Association of Expression Levels or Activation Status of STAT3 with Treatment Outcomes of Sunitinib in Patients with Renal Cell Carcinoma
- 53 Downloads
The expression level of signal transducer and activator of transcription 3 (STAT3) in tumor cells is reported to associate with response to therapy and with survival time in various types of cancer.
This retrospective study aimed to elucidate the association of STAT3 expression in tumor cells with the therapeutic outcomes of sunitinib in patients with renal cell carcinoma (RCC).
Patients and Methods
Patients with metastatic RCC who received sunitinib therapy were enrolled in this study. All patients underwent nephrectomy for RCC, and nephrectomy specimens were stained for STAT3 and phosphorylated STAT3 (p-STAT3) by immunohistochemistry.
We assessed 51 patients receiving sunitinib as a first-line therapy. STAT3 expression levels did not influence progression-free survival (PFS) and overall survival (OS); however, patients with p-STAT3-positive tumors exhibited significantly worse PFS compared with those with p-STAT3-negative tumors (log-rank test, P = 0.034). OS tended to be prolonged in patients with p-STAT3-negative tumors. Objective response rate or disease control rate based on the best overall response did not show a significant association with STAT3 or p-STAT3 expression. Univariate Cox proportional hazard regression analyses for clinical predictors revealed that p-STAT3 positivity significantly correlated with shorter PFS (hazard ratio [HR], 2.22, P = 0.041), whereas p-STAT3 expression was not related to the OS.
Activated STAT3 in tumor tissues shows a significant association with poor prognosis in patients with RCC who received sunitinib as a first-line therapy, and positive p-STAT3 expression could be a potential biomarker for refractoriness to sunitinib therapy.
The authors would like to thank Enago (www.enago.jp) for the English language review.
Compliance with Ethical Standards
This work was supported in part by a research grant from Kurozumi Medical Foundation.
Conflict of Interest
H. Miyake and M. Fujisawa have received lecture fees from Pfizer. K. Yamamoto, T. Hara, T. Nakagawa, M. Hirai, and I. Yano declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
- 2.Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280–9. https://doi.org/10.1200/jco.2008.19.3342.CrossRefPubMedGoogle Scholar
- 8.Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res. 2011;17:2538–48. https://doi.org/10.1158/1078-0432.ccr-10-3314.CrossRefPubMedGoogle Scholar
- 15.Yamamoto K, Ioroi T, Kanaya K, Shinomiya K, Komoto S, Hirata S, et al. STAT3 polymorphism rs4796793 may be a predictive factor of tumor response to multiple tyrosine kinase inhibitors in metastatic renal cell carcinoma in Japanese population. Med Oncol. 2016;33:24. https://doi.org/10.1007/s12032-016-0733-0.CrossRefPubMedGoogle Scholar
- 23.Hrab M, Olek-Hrab K, Antczak A, Kwias Z, Milecki T. Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC). Rep Pract Oncol Radiother. 2013;18:304–9. https://doi.org/10.1016/j.rpor.2013.06.002.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Mizumoto A, Yamamoto K, Nakayama Y, Takara K, Nakagawa T, Hirano T, et al. Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to Sunitinib resistance in human renal cell carcinoma cell lines. J Pharmacol Exp Ther. 2015;355:152–8. https://doi.org/10.1124/jpet.115.226639.CrossRefPubMedGoogle Scholar
- 27.Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90. https://doi.org/10.1200/jco.2008.20.1293.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Uemura H, Shinohara N, Yuasa T, Tomita Y, Fujimoto H, Niwakawa M, et al. A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol. 2010;40:194–202. https://doi.org/10.1093/jjco/hyp146.CrossRefPubMedGoogle Scholar
- 29.Tomita Y, Shinohara N, Yuasa T, Fujimoto H, Niwakawa M, Mugiya S, et al. Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. Jpn J Clin Oncol. 2010;40:1166–72. https://doi.org/10.1093/jjco/hyq146.CrossRefPubMedGoogle Scholar
- 30.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;27:5794–9. https://doi.org/10.1200/jco.2008.21.4809.CrossRefPubMedGoogle Scholar
- 31.Bamias A, Karadimou A, Lampaki S, Lainakis G, Malettou L, Timotheadou E, et al. Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the memorial Sloan-Kettering prognostic factors model. BMC Cancer. 2010;10:45. https://doi.org/10.1186/1471-2407-10-45.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, et al. Adjuvant Sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2017; https://doi.org/10.1016/j.eururo.2017.09.008.
- 33.Park YH, Ku JH, Kwak C, Kim HH. Post-treatment neutrophil-to-lymphocyte ratio in predicting prognosis in patients with metastatic clear cell renal cell carcinoma receiving sunitinib as first line therapy. Springerplus. 2014;3:243. https://doi.org/10.1186/2193-1801-3-243.CrossRefPubMedPubMedCentralGoogle Scholar