Prognostic and Predictive Markers, and Stratifications Tables, for the Detection and Treatment of Renal Cell Carcinoma

  • Helen Davis Bondarenko
  • Raisa S. Pompe
  • Emanuele Zaffuto
  • Shahrokh F. Shariat
  • Pierre I. Karakiewicz
Living reference work entry


Despite knowledge of disease stage, grade, and histological subtype (HS), patient outcome in RCC remains elusive. Therefore, a vast number of predictive and prognostic models as well as biological markers have been proposed. Many show promise in stratifying the survival curves or discriminating between stage distributions, while others achieved independent predictor status in specific end points of interest.

There is an increased interest in composite biomarker, such as the BioScore (Parker et al., Cancer 115(10):2092–2103, 2009), which has increased accuracy compared to other models. The search continues for an ideal model that is relevant, simple to use and understand, and that will be able to distinguish between different patient diseases and characteristics. The future in prognostic factors and predictive models lies in finding biomarkers that will assist in choosing select target therapies, immunotherapies, and chemotherapies. To improve patient prognosis, treatment sequences, with targeted agents and novel drugs, need to be individualized by using the patient’s genomic classifications.

Presently, Immune oncology agents (IO), notably immune checkpoint inhibitors targeting PD-1, are the most promising in treatment of RCC. It is postulated that a preestablished immune response can optimize immune checkpoint inhibition therapy. Therefore, even though past studies found few desired results, vaccinations may hold the key to future therapeutic success (Curtis et al., Curr Oncol Rep 18(9):57, 2016; Hammers H, Curr Opin Urol 26(6):543–547, 2016).

This chapter will focus on prognostic models specifically for metastatic RCC and models for all types of RCC. Second, this chapter will focus on molecular biomarkers, including tissue-based biomarkers, blood-based biomarkers, and immune system biomarkers.


  1. Brugarolas J. PBRM1 and BAP1 as novel targets for renal cell carcinoma. Cancer Journal (Sudbury, Mass). 2013;19(4):324–32.CrossRefGoogle Scholar
  2. Calvo E, Schmidinger M, Heng DY, Grunwald V, Escudier B. Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy. Cancer Treat Rev. 2016;50:109–17.CrossRefPubMedGoogle Scholar
  3. Choueiri TK, Cheng S, Qu AQ, Pastorek J, Atkins MB, Signoretti S. Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: analysis from the treatment approaches in renal cancer global evaluation trial (TARGET). Urol Oncol. 2013;31(8):1788–93.CrossRefPubMedGoogle Scholar
  4. Curtis SA, Cohen JV, Kluger HM. Evolving immunotherapy approaches for renal cell carcinoma. Curr Oncol Rep. 2016;18(9):57.CrossRefPubMedGoogle Scholar
  5. Elson PJ, Witte RS, Trump DL. Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res. 1988;48(24 Pt 1):7310–3.PubMedGoogle Scholar
  6. Escudier B, Choueiri TK, Oudard S, Szczylik C, Negrier S, Ravaud A, et al. Prognostic factors of metastatic renal cell carcinoma after failure of immunotherapy: new paradigm from a large phase III trial with shark cartilage extract AE 941. J Urol. 2007;178(5):1901–5.CrossRefPubMedGoogle Scholar
  7. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol. 2002;168(6):2395–400.CrossRefPubMedGoogle Scholar
  8. Funakoshi T, Lee CH, Hsieh JJ. A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma. Cancer Treat Rev. 2014;40(4):533–47.CrossRefPubMedGoogle Scholar
  9. Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, et al. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 2013;24(2):343–9.CrossRefPubMedGoogle Scholar
  10. Haddad AQ, Kapur P, Singla N, Raman JD, Then MT, Nuhn P, et al. Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma. Cancer. 2015;121(1):43–50.CrossRefPubMedGoogle Scholar
  11. Hammers H. Immunotherapy in kidney cancer: the past, present, and future. Curr Opin Urol. 2016;26(6):543–7.CrossRefPubMedGoogle Scholar
  12. Harshman LC, Xie W, Bjarnason GA, Knox JJ, MacKenzie M, Wood L, et al. Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. Lancet Oncol. 2012;13(9):927–35.CrossRefPubMedGoogle Scholar
  13. Health UNIo. Nivolumab combined with Ipilimumab versus Sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 214). 2016; web site.
  14. Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–9.CrossRefPubMedGoogle Scholar
  15. Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Heng DY, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66(4):704–10.CrossRefPubMedGoogle Scholar
  17. Hoffmann NE, Sheinin Y, Lohse CM, Parker AS, Leibovich BC, Jiang Z, et al. External validation of IMP3 expression as an independent prognostic marker for metastatic progression and death for patients with clear cell renal cell carcinoma. Cancer. 2008;112(7):1471–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jiang Z, Chu PG, Woda BA, Liu Q, Balaji KC, Rock KL, et al. Combination of quantitative IMP3 and tumor stage: a new system to predict metastasis for patients with localized renal cell carcinomas. Clin Cacer Res. 2008;14(17):5579–84.CrossRefGoogle Scholar
  19. Karakiewicz PI, Briganti A, Chun FK, Trinh QD, Perrotte P, Ficarra V, et al. Multi-institutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol. 2007a;25(11):1316–22.CrossRefPubMedGoogle Scholar
  20. Karakiewicz PI, Hutterer GC, Trinh QD, Jeldres C, Perrotte P, Gallina A, et al. C-reactive protein is an informative predictor of renal cell carcinoma-specific mortality: a European study of 313 patients. Cancer. 2007b;110(6):1241–7.CrossRefPubMedGoogle Scholar
  21. Karakiewicz PI, Trinh QD, Lam JS, Tostain J, Pantuck AJ, Belldegrun AS, et al. Platelet count and preoperative haemoglobin do not significantly increase the performance of established predictors of renal cell carcinoma-specific mortality. Eur Urol. 2007c;52(5):1428–36.CrossRefPubMedGoogle Scholar
  22. Karakiewicz PI, Suardi N, Capitanio U, Isbarn H, Jeldres C, Perrotte P, et al. Conditional survival predictions after nephrectomy for renal cell carcinoma. J Urol. 2009;182(6):2607–12.CrossRefPubMedGoogle Scholar
  23. Karakiewicz PI, Sun M, Bellmunt J, Sneller V, Escudier B. Prediction of progression-free survival rates after bevacizumab plus interferon versus interferon alone in patients with metastatic renal cell carcinoma: comparison of a nomogram to the Motzer criteria. Eur Urol. 2011;60(1):48–56.CrossRefPubMedGoogle Scholar
  24. Kattan MW, Shariat SF, Andrews B, Zhu K, Canto E, Matsumoto K, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003;21(19):3573–9.CrossRefPubMedGoogle Scholar
  25. Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005;173(5):1496–501.CrossRefPubMedGoogle Scholar
  26. Kutikov A, Egleston BL, Wong YN, Uzzo RG. Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Oncol. 2010;28(2):311–7.CrossRefPubMedGoogle Scholar
  27. Lam JS, Shvarts O, Said JW, Pantuck AJ, Seligson DB, Aldridge ME, et al. Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma. Cancer. 2005;103(12):2517–25.CrossRefPubMedGoogle Scholar
  28. Leibovich BC, Cheville JC, Lohse CM, Zincke H, Frank I, Kwon ED, et al. A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol. 2005;174(5):1759–63. discussion 63CrossRefPubMedGoogle Scholar
  29. Li H, Samawi H, Heng DY. The use of prognostic factors in metastatic renal cell carcinoma. Urol Oncol. 2015;33(12):509–16.CrossRefPubMedGoogle Scholar
  30. Ljungberg B, Cowan NC, Hanbury DC, Hora M, Kuczyk MA, Merseburger AS, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58(3):398–406.CrossRefPubMedGoogle Scholar
  31. Lughezzani G, Sun M, Budaus L, Thuret R, Perrotte P, Karakiewicz PI. Population-based external validation of a competing-risks nomogram for patients with localized renal cell carcinoma. J Clin Oncol. 2010;28(18):e299–300. author reply e1CrossRefPubMedGoogle Scholar
  32. Maroto P, Rini B. Molecular biomarkers in advanced renal cell carcinoma. Clin Cacer Res. 2014;20(8):2060–71.CrossRefGoogle Scholar
  33. McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol. 2014;65(3):577–84.CrossRefPubMedGoogle Scholar
  34. Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23(4):832–41.CrossRefPubMedGoogle Scholar
  35. Michigan A, Johnson TV, Master VA. Preoperative C-reactive protein level adjusted for comorbidities and lifestyle factors predicts overall mortality in localized renal cell carcinoma. Mol Diagn Therapy. 2011;15(4):229–34.CrossRefGoogle Scholar
  36. Molina AM, Motzer RJ. Clinical practice guidelines for the treatment of metastatic renal cell carcinoma: today and tomorrow. Oncologist. 2011;16(Suppl 2):45–50.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530–40.CrossRefPubMedGoogle Scholar
  38. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–96.CrossRefPubMedGoogle Scholar
  39. Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454–63.CrossRefPubMedGoogle Scholar
  40. Motzer RJ, Bukowski RM, Figlin RA, Hutson TE, Michaelson MD, Kim ST, et al. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2008;113(7):1552–8.CrossRefPubMedGoogle Scholar
  41. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefPubMedGoogle Scholar
  42. Negrier S, Gomez F, Douillard JY, Ravaud A, Chevreau C, Buclon M, et al. Prognostic factors of response or failure of treatment in patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d’Immunotherapie. World J Urol. 2005;23(3):161–5.CrossRefPubMedGoogle Scholar
  43. Ngo TC, Wood CG, Karam JA. Biomarkers of renal cell carcinoma. Urol Oncol. 2014;32(3):243–51.CrossRefPubMedGoogle Scholar
  44. Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer. 2007;109(11):2257–67.CrossRefPubMedGoogle Scholar
  45. Parker AS, Leibovich BC, Lohse CM, Sheinin Y, Kuntz SM, Eckel-Passow JE, et al. Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma. Cancer. 2009;115(10):2092–103.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ramankulov A, Lein M, Johannsen M, Schrader M, Miller K, Loening SA, et al. Serum amyloid A as indicator of distant metastases but not as early tumor marker in patients with renal cell carcinoma. Cancer Lett. 2008;269(1):85–92.CrossRefPubMedGoogle Scholar
  47. Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serum insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta oncologica (Stockholm, Sweden). 2004;43(8):744–8.CrossRefGoogle Scholar
  48. Schmitz-Drager BJ, Droller M, Lokeshwar VB, Lotan Y, Hudson MA, van Rhijn BW, et al. Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus. Urol Int. 2015;94(1):1–24.CrossRefPubMedGoogle Scholar
  49. Schraml P, Struckmann K, Hatz F, Sonnet S, Kully C, Gasser T, et al. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J Pathol. 2002;196(2):186–93.CrossRefPubMedGoogle Scholar
  50. Shariat SF, Walz J, Roehrborn CG, Zlotta AR, Perrotte P, Suardi N, et al. External validation of a biomarker-based preoperative nomogram predicts biochemical recurrence after radical prostatectomy. J Clin Oncol. 2008;26(9):1526–31.CrossRefPubMedGoogle Scholar
  51. Su Kim D, Choi YD, Moon M, Kang S, Lim JB, Kim KM, et al. Composite three-marker assay for early detection of kidney cancer. Cancer Epidemiol Biomark Prev. 2013;22(3):390–8.CrossRefGoogle Scholar
  52. Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol. 2011;60(4):644–61.CrossRefPubMedGoogle Scholar
  53. Templeton AJ, Knox JJ, Lin X, Simantov R, Xie W, Lawrence N, et al. Change in Neutrophil-to-lymphocyte Ratio in Response to Targeted Therapy for Metastatic Renal Cell Carcinoma as a Prognosticator and Biomarker of Efficacy. Eur Urol. 2016;70(2):358–64.CrossRefPubMedGoogle Scholar
  54. The Cancer Genome Atlas (TCGA) Data portal. Kidney renal clear cell carcinoma. Updated 30 June 2016; Cited 14 Oct2016. Available from:
  55. Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13(8):827–37.CrossRefPubMedGoogle Scholar
  56. Trinh QD, Sukumar S, Schmitges J, Bianchi M, Sun M, Shariat SF, et al. Effect of nodal metastases on cancer-specific mortality after cytoreductive nephrectomy. Ann Surg Oncol. 2013;20(6):2096–102.CrossRefPubMedGoogle Scholar
  57. Wang HK, Zhu Y, Yao XD, Zhang SL, Dai B, Zhang HL, et al. External validation of a nomogram using RENAL nephrometry score to predict high grade renal cell carcinoma. J Urol. 2012;187(5):1555–60.CrossRefPubMedGoogle Scholar
  58. Yao M, Yoshida M, Kishida T, Nakaigawa N, Baba M, Kobayashi K, et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst. 2002;94(20):1569–75.CrossRefPubMedGoogle Scholar
  59. Zhang T, Zhu J, George DJ, Nixon AB. Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies. Urol Oncol. 2016;34:510–8.CrossRefPubMedGoogle Scholar
  60. Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001;19(6):1649–57.CrossRefPubMedGoogle Scholar
  61. Zurita AJ, Jonasch E, Wang X, Khajavi M, Yan S, Du DZ, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23(1):46–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Helen Davis Bondarenko
    • 1
  • Raisa S. Pompe
    • 2
  • Emanuele Zaffuto
    • 3
  • Shahrokh F. Shariat
    • 5
  • Pierre I. Karakiewicz
    • 4
  1. 1.Department of UrologyUniversity of Montreal Health CentreMontrealCanada
  2. 2.Martini-Klinik Prostate Cancer CenterUniversity Hospital Hamburg-EppendorfHamburgGermany
  3. 3.Division of Oncology/Unit of UrologyUrological Research Institute, IRCCS Ospedale San RaffaeleMilanItaly
  4. 4.Cancer Prognostics and Health Outcomes UnitUniversity of Montreal Health CenterMontrealCanada
  5. 5.Departement of UrologyWeill Cornell Medical CenterNew YorkUSA

Section editors and affiliations

  • Mario W. Kramer
    • 1
  • Axel S. Merseburger
    • 2
  1. 1.Klinik für UrologieLübeckGermany
  2. 2.Department of UrologyUniversity Hospital Schleswig-HolsteinLübeckGermany

Personalised recommendations