Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma
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Javier Puente1, Nuria Laínez2, Marta Dueñas3,4, María José Méndez-Vidal5, Emilio Esteban6, Daniel Castellano4,7, Mónica Martinez-Fernández3,4, Laura Basterretxea8, María José Juan-Fita9, Luis Antón10, Luis León11, Julio Lambea12, Begoña Pérez-Valderrama13, Sergio Vázquez14, Cristina Suarez15, Xavier Garcia del Muro16, Enrique Gallardo17, José Pablo Maroto18, M Luz Samaniego19, Beatriz Suárez-Paniagua20, Julián Sanz21, Jesús M. Paramio3,4, SOGUG (Spanish Oncology Genitourinary Group)
1Medical Oncology Department, Instituto de Investigación Biomédica, Hospital Clínico Universitario San Carlos, Madrid, Spain
2Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
3Molecular Oncology Unit CIEMAT and Instituto Investigación Biomédica, Hospital Universitario 12 de Octubre, Madrid, Spain
5Medical Oncology Department, Hospital Universitario Reina Sofía, Córdoba, Spain
6Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
7Medical Oncology Department, and Instituto Investigación Biomédica, Hospital Universitario 12 de Octubre, Madrid, Spain
8Medical Oncology Department, Hospital Donostia, Donostia, Spain
9Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain
10Medical Oncology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
11Promoción e Planificación da Investigación Sanitaria, Axencia de Coñecemento en Saúde, Santiago de Compostela, Spain
12Medical Oncology Department, Hospital Clínico de Zaragoza, Zaragoza, Spain
13Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain
14Medical Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain
15Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d' Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
16Medical Oncology Department, Institut Català d’Oncologia, Hospital Duran i Reynals, L’Hospitalet, Barcelona, Spain
17Medical Oncology Department, Hospital Universitari Parc Taulí, Sabadell, Spain
18Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
19Statistical Department, Trial Form Support TFS people, Madrid, Spain
20Oncology Medical Department, Trial Form Support, Madrid, Spain
21Pathology Department, Hospital Clínico Universitario San Carlos, Madrid, Spain
Javier Puente, email: [email protected]
Keywords: sunitinib, metastatic renal cell carcinoma, biomarkers, long-term responders, primary refractory
Received: December 22, 2016 Accepted: February 24, 2017 Published: March 23, 2017
Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation.
Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS.
Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found.
Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response.
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