In this scenario the receptor tyrosine kinase inhibitors TKI

In this scenario, the receptor tyrosine kinase inhibitors (TKI), sunitinib, an anti-angiogenic agent, was tested in phase III trial, leading to a longer progressing free survival when compared to interferon (median: 11 vs. 5mo, respectively, hazard ratio (HR) = 0.42; 95% CI: 0.32–0.54; P<0.001) and an improved overall survival (OS) (median 26.4 vs. 21.8mo, HR = 0.82, 95% CI: 0.673–1.001, P = 0.051) [8], [9]. Consequently, sunitinib was approved and established as a standard of care in the treatment of advanced RCC worldwide [5], [10], [11], [12]. Despite of this rational, TKIs rarely cause durable tumor regressions and most patients will experience disease progression after an initial period of response [13]. Remarkable efforts are being made to identify biomarkers that may predict response to select and treat more effectively patients with metastatic RCC (mRCC) [14]. AXL, a gene that encodes a receptor tyrosine kinase, is involved with a wide variety of cancerous hallmarks such as proliferation, survival, evasion from apoptosis, enhanced angiogenesis, and invasiveness [15], [16]. Recently, AXL have been suggested as a biomarker of poor prognosis and a potential target for different types of cancers [17], [18], including RCC [19], [20]. Previously, our group suggested that in glioblastoma cell lines, AXL can constitute a predictive biomarker for sunitinib response [21], [22]. In this study, we evaluated the AXL presence in the primary tumor through its TTP 22 receptor in a cohort of 64 patients with mRCC treated with sunitinib and its association with clinical-pathological features and clinical outcome.
Materials and methods
Results
Discussion Despite the advanced systemic treatment in mRCC in the past 10 years and the multiples drugs available [5], [12], treatment decision is based in medical expertise rather than in objective predictive biomarkers [30]. With the in vitro evidences that tyrosine kinase AXL expression can be a predictive biomarker to sunitinib [21], our group investigated in the present study whether AXL overexpression in tumor renal tissue is associated with response rate in mRCC patients treated with sunitinib. We analyzed 64 patients with mRCC treated with sunitinib. Demographic parameters and OS were similar with previous studies [23], [31]. We could not correlate increased expression AXL with tumor response to sunitinib. However, we observed that AXL positivity in kidney cancer tissue is associated with shorter survival and a lack of response to the treatment. AXL overexpression in tumor tissue has been associated with poor prognoses in a variety of cancers, probably because its involvement in various aspects of cellular signaling and it is implication in a wide variety of hallmarks of cancer [16]. Recent reports showed that high tumor AXL was an independent prognostic factor in patients with RCC [32], [33]. Gustafsson et al. [32] in 2009, reported the tumor Axl mRNA was as an independent prognostic factor in cancer-specific survival, and Rankin et al. [33] in 2015 analyzed AXL expression in human RCC tissue within The Cancer Genome Atlas (TCGA) and samples with strong AXL expression was associated patients with reduced survival compared with patients whose samples had weak AXL expression. Our report, represents the first association of AXL positivity by immunohistochemistry with reduced survival in patients with mRCC treated with sunitinib. AXL has been suggested to promote both intrinsic and acquired resistance to different treatments, from chemotherapy to molecular targets [15]. In RCC xenograft models upregulation of AXL and MET showed resistance to long-term sunitinib therapy, as well as resensitisation to sunitinib after AXL and MET inhibition via treatment with the TKI cabozantinib [34]. Cabozantinib has been demonstrated efficacy in 2 trials in mRCC [35], [36]. A large phase III trial demonstrated that cabozantinib increased OS, delayed disease progression, and improved the objective response compared with everolimus after failing one or more anti-VEGF [35]. Recently cabozantinib was compared to sunitinib in first-line therapy in intermediated and poor risk IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group patients and was observed that cabozantinib had benefit in progression-free survival and overall response rate over sunitinib [36]. None of these 2 trials used a biomarker for predictive response to therapy. Despite of a variety promising new drugs emerging in the scenario of first-line therapy of mRCC, sunitinib might still have its place in some patients, namely in those cases with lack of AXL expression.