Luís Eduardo Zucca1, Mariana Andozia Morini Matushita2, Renato José da Silva Oliveira3, Cristovam Scapulatempo-Neto4, Marcos Alves de Lima5, Guilherme Gomes Ribeiro2, Cristiano Ribeiro Viana2, Flavio Mavignier Cárcano6, Rui Manuel Reis7. 1. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Department of Medical Oncology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. 2. Department of Pathology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. 3. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. 4. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. 5. Nucleous of Epidemiology and Statistics, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. 6. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Department of Medical Oncology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Barretos School of Health Sciences, Dr. Paulo Prata-FACISB, Barretos, São Paulo, Brazil. 7. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: ruireis.hcb@gmail.com.
Abstract
BACKGROUND: 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. OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: AXL expression was associated with worse clinical outcome and may be an important prognostic biomarker in sunitinib-treated patients with metastatic renal cell carcinoma.
BACKGROUND: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. OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: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. CONCLUSION:AXL expression was associated with worse clinical outcome and may be an important prognostic biomarker in sunitinib-treated patients with metastatic renal cell carcinoma.
Authors: Angelica M Gomes; Emily C Carron; Kylie L Mills; Alexa M Dow; Zane Gray; Christopher R Fecca; Meredith A Lakey; Peter Carmeliet; Frances Kittrell; Daniel Medina; Heather L Machado Journal: Oncogene Date: 2018-12-07 Impact factor: 9.867