Prognostic Biomarkers in Patients with Renal Cell Carcinoma: Where are We Going from Here?
Gaetano Aurilio （ Medical Oncology Division of Urogenital and Head and Neck Tumours, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy ）
Matteo Santoni （ 2.Oncology Unit, Macerata Hospital, via Santa Lucia 2, 62100, Macerata, Italy ）
Alessia Cimadamore （ Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, 60126 Ancona, Italy ）
Elena Verri （ Medical Oncology Division of Urogenital and Head and Neck Tumours, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy ）
Rodolfo Montironi （ Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, 60126 Ancona, Italy ）
https://doi.org/10.37155/2717-5278-0301-1Abstract
Treatment algorithm in metastatic renal cell carcinoma (RCC) patients has rapidly evolved during the last decade, and determining the prognosis of these patients has become a priority step for correctly planning the treatment. In the present article, we firstly address the most currently used prognostic models and how they have changed the treatment algorithm in routine clinical care; then we assess whether patient selection may be improved in the first-line treatment and the usefulness of a prognostic model following first-line failure; ultimately we culminate in new clinical and molecular prognostic factors under investigation. For this last issue, biomarkers for immunotherapy and angiogenesis inhibitors, as well as biomarkers for liquid analysis and for clinical obesity are presented.
Keywords
Metastatic renal cell carcinoma; Patients; Risk factors; Prognostic models; Clinical biomarkers; Molecular biomarkersFull Text
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[13].Wells JC, Stukalin I, Norton C, Srinivas S, Lee JL, Donskov F, Bjarnason GA, Yamamoto H, Beuselinck B, Rini BI, Knox JJ, Agarwal N, Ernst DS, Pal SK, Wood LA, Bamias A, Alva AS, Kanesvaran R, Choueiri TK, Heng DYC. Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2017 Feb;71(2):204-209.
[14].Stukalin I, Wells C, Fraccon AP, Pasini F, Porta C, Moreira RB, Srinivas S, Bowman IA, Brugarolas J, Lee JL, Donskov F, Beuselinck B, Bamias A, Rini BI, Sim HW, Agarwal N, Rha SY, Kanesvaran R, Choueiri TK, Heng DYC. Fourth-line targeted therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC). Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017) 498-498.
[15].Tamura K, Matsushita Y, Watanabe H, Motoyama D, Ito T, Sugiyama T, Otsuka A, Miyake H. Feasibility of the ACL (albumin, C-reactive protein and lactate dehydrogenase) model as a novel prognostic tool in patients with metastatic renal cell carcinoma previously receiving first-line targeted therapy. Urol Oncol. 2020 Jan;38(1):6.e9-6.e16.
[16].Aurilio G, Piva F, Santoni M, Cimadamore A, Sorgentoni G, Lopez-Beltran A, Cheng L, Battelli N, Nolè F, Montironi R. The Role of Obesity in Renal Cell Carcinoma Patients: Clinical-Pathological Implications. Int J Mol Sci. 2019 Nov 13;20(22):5683.
[17].Iacovelli R, Massari F, Albiges L, Loriot Y, Massard C, Fizazi K, Escudier B. Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma. Eur Urol. 2015 Jul;68(1):154-60.
[18].Iacovelli R, Nolè F, Verri E, Renne G, Paglino C, Santoni M, Cossu Rocca M, Giglione P, Aurilio G, Cullurà D, Cascinu S, Porta C. Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis. Target Oncol. 2016 Apr;11(2):143-8.
[19].Carretero-González A, Lora D, Martín Sobrino I, Sáez Sanz I, Bourlon MT, Anido Herranz U, Martínez Chanzá N, Castellano D, de Velasco G. The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials. Cancers (Basel). 2020 Jul 17;12(7):1945.
[20].Eckel-Passow JE, Ho TH, Serie DJ, Cheville JC, Thompson RH, Costello BA, Dong H, Kwon ED, Leibovich BC, Parker AS. Concordance of PD-1 and PD-L1 (B7-H1) in paired primary and metastatic clear cell renal cell carcinoma. Cancer Med. 2020 Feb;9(3):1152-1160.
[21].Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127.
[22].Lalani AA, Xie W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, Duquette A, Bossé D, Bellmunt J, Van Allen EM, McGregor BA, Creighton CJ, Harshman LC, Choueiri TK. Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer. 2018 Jan 22;6(1):5.
[23].Santoni M, Buti S, Conti A, Porta C, Procopio G, Sternberg CN, Bracarda S, Basso U, De Giorgi U, Rizzo M, Derosa L, Ortega C, Massari F, Milella M, Bersanelli M, Cerbone L, Muzzonigro G, Burattini L, Montironi R, Santini D, Cascinu S. Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy. Target Oncol. 2015 Dec;10(4):517-22.
[24].Lorente D, Arevalo J, Salcedo MT, Trilla E, de Torres I, Meseguer A, Morote J. Analysis of the nuclear expression of pSer727-STAT3 as a prognostic factor in patients with clear cell renal carcinoma. Actas Urol Esp. 2020 May;44(4):245-250.
[25].Aurilio G, Santoni M, Cimadamore A, Massari F, Scarpelli M, Lopez-Beltran A, Cheng L, Battelli N, Nolé F & Rodolfo Montironi (2020) Renal Cell Carcinoma: genomic landscape and clinical implications, Expert Review of Precision Medicine and Drug Development, 5:2, 95-100, DOI:10.1080/23808993.2020.1733407.
[26].Cappelletti V, Verzoni E, Ratta R, Vismara M, Silvestri M, Montone R, Miodini P, Reduzzi C, Claps M, Sepe P, Daidone MG, Procopio G. Analysis of Single Circulating Tumor Cells in Renal Cell Carcinoma Reveals Phenotypic Heterogeneity and Genomic Alterations Related to Progression. Int J Mol Sci. 2020 Feb 21;21(4):1475.
[27].Haga N. ASO Author Reflections: Increase of Circulating Tumor Cells After Open Radical Nephrectomy Compared with Other Surgical Modalities. Ann Surg Oncol. 2020 Apr;27(4):1282-1283.
[28].Bluemke K, Bilkenroth U, Meye A, Fuessel S, Lautenschlaeger C, Goebel S, Melchior A, Heynemann H, Fornara P, Taubert H. Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis. Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2190-4.
[29].Tamura K, Ando R, Takahara K, Ito T, Kanao K, Yasui T, Shiroki R, Miyake H. Development of novel ACN (albumin, C-reactive protein and neutrophil-to-lymphocyte ratio) prognostication model for patients with metastatic renal cell carcinoma receiving first-line molecular-targeted therapy. Urol Oncol. 2021 Jan;39(1):78.e1-78.e8.
Ciccarese C, Brunelli M, Montironi R, Fiorentino M, Iacovelli R, Heng D, Tortora G, Massari F. The prospect of precision therapy for renal cell carcinoma. Cancer Treat Rev. 2016 Sep;49:37-44.
[2].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 Aug;17(8):2530-40.
[3].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 Jan 1;20(1):289-96.
[4].Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P, Bukowski R. 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 Feb 1;23(4):832-41.
[5].Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK. 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 Dec 1;27(34):5794-9.
[6].Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK. 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 Feb;14(2):141-8.
[7].Clark GM, Zborowski DM, Culbertson JL, Whitehead M, Savoie M, Seymour L, Shepherd FA. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol. 2006 Oct;1(8):837-46.
[8].Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591-597.
[9].Motzer RJ, Tannir NM, McDermott DF, Frontera OA, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B, CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290.
[10].Iacovelli R, De Giorgi U, Galli L, Zucali P, Nolè F, Sabbatini R, Fraccon AP, Basso U, Mosca A, Atzori F, Santini D, Facchini G, Fornarini G, Pasini F, Masini C, Massari F, Buti S, Sava T, Sacco C, Ricotta R, Sperduti I, Tortora G, Porta C. Is It Possible to Improve Prognostic Classification in Patients Affected by Metastatic Renal Cell Carcinoma With an Intermediate or Poor Prognosis? Clin Genitourin Cancer. 2018 Oct;16(5):355-359.e1.
[11].Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, Bjarnason GA, Srinivas S, Pal SK, Yuasa T, Smoragiewicz M, Donskov F, Kanesvaran R, Wood L, Ernst DS, Agarwal N, Vaishampayan UN, Rha SY, Choueiri TK, Heng DY. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015 Mar;16(3):293-300.
[12].Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004 Feb 1;22(3):454-63.
[13].Wells JC, Stukalin I, Norton C, Srinivas S, Lee JL, Donskov F, Bjarnason GA, Yamamoto H, Beuselinck B, Rini BI, Knox JJ, Agarwal N, Ernst DS, Pal SK, Wood LA, Bamias A, Alva AS, Kanesvaran R, Choueiri TK, Heng DYC. Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2017 Feb;71(2):204-209.
[14].Stukalin I, Wells C, Fraccon AP, Pasini F, Porta C, Moreira RB, Srinivas S, Bowman IA, Brugarolas J, Lee JL, Donskov F, Beuselinck B, Bamias A, Rini BI, Sim HW, Agarwal N, Rha SY, Kanesvaran R, Choueiri TK, Heng DYC. Fourth-line targeted therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC). Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017) 498-498.
[15].Tamura K, Matsushita Y, Watanabe H, Motoyama D, Ito T, Sugiyama T, Otsuka A, Miyake H. Feasibility of the ACL (albumin, C-reactive protein and lactate dehydrogenase) model as a novel prognostic tool in patients with metastatic renal cell carcinoma previously receiving first-line targeted therapy. Urol Oncol. 2020 Jan;38(1):6.e9-6.e16.
[16].Aurilio G, Piva F, Santoni M, Cimadamore A, Sorgentoni G, Lopez-Beltran A, Cheng L, Battelli N, Nolè F, Montironi R. The Role of Obesity in Renal Cell Carcinoma Patients: Clinical-Pathological Implications. Int J Mol Sci. 2019 Nov 13;20(22):5683.
[17].Iacovelli R, Massari F, Albiges L, Loriot Y, Massard C, Fizazi K, Escudier B. Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma. Eur Urol. 2015 Jul;68(1):154-60.
[18].Iacovelli R, Nolè F, Verri E, Renne G, Paglino C, Santoni M, Cossu Rocca M, Giglione P, Aurilio G, Cullurà D, Cascinu S, Porta C. Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis. Target Oncol. 2016 Apr;11(2):143-8.
[19].Carretero-González A, Lora D, Martín Sobrino I, Sáez Sanz I, Bourlon MT, Anido Herranz U, Martínez Chanzá N, Castellano D, de Velasco G. The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials. Cancers (Basel). 2020 Jul 17;12(7):1945.
[20].Eckel-Passow JE, Ho TH, Serie DJ, Cheville JC, Thompson RH, Costello BA, Dong H, Kwon ED, Leibovich BC, Parker AS. Concordance of PD-1 and PD-L1 (B7-H1) in paired primary and metastatic clear cell renal cell carcinoma. Cancer Med. 2020 Feb;9(3):1152-1160.
[21].Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127.
[22].Lalani AA, Xie W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, Duquette A, Bossé D, Bellmunt J, Van Allen EM, McGregor BA, Creighton CJ, Harshman LC, Choueiri TK. Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer. 2018 Jan 22;6(1):5.
[23].Santoni M, Buti S, Conti A, Porta C, Procopio G, Sternberg CN, Bracarda S, Basso U, De Giorgi U, Rizzo M, Derosa L, Ortega C, Massari F, Milella M, Bersanelli M, Cerbone L, Muzzonigro G, Burattini L, Montironi R, Santini D, Cascinu S. Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy. Target Oncol. 2015 Dec;10(4):517-22.
[24].Lorente D, Arevalo J, Salcedo MT, Trilla E, de Torres I, Meseguer A, Morote J. Analysis of the nuclear expression of pSer727-STAT3 as a prognostic factor in patients with clear cell renal carcinoma. Actas Urol Esp. 2020 May;44(4):245-250.
[25].Aurilio G, Santoni M, Cimadamore A, Massari F, Scarpelli M, Lopez-Beltran A, Cheng L, Battelli N, Nolé F & Rodolfo Montironi (2020) Renal Cell Carcinoma: genomic landscape and clinical implications, Expert Review of Precision Medicine and Drug Development, 5:2, 95-100, DOI:10.1080/23808993.2020.1733407.
[26].Cappelletti V, Verzoni E, Ratta R, Vismara M, Silvestri M, Montone R, Miodini P, Reduzzi C, Claps M, Sepe P, Daidone MG, Procopio G. Analysis of Single Circulating Tumor Cells in Renal Cell Carcinoma Reveals Phenotypic Heterogeneity and Genomic Alterations Related to Progression. Int J Mol Sci. 2020 Feb 21;21(4):1475.
[27].Haga N. ASO Author Reflections: Increase of Circulating Tumor Cells After Open Radical Nephrectomy Compared with Other Surgical Modalities. Ann Surg Oncol. 2020 Apr;27(4):1282-1283.
[28].Bluemke K, Bilkenroth U, Meye A, Fuessel S, Lautenschlaeger C, Goebel S, Melchior A, Heynemann H, Fornara P, Taubert H. Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis. Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2190-4.
[29].Tamura K, Ando R, Takahara K, Ito T, Kanao K, Yasui T, Shiroki R, Miyake H. Development of novel ACN (albumin, C-reactive protein and neutrophil-to-lymphocyte ratio) prognostication model for patients with metastatic renal cell carcinoma receiving first-line molecular-targeted therapy. Urol Oncol. 2021 Jan;39(1):78.e1-78.e8.
Ciccarese C, Brunelli M, Montironi R, Fiorentino M, Iacovelli R, Heng D, Tortora G, Massari F. The prospect of precision therapy for renal cell carcinoma. Cancer Treat Rev. 2016 Sep;49:37-44.
Copyright © 2021 Gaetano Aurilio, Matteo Santoni, Alessia Cimadamore, Elena Verri, Rodolfo Montironi
Publishing time:2021-06-30
This work is licensed under a Creative Commons Attribution 4.0 International License
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