Management of kidney cancer has undergone a paradigm shift with the approval of new therapies over the last two decades. Although these drugs have improved clinical outcomes in patients with kidney cancer, there are still a large number of patients who do not show objective responses. A multitude of investigators, including those for The Cancer Genome Atlas have biologically characterized and sub-classified kidney cancer. However, we have not been able to identify molecular targets to effectively treat patients with kidney cancer. As we familiarize ourselves with newer drugs for patients with kidney cancer, it is important to understand that these drugs may not work in every patient and instead may expose patients to unnecessary toxic effects along with burdening society with the financial impact. As we head toward the era of “precision medicine”, validated biomarkers are being utilized to guide treatment choices and help identify pathways of resistance in other tumor types. The current review aims at evaluating the progress made so far in this realm for patients with kidney cancer.
. [J]. Asian Journal of Urology, 2021, 8(4): 362-375.
Shuchi Gulati,Nicholas J. Vogelzang. Biomarkers in renal cell carcinoma: Are we there yet?. Asian Journal of Urology, 2021, 8(4): 362-375.
-21.8 mo for Nivo vs. 18.8 mo for everolimus (HR 0.78)
-25.0 vs. 19.6 mo (95% CI 17.6-23.1)
NR
-4.6 vs. 4.4 mo (HR 0.88; 95% CI, 0.75-1.03; p=0.11)
IMmotion151 [10]
Atezolizumab+bevacizumab vs. sunitinib
-HR 0.84; 95% CI 0.62-1.15; p=0.2857
-HR 0.93; 95% CI 0.76-1.14; p=0.4751
-11.2 mo vs. 7.7 mo (HR 0.74; 95% CI 0.57-0·96; p=0.0217)
-11.2 vs. 8.4 mo (HR 0.83; 95% CI 0.70-0.97)
CheckMate 214 [4]
Nivo+Ipi vs. sunitinib
-NR for Ipi/Nivo vs. 19.6 mo (HR 0.45; 95% CI 0.29-0.71)
-NR vs. 26.0 mo (HR 0.63)
-22.8 mo for Ipi/Nivo vs. 5.9 mo (HR 0.46; 95% CI, 0.31-0.67)
-11.6 vs. 8.4 mo (HR 0.82; 99.1% CI 0.64-1.05; p=0.03)
KEYNOTE-426 [5,19]
Pembro+Axi vs. sunitinib
-HR 0.54; 95% CI 0.34-1.03 (12-mo OS)
-Pembro+Axi improved OS (HR, 0.68; 95% CI 0.55-0.85; p<0.001)
-15.3 mo for Pembro/Axi vs. 8.9 mo (HR 0.62; 95% CI 0.47-0.80)
-Pembro+Axi improved PFS (HR 0.71; 95% CI 0.60-0.84; p<0.001)
JAVELIN Renal 101 [26,27]
Avelumab+Axi vs. sunitinib
-NR in avelumab/Axi group vs. 25.8 mo (HR 0.83; 95% CI 0.596-1.151; p=0.1301)
-NR vs. NR (HR 0.80; 95% CI 0.616-1.027; p=0.03920)
-13.8 mo for avelumab/Axi vs. 7 mo (HR 0.62; 95% CI 0.490-0.777; p<0.0001)
-13.3 mo in avelumab/Axi arm vs. 8 mo in sunitinib arm (HR 0.69; 95% CI 0.574-0.825; p<0.0001)
[1]
Key statistics about kidney cancer [Internet], https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. [Accessed 9 June 2020].
[2]
Kidney cancer. World Cancer Research Fund; 2018 [Internet], https://www.wcrf.org/dietandcancer/kidney-cancer. [Accessed 9 June 2020].
[3]
Gulati S, Vaishampayan U. Current state of systemic thera-pies for advanced renal cell carcinoma. Curr Oncol Rep 2020; 22:26. https://doi.org/10.1007/s11912-020-0892-1.
[4]
Motzer RJ, Tannir NM, McDermott DF, Frontera OA, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378:1277e90.
[5]
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380:1116e27.
[6]
Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983e1993. Semin Oncol 1995; 22:42e60.
[7]
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 5;373: 1803e13.
[8]
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 201921; 380:1103e15.
[9]
Choueiri TK, Powles T, Burotto M, Bourlon MT, Zurawski B, Juárez VMO, et al. 696O_PR Nivolumabþcabozantinib vs. sunitinib in first-line treatment for advanced renal cell carci-noma: First results from the randomized phase III CheckMate 9ER trial. Ann Oncol 2020;31:S1159. https://doi.org/10.1016/j.annonc.2020.08.2257.
[10]
Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomised controlled trial. Lancet 2019; 393:2404e15.
[11]
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271e81.
[12]
Heng DYC, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in pa-tients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter Study. J Clin Oncol 2009; 27:5794e9.
[13]
Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 pa-tients with advanced renal cell carcinoma. J Clin Oncol 1999; 17:2530e40.
[14]
Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. External validation and compari-son with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncol 2013; 14:141e8.
[15]
Pérez-Valderrama B, Arranz Arija JA, Rodríguez Sánchez A, Pinto Marín A, Borrega García P, Castellano Gaunas DE, et al. Validation of the international metastatic renal-cell carci-noma Database consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: The Spanish oncologic genitourinary group (SOGUG) SPAZO study. Ann Oncol 2016; 27:706e11.
[16]
Kroeger N, Xie W, Lee J-L, Bjarnason GA, Knox JJ, MacKenzie MJ, et al. Metastatic non-clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Characterization of survival outcome and application of the International mRCC Database Consortium (IMDC) Criteria. Cancer 2013; 119:2999e3006.
[17]
Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019; 20:1370e85.
[18]
de Peralta-Venturina M, Moch H, Amin M, Tamboli P, Hailemariam S, Mihatsch M, et al. Sarcomatoid differentia-tion in renal cell carcinoma: A study of 101 cases. Am J Surg Pathol 2001; 25:275e84.
[19]
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell car-cinoma (mRCC): Outcomes in the combined IMDC inter-mediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol 2019;37:4500. https://doi.org/10.1200/JCO.2019.37.15_suppl.4500.
[20]
McDermott DF, Choueiri TK, Motzer RJ, Aren OR, George S, Powles T, et al. CheckMate 214 post-hoc analyses of nivolu-mab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. J Clin Orthod 2019 May 20;37:4513. https://doi.org/10.1200/JCO.2019.37.15_suppl.4513.
[21]
Bakouny Z, Braun DA, Shukla SA, Pan W, Gao X, Hou Y, et al. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nat Commun 2021;12:808. https://doi.org/10.1038/s41467-021-21068-9.
[22]
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory B7-H1 in renal cell carci-noma patients: Indicator of tumor aggressiveness and po-tential therapeutic target. Proc Natl Acad Sci U S A 2004; 101:17174e9.
[23]
Iacovelli R, Nolè F, Verri E, Renne G, Paglino C, Santoni M, et al. Prognostic role of PD-L1 expression in renal cell car-cinoma. A systematic review and meta-analysis. Target Oncol 2016; 11:143e8.
[24]
Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: Results from COMPARZ, a randomized controlled trial. Clin Canc Res 2015; 21:1071e7.
[25]
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018; 24:749e57.
[26]
Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: Biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat Med 2020; 26:1733e41.
[27]
Zhu J, Armstrong AJ, Friedlander TW, Kim W, Pal SK, George DJ, et al. Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond. J Immunother Cancer 2018;6:4. https://doi.org/10.1186/s40425-018-0314-1.
[28]
Callea M, Albiges L, Gupta M, Cheng S-C, Genega EM, Fay AP, et al. Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 2015; 3:1158e64.
[29]
Samstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019; 51:202e6.
[30]
Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): A hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular Oncology. J Mol Diagn 2015; 17:251e64.
[31]
Labriola MK, Zhu J, Gupta R, McCall S, Jackson J, Kong EF, et al. Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune check-point inhibitors response in metastatic renal cell carcinoma. J Immunother Cancer 2020;8:e000319. https://doi.org/10.1136/jitc-2019-000319.
[32]
Wood MA, Weeder BR, David JK, Nellore A, Thompson RF. Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival. Genome Med 2020;12:33. https://doi.org/10.1186/s13073-020-00729-2.
[33]
Dizman N, Lyou Y, Salgia N, Bergerot PG, Hsu J, Enriquez D, et al. Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: Comprehensive genomic and transcriptomic analysis. J Immunother Cancer 2020;8:e000953. https://doi.org/10.1136/jitc-2020-000953.
[34]
Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med 2020; 26:909e18.
[35]
Motzer RJ, Choueiri TK, McDermott DF, Powles T, Yao J, Ammar R, et al. Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (NþI) or sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol 2020;38:5009. https://doi.org/10.1200/JCO.2020.38.15_suppl.5009.
[36]
FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA [Internet] Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. [Accessed 18 June 2020].
[37]
Czyzyk-Krzeska MF, Landero Figueroa JA, Gulati S, Cunningham JT, Meller J, ShamsaeI B, et al. Molecular and metabolic subtypes in sporadic and inherited clear cell renal cell carcinoma. Genes (Basel) 2021;12:388. https://doi.org/10.3390/genes12030388.
[38]
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 2013; 45:860e7.
[39]
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of tumours of the urinary system and male genital organsdPart A: Renal, penile, and testic-ular tumours. Eur Urol 2016; 70:93e105.
[40]
Liu YJ, Houldsworth J, Emmadi R, Dyer L, Wolff DJ. Assessing genomic copy number alterations as best practice for renal cell neoplasia: An evidence-based review from the cancer genomics consortium workgroup. Cancer Genet 2020; 244:40e54.
[41]
Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004; 22:4991e5004.
[42]
Choueiri TK, Kaelin WG. Targeting the HIF2eVEGF axis in renal cell carcinoma. Nat Med 2020; 26:1519e30.
[43]
Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan V, Maughan BL, et al. Phase II study of the oral HIF2a inhibitor MK-6482 for Von Hippel-Lindau disease-associated renal cell carcinoma. J Clin Oncol 2020;38(Suppl. 15):5003. https://doi.org/10.1200/JCO.2020.38.15_suppl.5003.
[44]
Cowey CL, Rathmell WK. VHL gene mutations in renal cell carcinoma: Role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep 2009; 11:94e101.
[45]
Büscheck F, Fraune C, Simon R, Kluth M, Hube-Magg C, Möl-ler-Koop C, et al. Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes. Oncotarget 2020; 11:237e49.
[46]
Choueiri TK, Vaziri SAJ, Jaeger E, Elson P, Wood L, Bhalla IP, et al. von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol 2008; 180:860e6.
[47]
Choueiri TK, Fay AP, Gagnon R, Lin Y, Bahamon B, Brown V, et al. The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Canc Res 2013; 19:5218e26.
[48]
Kim BJ, Kim JH, Kim HS, Zang DY. Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: a meta-analysis and review. Oncotarget 2017; 8:13979e85.
[49]
Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PloS One 2013;8:e55119. https://doi.org/10.1371/journal.pone.0055119.
[50]
Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2011; 469:539e42.
[51]
Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep 2018;23: 313e26. e5. https://10.1016/j.celrep.2018.03.075.
[52]
Ho TH, Choueiri TK, Wang K, Karam JA, Chalmers Z, Frampton G, et al. Correlation between molecular sub-classifications of clear cell renal cell carcinoma and targeted therapy response. Eur Urol Focus 2016; 2:204e9.
[56]
Carbone M, Harbour JW, Brugarolas J, Bononi A, Pagano I, Dey A, et al. Biological mechanisms and clinical significance of BAP1 mutations in human cancer. Canc Discov 2020; 10:1103e20.
[57]
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012; 44:751e9.
[58]
Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carci-noma: A retrospective analysis with independent validation. Lancet Oncol 2013; 14:159e67.
[59]
Joseph RW, Kapur P, Serie DJ, Eckel-Passow JE, Parasramka M, Ho T, et al. Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low risk clear cell renal cell carcinoma. Cancer 2014; 120:1059e67.
[60]
Voss MH, Reising A, Cheng Y, Patel P, Marker M, Kuo F, et al. Genomically annotated risk model for advanced renal-cell carcinoma: A retrospective cohort study. Lancet Oncol 2018; 19:1688e98.
[61]
Fahey CC, Davis IJ. SETting the stage for cancer develop-ment: SETD2 and the consequences of lost methylation. Cold Spring Harb Perspect Med 2017;7:a026468. https://doi.org/10.1101/cshperspect.a026468.
[62]
González-Rodríguez P, Engskog-Vlachos P, Zhang H, Murgoci A-N, Zerdes I, Joseph B. SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. Cell Death Dis 2020;11:69. https://doi.org/10.1038/s41419-020-2266-x.
[63]
Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen Y-B, Gonen M, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: A report by MSKCC and the KIRC TCGA research network. Clin Canc Res 2013; 19:3259e67.
[64]
Mamdani H, Chen J, Kim S, Ibrahim Y, Asad MFB, Nieva JJ, et al. DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC). J Clin Oncol 2019;37:9100. https://doi.org/10.1200/JCO.2019.37.15_suppl.9100.
[65]
Ricciuti B, Recondo G, Spurr LF, Li YY, Lamberti G, Venkatraman D, et al. Impact of DNA damage response and repair (DDR) gene mutations on efficacy of PD-(L)1 immune checkpoint inhibition in non-small cell lung cancer. Clin Canc Res 2020; 26:4135e42.
[66]
Ged Y, Chaim JL, DiNatale RG, Knezevic A, Kotecha RR, Carlo MI, et al. DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy. J Immunother Cancer 2020;8:e000230. https://doi.org/10.1136/jitc-2019-000230.
[67]
Home-ClinicalTrials.gov [Internet], https://clinicaltrials.gov/. [Accessed 1 February 2021].
[68]
Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for pa-tients with localized and locally advanced renal cell carci-noma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005; 174:466e72.
[69]
Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, et al. Adjuvant sunitinib in high-risk renal-cell car-cinoma after nephrectomy. N Engl J Med 2016; 375:2246e54.
[70]
Haas NB, Manola J, Dutcher JP, Flaherty KT, Uzzo RG, Atkins MB, et al. Adjuvant treatment for high-risk clear cell renal cancer: Updated results of a high-risk subset of the ASSURE Randomized Trial. JAMA Oncol 2017; 3:1249e52.
[71]
Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol 2017; 35:3916e23.
[72]
Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: Results from the phase III, randomized ATLAS trial. Ann Oncol 2018; 29:2371e8.
[73]
Wood E, Donin N, Shuch B. Adjuvant therapy for localized high-risk renal cell carcinoma. Urol Clin North Am 2020; 47:345e58.
[74]
Rini B, Goddard A, Knezevic D, Maddala T, Zhou M, Aydin H, et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: Development and validation studies. Lancet Oncol 2015; 16:676e85.
[75]
Brooks SA, Brannon AR, Parker JS, Fisher JC, Sen O, Kattan MW, et al. ClearCode34: A prognostic risk predictor for localized clear cell renal cell carcinoma. Eur Urol 2014; 66:77e84.
[76]
Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, et al. Prognostic value of an RNA expression signa-ture derived from cell cycle proliferation genes in patients with prostate cancer: A retrospective study. Lancet Oncol 2011; 12:245e55.
[77]
Dancik GM, Theodorescu D. Robust prognostic gene expres-sion signatures in bladder cancer and lung adenocarcinoma depend on cell cycle related genes. PloS One 2014;9:e85249. https://doi.org/10.1371/journal.pone.0085249. eCollection 2014.
[78]
Morgan TM, Mehra R, Tiemeny P, Wolf JS, Wu S, Sangale Z, et al. A multigene signature based on cell cycle proliferation improves prediction of mortality within 5 yr of radical ne-phrectomy for renal cell carcinoma. Eur Urol 2018; 73:763e9.
[79]
Ueno D, Dancik GM, Shuch B. The cell cycle progression score: Unclear role in renal cell carcinoma. Eur Urol 2018; 74:128e9.
[80]
Zhan Y, Guo W, Zhang Y, Wang Q, Xu X, Zhu L. A five-gene signature predicts prognosis in patients with kidney renal clear cell carcinoma. Comput Math Methods Med 2015;2015: 842784. https://doi.org/10.1155/2015/842784.
[81]
Yao M, Huang Y, Shioi K, Hattori K, Murakami T, Sano F, et al. A three-gene expression signature model to predict clinical outcome of clear cell renal carcinoma. Int J Canc 2008; 123:1126e32.
[82]
Dai J, Lu Y, Wang J, Yang L, Han Y, Wang Y, et al. A four-gene signature predicts survival in clear-cell renal-cell carcinoma. Oncotarget 2016; 7:82712e26.
[83]
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369:722e31.
[84]
Hakimi AA, Voss MH, Kuo F, Sanchez A, Liu M, Nixon BG, et al. Transcriptomic profiling of the tumor microenvironment re-veals distinct subgroups of clear cell renal cell cancer: Data from a randomized phase III trial. Canc Discov 2019; 9:510e25.
[85]
Gulati S, Philip E, Salgia S, Pal SK. Evolving treatment para-digm in metastatic non clear cell renal cell carcinoma. Cancer Treat Res Commun 2020;23:100172. https://doi.org/10.1016/j.ctarc.2020.100172.
[86]
Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med 2016; 374:135e45.
[87]
Choueiri TK, Heng DYC, Lee JL, Cancel M, Verheijen RB, Mellemgaard A, et al. Efficacy of savolitinib vs. sunitinib in patients with MET-driven papillary renal cell carcinoma. JAMA Oncol 2020; 6:1247e55.
[88]
Pal SK, Tangen C, Thompson IM, Balzer-Haas N, George DJ, Heng DYC, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: A randomised, open-label, phase 2 trial. Lancet 2021; 397:695e703.
[89]
Powles T, Larkin JMG, Patel P, Pérez-Valderrama B, Rodri-guez-Vida A, Glen H, et al. A phase II study investigating the safety and efficacy of savolitinib and durvalumab in meta-static papillary renal cancer (CALYPSO). J Clin Oncol 2019; 37 (Suppl. 7):545. https://doi.org/10.1200/JCO.2019.37.7_suppl.545.
[90]
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499:43e9.
[91]
Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007; 39:231e4.
[92]
Gatto F, Nookaew I, Nielsen J. Chromosome 3p loss of het-erozygosity is associated with a unique metabolic network in clear cell renal carcinoma. Proc Natl Acad Sci U S A 2014;111: e866e75. https://doi.org/10.1073/pnas.1319196111.
Li H, Bullock K, Gurjao C, Braun D, Shukla SA, Bossé D, et al. Metabolomic adaptations and correlates of survival to im-mune checkpoint blockade. Nat Commun 2019;10:4346. https://doi.org/10.1038/s41467-019-12361-9.
[95]
Giannakis M, Li H, Jin C, Gopal S, Desai K, Horak C, et al. Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients. J Clin Oncol 2017;35 (Suppl. 15):3036. https://doi.org/10.1200/JCO.2017.35.15_suppl.3036.
[96]
Bagley SJ, Kothari S, Aggarwal C, Bauml JM, Alley EW, Evans TL, et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated pa-tients with advanced non-small-cell lung cancer. Lung Can-cer 2017; 106:1e7.
[97]
Nunno VD, Mollica V, Gatto L, Santoni M, Cosmai L, Porta C, et al. Prognostic impact of neutrophil-to-lymphocyte ratio in renal cell carcinoma: A systematic review and meta-analysis. Immunotherapy 2019; 11:631e43.
[98]
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; 70:358e64.
[99]
Jeyakumar G, Kim S, Bumma N, Landry C, Silski C, Suisham S, et al. Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy. J Immunother Cancer 2017;5:82. https://doi.org/10.1186/s40425-017-0287-5.
[100]
Lalani A-KA, Xie W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, et al. Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 2018;6:5. https://doi.org/10.1186/s40425-018-0315-0.
[101]
Shao Y, Wu B, Jia W, Zhang Z, Chen Q, Wang D. Prognostic value of pretreatment neutrophil-to-lymphocyte ratio in renal cell carcinoma: A systematic review and meta-analysis. BMC Urol 2020;20:90. https://doi.org/10.1186/s12894-020-00665-8.
[102]
Smith CG, Moser T, Burge J, Eldridge M, Riediger AL, Mouliere F, et al. Comprehensive characterisation of cell-free tumour DNA in plasma and urine of patients with renal tumours. Genome Med 2020;12:23. https://doi.org/10.1186/s13073-020-00723-8.
[103]
Hahn AW, Gill DM, Maughan B, Agarwal A, Arjyal L, Gupta S, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): Po-tential clinical implications. Oncotarget 2017; 8:33614e20.
[104]
Pal SK, Sonpavde G, Agarwal N, Vogelzang NJ, Srinivas S, Haas NB, et al. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur Urol 2017; 72:557e64.
[105]
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome in?uences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359:91e7.
[106]
Salgia NJ, Bergerot PG, Maia MC, Dizman N, Hsu J, Gillece JD, et al. Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors. Eur Urol 2020; 78:498e502.
[107]
Pal SK, Li SM, Wu X, Qin H, Kortylewski M, Hsu J, et al. Stool bacteriomic profiling in patients with metastatic renal cell car-cinoma receiving vascular endothelial growth factordtyrosine kinase inhibitors. Clin Canc Res 2015; 21:5286e93.
