Predictive biomarkers for response to treatment with sunitinib in renal cancer patients
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Aims: Patients with metastatic or inoperable kidney cancer with positive biomarkers of vascular endothelial growth factor (VEGF) driven angiogenesis might have improved clinical benefit from treatment with an anti-VEGF-receptor kinase inhibitor. The primary goal in this study was to identify predictive markers of response in first line treatment with sunitinib against kidney cancer, and the secondary goal was to estimate response, proportion of patients with stable disease on treatment, time to progression, and survival. Material and methods: Forty-six patients with metastatic clear cell renal cell carcinoma (ccRCC) were enrolled in a prospective single-arm study of predictive markers for sunitinib response. In paper I, response rates according to RECIST v.1.1. were used as primary end- point. Secondary objectives were to evaluate prognostic value of candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life were reported. In paper II, we investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in metastatic ccRCC. Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumor tissue were stained by immunohistochemistry for selected markers related to angiogenesis (VEGF-A, VEGFR2, PDGFRβ, HSP27) and immune responses (IL6, IL6Rα, JAG1). The predictive potential of the candidate markers was assessed by correlations with response rates. In addition, PFS and OS were analyzed. In paper III, full blood samples were collected at baseline before start of sunitinib and after every second cycle of treatment during the study time. Markers of immune response (pIL6, pIL6Rα and pIL6ST) at baseline and week 12 were analyzed by ELISA. The predictive potential of the candidate markers was assessed by correlation with response rates. In addition, PFS and OS were analyzed. Results: Paper I: Median PFS and OS were 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (Fisher’s exact test, p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and < 0.01, respectively). Early hypertension, neutrophil-to-lymphocyte ratio (NLR) and IMDC risk score were not significantly associated with response rates or survival. Paper II: Low tumor cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher’s exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF-A and HSP27. Furthermore, low tumor cell expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF- A, VEGFR2 and PDGFRβ. Paper III: Low pIL6 at baseline was significantly associated with improved response to sunitinib (Fisher's exact test, p < 0.01). Furthermore, low pIL6 at baseline was significantly associated with improved PFS (Log rank, p = 0.04). In addition, patients with a decrease in concentration of pIL6Rα between baseline and week 12 showed significantly improved PFS (Log rank, p = 0.04) and patients with high pIL6ST at baseline showed significantly improved OS (Log rank, p = 0.03). Conclusion: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of metastatic ccRCC. Loss of tumor cell expression of IL6Rα in patients with metastatic ccRCC patients treated with sunitinib predicts improved treatment response. Low pIL6 at baseline in metastatic ccRCC patients treated with sunitinib predicts improved treatment response. Both might represent candidate predictive markers. Because of the relatively small sample size, the results need validation in larger studies.
Has partsPaper I: Pilskog, M., Beisland, C., Akslen, L.A., Bostad, L., Haug, Å., Heinrich, D., Hjelle, K.M., Straume, O. (2017): “Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.” BMC Urology 17:74. The article is available in the main thesis. The article is also available at: https://doi.org/10.1186/s12894-017-0267-6.
Paper II: Pilskog, M., Bostad, L., Edelmann, R.J., Akslen, L.A., Beisland, C., Straume, O. (2018): «Tumor cell expression of Interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.” J Pathol Clin Res. 2018 Apr;4 (2):114-123. The article is available in the main thesis. The article is also available at: https://doi.org/10.1002/cjp2.96.
Paper III: Pilskog, M., Nilsen, G.H., Beisland, C. and Straume, O. (2019). "Elevated plasma interleukin 6 predicts poor response in patients treated with sunitinib for metastatic clear cell renal cell carcinoma." Cancer Treat Res Commun 19: 100127. The article is available in the main thesis. The article is also available at: https://doi.org/10.1016/j.ctarc.2019.100127.