Expression of tyrosine kinase receptor AXL is associated with worse outcome of metastatic renal cell carcinomas treated with sunitinib

• Published in: Urologic oncology 2018-01, Vol.36 (1), p.11.e13-11.e21
• Main Authors: Zucca, Luís Eduardo, Morini Matushita, Mariana Andozia, da Silva Oliveira, Renato José, Scapulatempo-Neto, Cristovam, de Lima, Marcos Alves, Ribeiro, Guilherme Gomes, Viana, Cristiano Ribeiro, Cárcano, Flavio Mavignier, Reis, Rui Manuel
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; AXL; Cabozantinib; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; Female; Humans; Immunohistochemistry - methods; Indoles - pharmacology; Indoles - therapeutic use; Male; Middle Aged; Neoplasm Metastasis; Prognostic biomarker; Pyrroles - pharmacology; Pyrroles - therapeutic use; Receptor Protein-Tyrosine Kinases - metabolism; Renal cell carcinoma; Sunitinib; Treatment Outcome
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2017.09.003

Renal cell carcinoma (RCC) represents 2%–3% of all cancers of the Western countries. Currently, sunitinib, a receptor tyrosine kinase inhibitor, particularly of PDGF and VEGF receptors, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, others and our group suggested that the receptor tyrosine kinase AXL may modify the response to sunitinib. To study the expression of AXL in a series patients with of mRCC treated with sunitinib and to correlate it with patient's clinic-pathological features and therapeutic response. Sixty-four patients with mRCC (51 clear cell carcinomas (CCCs) and 13 non-CCCs) were evaluated for AXL expression by immunohistochemistry in the primary tumor. AXL positivity was observed in 47% (30/64) of cases, namely in 43% (22/51) of CCCs and 61% (8/13) of non-CCC. Considering only the clear cell subtype, the univariate analysis showed that AXL expression was statistically associated with a poor prognosis, with a median overall survival of 13 months vs. 43 months in patients with negative AXL. In this subtype, along with the AXL positivity, other prognostic factors were absence of nephrectomy, Karnofsky performance status, more than 1 site of metastasis and liver metastasis. Moreover, AXL expression was associated with shorter progression to sunitinib. Overall, the multivariate survival analysis showed that absence of nephrectomy (HR = 4.85, P = 0.001), more than 1 site of metastasis (HR = 2.99, P = 0.002), bone metastasis (HR = 2.95, P = 0.001), together with AXL expression (HR = 2.01, P = 0.048) were independent poor prognostic factor in patients with mRCC. AXL expression was associated with worse clinical outcome and may be an important prognostic biomarker in sunitinib-treated patients with metastatic renal cell carcinoma. •AXL is overexpressed in approximately half of metastatic renal cell carcinomas (mRCC).•In mRCC, AXL overexpression is an independent poor prognostic factor, together with absence of nephrectomy, KPS less than 70, more than one site of metastasis, and presence of bone and liver metastasis.•AXL overexpression is associated with shorter progression to sunitinib in mRCC.•AXL expression is a prognostic biomarker in sunitinib-treated patients with mRCC, and could also constitute a predictive biomarker of new and effective anti-AXL drugs, such as cabozantinib.