMed Central  Google Scholar 

  25. Lodewijk I, Duenas M, Rubio C et al (2018) Liquid biopsy biomarkers in bladder cancer: a current need for patient diagnosis and monitoring. Int J Mol Sci 19:E2514

    PubMed  Google Scholar 

  26. Mariathasan S, Turley SJ, Nickles D et al (2018) TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–548

    CAS  PubMed  PubMed Central  Google Scholar 

  27. McConkey DJ, Lee S, Choi W et al (2010) Molecular genetics of bladder cancer: emerging mechanisms of tumor initiation and progression. Urol Oncol 28:429–440

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Paul-Ehrlich-Institut (2018) Rote-Hand-Brief: Keytruda (Pembrolizumab): Einschränkung des Anwendungsgebiets „Zur Behandlung des lokal fortgeschrittenen oder metastasierenden Urothelkarzinoms bei Erwachsenen, die nicht für eine Cisplatin-basierte Therapie geeignet sind“. https://www.pei.de/DE/arzneimittelsicherheit-vigilanz/archivsicherheitsinformationen/2018/ablage2018/2018-07-11-rhb-keytruda-pembrolizumab.html. Zugegriffen: 29. Jan. 2019

    Google Scholar 

  29. Paul-Ehrlich-Institut (2018) Rote-Hand-Brief: Tecentriq (Atezolizumab): Einschränkung der Indikation zur Behandlung des lokal fortgeschrittenen oder metastasierten Urothelkarzinoms bei erwachsenen Patienten, die für eine cisplatinbasierte Chemotherapie ungeeignet sind. https://www.pei.de/DE/arzneimittelsicherheit-vigilanz/archivsicherheitsinformationen/2018/ablage2018/2018-07-09-rhb-tecentriq-atezolizumab.html. Zugegriffen: 29. Jan. 2019

    Google Scholar 

  30. Pietzak EJ, Zabor EC, Bagrodia A et al (2019) Genomic differences between “primary” and “secondary” muscle-invasive bladder cancer as a basis for disparate outcomes to cisplatin-based neoadjuvant chemotherapy. Eur Urol 75:231–239

    PubMed  Google Scholar 

  31. Plimack ER, Dunbrack RL, Brennan TA et al (2015) Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 68:959–967

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Reis H, Serrette R, Posada J et al (2019) PD-L1 expression in urothelial carcinoma with predominant or pure variant histology: concordance among 3 commonly used and commercially available antibodies. Am J Surg Pathol 43:920–927

    PubMed  Google Scholar 

  33. Reis H, Szarvas T (2018) Urachal cancer—current concepts of a rare cancer (German version). Pathologe 39:291–300

    CAS  PubMed  Google Scholar 

  34. Reis H, Szarvas T, Grunwald V (2019) Predictive biomarkers in oncologic uropathology. Pathologe 40:264–275

    CAS  PubMed  Google Scholar 

  35. Robertson AG, Kim J, Al-Ahmadie H et al (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171:540–556.e25

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schildhaus HU (2018) Predictive value of PD-L1 diagnostics. Pathologe 39:498–519

    PubMed  Google Scholar 

  38. Seiler R, Al-Deen Ashab H, Erho N et al (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72:544–554

    CAS  PubMed  Google Scholar 

  39. Seiler R, Gibb EA, Wang NQ et al (2018) Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Clin Cancer Res 25:5082–5093

    PubMed  Google Scholar 

  40. Sharma P, Retz M, Siefker-Radtke A et al (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322

    CAS  PubMed  Google Scholar 

  41. Siefker-Radtke A, Necchi A, Park SH et al (2018) First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). J Clin Oncol 36(15 Suppl):4503

    Google Scholar 

  42. Sjodahl G, Abrahamsson J, Holmsten K et al (2019) Pathologic downstaging after neoadjuvant cisplatin-based combination chemotherapy in immunohistochemistry-defined molecular subtypes of bladder cancer. Eur Urol Suppl 18:e2106–e2107

    Google Scholar 

  43. Sjodahl G, Eriksson P, Liedberg F et al (2017) Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J Pathol 242:113–125

    PubMed  PubMed Central  Google Scholar 

  44. Sjodahl G, Lauss M, Lovgren K et al (2012) A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 18:3377–3386

    PubMed  Google Scholar 

  45. Su H, Jiang H, Tao T et al (2019) Hope and challenge: precision medicine in bladder cancer. Cancer Med 8:1806–1816

    PubMed  PubMed Central  Google Scholar 

  46. Szarvas T, Kramer G, Hess J et al (2012) Tissue mmp‑7 expression predicts survival in bladder cancer patients treated with cisplatin-based chemotherapy. J Urol 187:e575–e575

    Google Scholar 

  47. Szarvas T, Olah C, Reis H (2019) Neoadjuvant cisplatin-based chemotherapy in “primary” and “secondary” muscle-invasive bladder cancer—Is it a surrogate for molecular subtypes? Transl Cancer Res 8:S176–S179

    CAS  Google Scholar 

  48. Tan MP, Attard G, Huddart RA (2018) Circulating tumour DNA in muscle-invasive bladder cancer. Int J Mol Sci 19:E2568

    PubMed  Google Scholar 

  49. Taubert H, Wach S, Jung R et al (2015) Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients. Mol Med 21:371–380

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Teo MY, Bambury RM, Zabor EC et al (2017) DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma. Clin Cancer Res 23:3610–3618

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Thomsen MBH, Nordentoft I, Lamy P et al (2017) Comprehensive multiregional analysis of molecular heterogeneity in bladder cancer. Sci Rep 7:11702

    PubMed  PubMed Central  Google Scholar 

  52. Turney A (2019) FDA approves first targeted therapy for metastatic bladder cancer. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm635906.htm. Zugegriffen: 29. Jan. 2019

    Google Scholar 

  53. Udager AM, McDaniel AS, Hovelson DH et al (2018) Frequent PD-L1 protein expression and molecular correlates in urinary bladder squamous cell carcinoma. Eur Urol 74:529–531

    PubMed  Google Scholar 

  54. Van Allen EM, Mouw KW, Kim P et al (2014) Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 4:1140–1153

    PubMed  PubMed Central  Google Scholar 

  55. Warrick JI, Sjodahl G, Kaag M et al (2019) Intratumoral heterogeneity of bladder cancer by molecular subtypes and histologic variants. Eur Urol 75:18–22

    CAS  PubMed  Google Scholar 

  56. Wessolly M, Mairinger FD, Herold T et al (2019) Proteasomale Immunescape-Mechanismen beim Urothelkarzinom. Pathologe 40:S100

    Google Scholar 

  57. Wild PJ, Herr A, Wissmann C et al (2005) Gene expression profiling of progressive papillary noninvasive carcinomas of the urinary bladder. Clin Cancer Res 11:4415–4429

    CAS  PubMed  Google Scholar 

  58. Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD‑1 inhibition. N Engl J Med 377:2500–2501

    PubMed  PubMed Central  Google Scholar 

Download references

Förderung

Unterstützt durch das ungarische Wissenschafts‑, Entwicklungs- und Innovationsministerium (NKFIH/FK 12443, NVKP_16-1-2016-004, ÙNKP-18-4-SE-66). T. Szarvas hat ein JánosBolyai-Forschungsstipendium von der ungarischen Akademie der Wissenschaften erhalten.

Author information

Authors and Affiliations

  1. Institut für Pathologie, Westdeutsches Tumorzentrum, Universitätsmedizin Essen, Universität Duisburg-Essen, Essen, Deutschland

    H. Reis

  2. Klinik für Urologie, Semmelweis Universität, Budapest, Ungarn

    T. Szarvas Priv.-Doz. Dr.

  3. Klinik für Urologie, Westdeutsches Tumorzentrum, Universitätsmedizin Essen, Universität Duisburg-Essen, Essen, Deutschland

    T. Szarvas Priv.-Doz. Dr.

Authors
  1. H. Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Szarvas Priv.-Doz. Dr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Reis.

Ethics declarations

Interessenkonflikt

H. Reis: Honorare von Roche und Bristol-Myers Squibb; Forschungsunterstützung von Bristol-Myers Squibb; Aufwandsentschädigung von Philips. T. Szarvas: Honorare von Sando.

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.

The supplement containing this article is not sponsored by industry.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reis, H., Szarvas, T. Therapieprädiktive Biomarker des Harnblasenkarzinoms. Pathologe 40 (Suppl 3), 331–338 (2019). https://doi.org/10.1007/s00292-019-00688-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-019-00688-5

Schlüsselwörter

Keywords

Search

Navigation