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The molecular limitations of biomarker research in bladder cancer

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World Journal of Urology Aims and scope Submit manuscript

Abstract

Purpose

Urothelial carcinoma of the bladder (UCB) is a common malignancy with limited systemic treatment options in advanced stages. Despite recent advances in immunotherapy, the majority of patients do not respond to these treatments. There is an unmet need for developing robust biomarkers to inform treatment decisions and identify patients who are likely to respond.

Methods

A MEDLINE/PubMed literature search was performed, focusing on tissue-based and circulating biomarkers, and their potential in muscle-invasive UCB.

Results

UCB is a heterogeneous disease that consists of several clonal and subclonal populations, each with a mix of truncal and private genomic alterations. This inter- and intra-tumoral heterogeneous landscape results in the development of treatment resistance. Tumor heterogeneity also constitutes a barrier to the development of robust markers of response and resistance to chemotherapy and immunotherapy. Defects in DNA repair genes and a high tumor mutational burden independently confer sensitivity to cisplatin-based chemotherapy and checkpoint inhibitors. Oncogenic alterations such as FGFR3 mutations and fusions are associated with response to FGFR3 inhibitors. Several emerging potential biomarkers, including gene expression-based molecular subtypes, T-cell receptor clonality, and tissue- or blood-based immune-gene profiling, require prospective testing and validation. Tissue-based biomarkers such as PD-L1 immunohistochemistry have several limitations due to discordance in assay methodology and trial designs. Novel liquid-biopsy techniques are promising as potential biomarkers.

Conclusions

Validated biomarkers that capture the complexity of the biology of both the tumor and the tumor microenvironment are needed in muscle-invasive UCB. Standardization of methods is critical to developing reliable biomarkers to guide clinical management.

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References

  1. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F (2017) Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 71:96–108. https://doi.org/10.1016/j.eururo.2016.06.010

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  3. National Cancer Institute (2018) Surveillance, Epidemiology and End Results Program. In: Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed 23 June 2018

  4. Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM et al (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71(3):462–475. https://doi.org/10.1016/j.eururo.2016.06.020

    Article  CAS  PubMed  Google Scholar 

  5. Kelloff GJ, Sigman CC (2012) Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov 11:201–214. https://doi.org/10.1038/nrd3651

    Article  CAS  PubMed  Google Scholar 

  6. WHO (2001) International Programme on Chemical Safety Biomarkers. In: Risk assessment: validity and validation. http://www.inchem.org/documents/ehc/ehc/ehc222.htm. Accessed 23 June 2018

  7. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource. Silver Spring (MD): Food and Drug Administration (US); 2016-. Co-published by National Institutes of Health (US), Bethesda (MD) Available from: https://www.ncbi.nlm.nih.gov/books/NBK326791/. Accessed 2 July 2018

  8. Poste G (2011) Bring on the biomarkers. Nature 469:156–157. https://doi.org/10.1038/469156a

    Article  CAS  PubMed  Google Scholar 

  9. McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168:613–628. https://doi.org/10.1016/j.cell.2017.01.018

    Article  CAS  PubMed  Google Scholar 

  10. Li Y, Lin K, Yang Z, Han N, Quan X, Guo X et al (2017) Bladder cancer stem cells: clonal origin and therapeutic perspectives. Oncotarget 8:66668–66679. https://doi.org/10.18632/oncotarget.19112

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  12. Vlachostergios PJ, Faltas BM (2018) Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nat Rev Clin Oncol. https://doi.org/10.1038/s41571-018-0026-y

    Article  PubMed  Google Scholar 

  13. Ye F, Wang L, Castillo-Martin M, McBride R, Galsky MD, Zhu J et al (2014) Biomarkers for bladder cancer management: present and future. Am J Clin Exp Urol 2:1–14

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nagel R, Semenova EA, Berns A (2016) Drugging the addict: non-oncogene addiction as a target for cancer therapy. EMBO Rep 17:1516–1531. https://doi.org/10.15252/embr.201643030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE 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. https://doi.org/10.1073/pnas.1318376111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165. https://doi.org/10.1016/j.ccr.2014.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD et al (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171:540–556.e25. https://doi.org/10.1016/j.cell.2017.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marzouka NA, Eriksson P, Rovira C, Liedberg F, Sjödahl G, Höglund M (2018) A validation and extended description of the Lund taxonomy for urothelial carcinoma using the TCGA cohort. Sci Rep 8:3737. https://doi.org/10.1038/s41598-018-22126-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gerlinger M, Catto JW, Orntoft TF, Real FX, Zwarthoff EC, Swanton C (2015) Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur Urol 67:729–737. https://doi.org/10.1016/j.eururo.2014.04.014

    Article  CAS  PubMed  Google Scholar 

  20. Warrick JI, Hovelson DH, Amin A, Liu CJ, Cani AK, McDaniel AS et al (2015) Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma. Virchows Arch 466:297–311. https://doi.org/10.1007/s00428-014-1699-y

    Article  CAS  PubMed  Google Scholar 

  21. Nordentoft I, Lamy P, Birkenkamp-Demtröder K, Shumansky K, Vang S, Hornshøj H et al (2014) Mutational context and diverse clonal development in early and late bladder cancer. Cell Rep 7:1649–1663. https://doi.org/10.1016/j.celrep.2014.04.038

    Article  CAS  PubMed  Google Scholar 

  22. Lamy P, Nordentoft I, Birkenkamp-Demtröder K, Thomsen MB, Villesen P, Vang S et al (2016) Paired exome analysis reveals clonal evolution and potential therapeutic targets in urothelial carcinoma. Cancer Res 76:5894–5906. https://doi.org/10.1158/0008-5472.CAN-16-0436

    Article  CAS  PubMed  Google Scholar 

  23. Thomsen MBH, Nordentoft I, Lamy P, Vang S, Reinert L, Mapendano CK et al (2017) Comprehensive multiregional analysis of molecular heterogeneity in bladder cancer. Sci Rep 7:11702. https://doi.org/10.1038/s41598-017-11291-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Höglund M (2007) On the origin of syn- and metachronous urothelial carcinomas. Eur Urol 51:1185–1193. https://doi.org/10.1016/j.eururo.2006.11.025 (discussion 1193)

    Article  CAS  PubMed  Google Scholar 

  25. Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C et al (2016) Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet 48:1490–1499. https://doi.org/10.1038/ng.3692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim IS, Zhang XH (2016) One microenvironment does not fit all: heterogeneity beyond cancer cells. Cancer Metastasis Rev 35:601–629. https://doi.org/10.1007/s10555-016-9643-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kang HW, Kim WJ, Yun SJ (2017) The role of the tumor microenvironment in bladder cancer development and progression. Transl Cancer Res 6:S744–S758. https://doi.org/10.21037/tcr.2017.06.48

    Article  CAS  Google Scholar 

  28. Jiménez-Sánchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA et al (2017) Heterogeneous tumor–immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170:927–938.e20. https://doi.org/10.1016/j.cell.2017.07.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cheah MT, Chen JY, Sahoo D, Contreras-Trujillo H, Volkmer AK, Scheeren FA et al (2015) CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. Proc Natl Acad Sci U S A 112:4725–4730. https://doi.org/10.1073/pnas.1424795112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT et al (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924. J Clin Oncol 19:2638–2646. https://doi.org/10.1200/JCO.2001.19.10.2638

    Article  CAS  PubMed  Google Scholar 

  31. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I et al (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational multicenter, phase III study. J Clin Oncol 18:3068–3077. https://doi.org/10.1200/JCO.2000.18.17.3068

    Article  PubMed  Google Scholar 

  32. Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A et al (2014) Systems biology of cisplatin resistance: past, present and future. Cell Death Dis 5:e1257. https://doi.org/10.1038/cddis.2013.428.hgbc

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bellmunt J, Paz-Ares L, Cuello M, Cecere FL, Albiol S, Guillem V et al (2007) Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol 18:522–528. https://doi.org/10.1093/annonc/mdl435

    Article  CAS  PubMed  Google Scholar 

  34. Font A, Taron M, Gago JL, Costa C, Sánchez JJ, Carrato C et al (2011) BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer. Ann Oncol 22:139–144. https://doi.org/10.1093/annonc/mdq333

    Article  CAS  PubMed  Google Scholar 

  35. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H et al (2014) Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 4:1140–1153. https://doi.org/10.1158/2159-8290.CD-14-0623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E et al (2016) Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol 2:1094–1096. https://doi.org/10.1001/jamaoncol.2016.1056

    Article  PubMed  PubMed Central  Google Scholar 

  37. Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG 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. https://doi.org/10.1016/j.eururo.2015.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Teo MY, Bambury RM, Zabor EC, Jordan E, Al-Ahmadie H, Boyd ME 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. https://doi.org/10.1158/1078-0432.CCR-16-2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kardos J, Chai S, Mose LE, Selitsky SR, Krishnan B, Saito R et al (2016) Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1(3):e85902. https://doi.org/10.1172/jci.insight.85902

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lerner SP, McConkey DJ, Hoadley KA, Chan KS, Kim WY, Radvanyi F et al (2016) Bladder cancer molecular taxonomy: summary from a consensus meeting. Bladder Cancer 2:37–47. https://doi.org/10.3233/BLC-150037

    Article  PubMed  PubMed Central  Google Scholar 

  41. McConkey DJ, Choi W, Shen Y, Lee IL, Porten S, Matin SF, Kamat AM (2016) A prognostic gene expression signature in the molecular classification of chemotherapy-naïve urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer. Eur Urol 69:855–862. https://doi.org/10.1016/j.eururo.2015.08.034

    Article  CAS  PubMed  Google Scholar 

  42. Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A et al (2016) Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use. EBioMedicine 12:105–117. https://doi.org/10.1016/j.ebiom.2016.08.036

    Article  PubMed  PubMed Central  Google Scholar 

  43. Seiler R, Ashab HAD, Erho N, van Rhijn BWG, Winters B, Douglas J (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72:544–554. https://doi.org/10.1016/j.eururo.2017.03.030

    Article  CAS  PubMed  Google Scholar 

  44. Sjödahl G, Eriksson P, Liedberg F, Höglund M (2017) Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J Pathol 242:113–125. https://doi.org/10.1002/path.4886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Seiler R, Thalmann GN, Rotzer D, Perren A, Fleischmann A (2014) CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response. Mod Pathol 27:87–95. https://doi.org/10.1038/modpathol.2013.125

    Article  CAS  PubMed  Google Scholar 

  46. Sjödahl G, Eriksson P, Lövgren K, Marzouka NA, Bernardo C, Nordentoft I et al (2018) Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases. Mod Pathol. https://doi.org/10.1038/s41379-018-0096-5

    Article  PubMed  Google Scholar 

  47. Smith SC, Baras AS, Lee JK, Theodorescu D (2010) The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res 70:1753–1758. https://doi.org/10.1158/0008-5472.CAN-09-3562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015–1026. https://doi.org/10.1056/NEJMoa1613683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U et al (2018) Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391:748–757. https://doi.org/10.1016/S0140-6736(17)33297-X

    Article  CAS  PubMed  Google Scholar 

  50. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322. https://doi.org/10.1016/S1470-2045(17)30065-7

    Article  CAS  PubMed  Google Scholar 

  51. Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ et al (2017) Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 3:e172411. https://doi.org/10.1001/jamaoncol.2017.2411

    Article  PubMed  PubMed Central  Google Scholar 

  52. Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K et al (2017) Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol 35:2117–2124. https://doi.org/10.1200/JCO.2016.71.6795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012

    Article  CAS  PubMed  Google Scholar 

  54. Tretiakova M, Fulton R, Kocherginsky M, Long T, Ussakli C, Antic T et al (2018) Concordance study of PD-L1 expression in primary and metastatic bladder carcinomas: comparison of four commonly used antibodies and RNA expression. Mod Pathol 31:623–632. https://doi.org/10.1038/modpathol.2017.188

    Article  CAS  PubMed  Google Scholar 

  55. Powles T, Gschwend JE, Loriot Y, Bellmunt J, Geczi L, Vulsteke C et al (2017) Phase 3 KEYNOTE-361 trial: pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2017.35.15_suppl.TPS4590 (abst TPS4590)

    Article  PubMed  PubMed Central  Google Scholar 

  56. Galsky MD, Grande E, Davis ID, De Santis M, Arranz Arija JA, Kikuchi E et al (2018) IMvigor130: a randomized, phase III study evaluating first-line (1L) atezolizumab (atezo) as monotherapy and in combination with platinum-based chemotherapy (chemo) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol 36(suppl; 4589)

  57. FDA (2018) Keytruda (pembrolizumab) or Tecentriq (atezolizumab): FDA Alerts Health Care Professionals and Investigators: FDA Statement—Decreased Survival in Some Patients in Clinical Trials Associated with Monotherapy. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm608253.htm. Accessed 28 June 2018

  58. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu XS, Mardis ER (2017) Applications of immunogenomics to cancer. Cell 168:600–612. https://doi.org/10.1016/j.cell.2017.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A 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. https://doi.org/10.1016/S0140-6736(16)00561-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J 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. https://doi.org/10.1016/S0140-6736(16)32455-2

    Article  CAS  PubMed  Google Scholar 

  63. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y et al (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–548. https://doi.org/10.1038/nature25501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stadler ZK, Battaglin F, Middha S, Hechtman JF, Tran C, Cercek A et al (2016) Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol 34:2141–2147. https://doi.org/10.1200/JCO.2015.65.1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D et al (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36:633–641. https://doi.org/10.1200/JCO.2017.75.3384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/NEJMoa1500596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–413. https://doi.org/10.1126/science.aan6733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Teo MY, Seier K, Ostrovnaya I, Regazzi AM, Kania BE, Moran MM et al (2018) Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol 36:1685–1694. https://doi.org/10.1200/JCO.2017.75.7740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Snyder A, Nathanson T, Funt SA, Ahuja A, Buros Novik J, Hellmann MD et al (2017) Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: an exploratory multi-omic analysis. PLoS Med 14:e1002309. https://doi.org/10.1371/journal.pmed.1002309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sharma P, Baron A, Necchi A, Plimack ER, Pal SK, Bedke J et al (2018) Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275. In: American Association for Cancer Research Annual Meeting, April 14–18, 2018, Chicago, IL

  71. Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S (2017) COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A 114:1117–1122. https://doi.org/10.1073/pnas.1612920114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Powles T, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijde MS, Font Pous A et al (2018) A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J Clin Oncol 36(suppl; 4506)

  73. Necchi A, Briganti A, Bianchi M, Raggi D, Giannatempo P, Luciano R et al (2018) Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. J Clin Oncol 36(suppl; 4507)

  74. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322. https://doi.org/10.1038/nature12965

    Article  CAS  Google Scholar 

  75. Torti D, Trusolino L (2011) Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 3:623–636. https://doi.org/10.1002/emmm.201100176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Karkera JD, Cardona GM, Bell K, Gaffney D, Portale JC, Santiago-Walker A et al (2017) Oncogenic characterization and pharmacologic sensitivity of activating fibroblast growth factor receptor (FGFR) genetic alterations to the selective FGFR inhibitor erdafitinib. Mol Cancer Ther 16:1717–1726. https://doi.org/10.1158/1535-7163.MCT-16-0518

    Article  CAS  PubMed  Google Scholar 

  77. Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M et al (2017) Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol 35:157–165. https://doi.org/10.1200/JCO.2016.67.2048

    Article  CAS  PubMed  Google Scholar 

  78. Siefker-Radtke AO, Necchi A, Park SH, Garcia-Donas J, Huddart RA, Burgess EF 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(suppl; 4503)

  79. Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr et al (2007) Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25:2218–2224. https://doi.org/10.1200/JCO.2006.08.0994

    Article  CAS  PubMed  Google Scholar 

  80. Oudard S, Culine S, Vano Y, Goldwasser F, Théodore C, Nguyen T et al (2015) Multicentre randomised phase II trial of gemcitabine + platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer 51:45–54. https://doi.org/10.1016/j.ejca.2014.10.009

    Article  CAS  PubMed  Google Scholar 

  81. Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R et al (2017) Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol 35:48–55. https://doi.org/10.1200/JCO.2015.66.3468

    Article  CAS  PubMed  Google Scholar 

  82. Kiss B, Wyatt AW, Douglas J, Skuginna V, Mo F, Anderson S et al (2017) Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep 7:42713. https://doi.org/10.1038/srep42713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Eriksson P, Sjödahl G, Chebil G, Liedberg F, Höglund M (2017) HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts. Oncotarget 8:48905–48914. https://doi.org/10.18632/oncotarget.16554

    Article  PubMed  PubMed Central  Google Scholar 

  84. Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL III et al (2016) Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with erbb alterations. J Clin Oncol 34:2165–2171. https://doi.org/10.1200/JCO.2015.66.3047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L et al (2018) Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 128:805–815. https://doi.org/10.1172/JCI96113

    Article  PubMed  PubMed Central  Google Scholar 

  86. Aggen DH, Drake CG (2017) Biomarkers for immunotherapy in bladder cancer: a moving target. J Immunother Cancer 5:94. https://doi.org/10.1186/s40425-017-0299-1

    Article  PubMed  PubMed Central  Google Scholar 

  87. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Zelig Szmulewitz R, et al (2018) The PROPHECY trial: multicenter prospective trial of circulating tumor cell (CTC) AR-V7 detection in men with mCRPC receiving abiraterone (A) or enzalutamide (E). J Clin Oncol 36(suppl; 5004)

  88. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469. https://doi.org/10.1126/science.aaf1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V et al (2018) Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359:582–587. https://doi.org/10.1126/science.aao4572

    Article  CAS  PubMed  Google Scholar 

  90. Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J et al (2017) Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J Immunother Cancer 5:44. https://doi.org/10.1186/s40425-017-0243-4

    Article  PubMed  PubMed Central  Google Scholar 

  91. Agarwal N, Pal SK, Hahn AW, Nussenzveig RH, Pond GR, Gupta SV et al (2018) Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer 124:2115–2124. https://doi.org/10.1002/cncr.31314

    Article  CAS  PubMed  Google Scholar 

  92. Gandara DR, Kowanetz M, Mok TSK, Rittmeyer A, Fehrenbacher L, Fabrizio D et al (2017) Blood-based biomarkers for cancer immunotherapy: Tumor mutational burden in blood (bTMB) is associated with improved atezolizumab (atezo) efficacy in 2L+ NSCLC (POPLAR and OAK). Ann Oncol. https://doi.org/10.1093/annonc/mdx380

    Article  Google Scholar 

  93. Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME et al (2017) Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 28:1988–1995. https://doi.org/10.1093/annonc/mdx190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S et al (2017) T cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60–65. https://doi.org/10.1038/nature22079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Bishoy M. Faltas is the recipient of the Congressionally Directed Medical Research Program (CDMRP) Peer-Reviewed Cancer Career Development Award, CA160212.

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  1. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Panagiotis J. Vlachostergios & Bishoy M. Faltas

  2. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Bishoy M. Faltas

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  1. Panagiotis J. Vlachostergios
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Vlachostergios, P.J., Faltas, B.M. The molecular limitations of biomarker research in bladder cancer. World J Urol 37, 837–848 (2019). https://doi.org/10.1007/s00345-018-2462-9

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