Abstract
Introduction
We analyzed the clinicopathological data of patients undergoing radical nephrectomy for clear cell type renal cell carcinoma (RCC) who presented with metastasis and were subsequently treated with sunitinib and identified molecular markers in nephrectomy specimens to predict susceptibility to sunitinib.
Patients and methods
The medical records of 65 patients who underwent nephrectomy for metastatic clear cell type RCC and were then treated with sunitinib were reviewed. The nephrectomy specimens were subjected to prospective immunohistochemical staining for vascular endothelial growth factor, vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor-B, and platelet-derived growth factor receptor-β expression.
Results
In 58 evaluable patients, the median value of initial and best overall response was −9.69 and −24.04 %, respectively. VEGFR-2 expression was associated significantly with initial and best overall responses to sunitinib, along with Karnofsky performance status and Memorial Sloan-Kettering Cancer Center prognostic risk group. Multiple linear regression analyses revealed that strong VEGFR-2 expression was positively associated with the best reduction in tumor response (β = −0.275, P = 0.016) and poor Karnofsky performance status was negatively associated it (β = 0.477, P < 0.001). Karnofsky performance status and retroperitoneal lymph node involvement associated independently with progression-free- and overall survivals. None of the molecular markers associated significantly with survival.
Conclusion
VEGFR-2 expression might be a useful biomarker for predicting the response to sunitinib by patients with metastatic RCC. Karnofsky performance status and retroperitoneal lymph node involvement were predictive of disease progression and death.
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References
Brugarolas J (2007) Renal-cell carcinoma-molecular pathways and therapies. N Engl J Med 356:185–187
Cancer Genome Atlas Research Network (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N, AVOREN Trial Investigators (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068
National Comprehensive Cancer Network (2012) NCCN clinical practice guidelines in oncology. Kidney cancer. Version 2.2012. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 2 June
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Hsu S-M, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580
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 (2009) 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 27:5794–5799
Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, Pantuck AJ, Zigeuner R, Karakiewicz PI (2011) Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol 60:644–661
Kontovinis LF, Papazisis KT, Touplikioti P, Andreadis C, Mouratidou D, Kortsaris AH (2009) Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers. BMC Cancer 9:82
Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32
Gruenwald V, Beutel G, Schuch-Jantsch S, Reuter C, Ivanyi P, Ganser A, Haubitz M (2010) Circulating endothelial cells are an early predictor in renal cell carcinoma for tumor response to sunitinib. BMC Cancer 10:695
Terakawa T, Miyake H, Kusuda Y, Fujisawa M (2013) Expression level of vascular endothelial growth factor receptor-2 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with sunitinib. Urol Oncol 31:493–498
Dornbusch J, Zacharis A, Meinhardt M, Erdmann K, Wolff I, Froehner M, Wirth MP, Zastrow S, Fuessel S (2013) Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma. PLoS ONE 8:e76386
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590
Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R (2009) Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 10:757–763
Yoo C, Kim JE, Lee JL, Ahn JH, Lee DH, Lee JS, Na S, Kim CS, Hong JH, Hong B, Song C, Ahn H (2010) The efficacy and safety of sunitinib in Korean patients with advanced renal cell carcinoma: high incidence of toxicity leads to frequent dose reduction. Jpn J Clin Oncol 40:980–985
Oh WK, McDermott D, Porta C, Levy A, Elaidi R, Scotte F, Hawkins R, Castellano D, Bellmunt J, Rha SY, Sun JM, Nathan P, Feinberg BA, Scott J, McDermott R, Ahn JH, Wagstaff J, Chang YH, Ou YC, Donnellan P, Huang CY, McCaffrey J, Chiang PH, Chuang CK, Korves C, Neary MP, Diaz JR, Mehmud F, Duh MS (2014) Angiogenesis inhibitor therapies for advanced renal cell carcinoma: toxicity and treatment patterns in clinical practice from a global medical chart review. Int J Oncol 44:5–16
Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337
Motzer RJ, Bukowski RM, Figlin RA, Hutson TE, Michaelson MD, Kim ST, Baum CM, Kattan MW (2008) Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer 113:1552–1558
Patil S, Figlin RA, Hutson TE, Michaelson MD, Négrier S, Kim ST, Huang X, Motzer RJ (2011) Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol 22:295–300
Santoni M, Santini D, Massari F, Conti A, Iacovelli R, Burattini L, Tortora G, Falconi M, Montironi R, Cascinu S (2013) Heterogeneous drug target expression as possible basis for different clinical and radiological response to the treatment of primary and metastatic renal cell carcinoma: suggestions from bench to bedside. Cancer Metastasis Rev. doi:10.1007/s10555-013-9453-5
Aziz SA, Sznol JA, Adeniran A, Parisi F, Kluger Y, Camp RL, Kluger HM (2013) Expression of drug targets in primary and matched metastatic renal cell carcinoma tumors. BMC Clin Pathol 13:3
Choudhury KR, Yagle KJ, Swanson PE, Krohn KA, Rajendran JG (2010) A robust automated measure of average antibody staining in immunohistochemistry images. J Histochem Cytochem 58:95–107
Jacobs TW, Prioleau JE, Stillman IE, Schnitt SJ (1996) Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer. J Natl Cancer Inst 88:1054–1059
Fergenbaum JH, Garcia-Closas M, Hewitt SM, Lissowska J, Sakoda LC, Sherman ME (2004) Loss of antigenicity in stored sections of breast cancer tissue microarrays. Cancer Epidemiol Biomark Prev 13:667–672
Ginsburg GS, McCarthy JJ (2001) Personalized medicine: revolutionizing drug discovery and patient care. Trends Biotechnol 19:491–496
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You, D., Song, S.H., Cho, Y.M. et al. Predictive role of tissue-based molecular markers in patients treated with sunitinib for metastatic renal cell carcinoma. World J Urol 33, 111–118 (2015). https://doi.org/10.1007/s00345-014-1295-4
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DOI: https://doi.org/10.1007/s00345-014-1295-4