Portal de Periódicos da CAPES

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

2017; Impact Journals LLC; Volume: 8; Issue: 18 Linguagem: Inglês

10.18632/oncotarget.16494

1949-2553

Javier Puente, Núria Laínez, Marta Dueñas, María José Méndez-Vidal, Emilio Esteban, Daniel Castellano, Mónica Martínez‐Fernández, Laura Basterretxea, María José Juan-Fita, Luis Antón, Luís León, J. Lambea, Begoña Pérez-Valderrama, Sergio Vázquez‐Estévez, Cristina Suárez, Xavier García del Muro, Enrique Gallardo, Pablo Maroto, M Luz Samaniego, Beatriz Suárez-Paniagua, Julián Sanz‐Ortega, Jesús M. Paramio,

Cancer Genomics and Diagnostics

// Javier Puente 1 , Nuria Laínez 2 , Marta Dueñas 3, 4 , María José Méndez-Vidal 5 , Emilio Esteban 6 , Daniel Castellano 4, 7 , Mónica Martinez-Fernández 3, 4 , Laura Basterretxea 8 , María José Juan-Fita 9 , Luis Antón 10 , Luis León 11 , Julio Lambea 12 , Begoña Pérez-Valderrama 13 , Sergio Vázquez 14 , Cristina Suarez 15 , Xavier Garcia del Muro 16 , Enrique Gallardo 17 , José Pablo Maroto 18 , M Luz Samaniego 19 , Beatriz Suárez-Paniagua 20 , Julián Sanz 21 , Jesús M. Paramio 3, 4 , SOGUG (Spanish Oncology Genitourinary Group) 1 Medical Oncology Department, Instituto de Investigación Biomédica, Hospital Clínico Universitario San Carlos, Madrid, Spain 2 Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain 3 Molecular Oncology Unit CIEMAT and Instituto Investigación Biomédica, Hospital Universitario 12 de Octubre, Madrid, Spain 4 CIBERONC, Spain 5 Medical Oncology Department, Hospital Universitario Reina Sofía, Córdoba, Spain 6 Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain 7 Medical Oncology Department, and Instituto Investigación Biomédica, Hospital Universitario 12 de Octubre, Madrid, Spain 8 Medical Oncology Department, Hospital Donostia, Donostia, Spain 9 Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain 10 Medical Oncology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain 11 Promoción e Planificación da Investigación Sanitaria, Axencia de Coñecemento en Saúde, Santiago de Compostela, Spain 12 Medical Oncology Department, Hospital Clínico de Zaragoza, Zaragoza, Spain 13 Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain 14 Medical Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain 15 Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d' Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain 16 Medical Oncology Department, Institut Català d'Oncologia, Hospital Duran i Reynals, L'Hospitalet, Barcelona, Spain 17 Medical Oncology Department, Hospital Universitari Parc Taulí, Sabadell, Spain 18 Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 19 Statistical Department, Trial Form Support TFS people, Madrid, Spain 20 Oncology Medical Department, Trial Form Support, Madrid, Spain 21 Pathology Department, Hospital Clínico Universitario San Carlos, Madrid, Spain Correspondence to: Javier Puente, email: javier.puente@salud.madrid.org Keywords: sunitinib, metastatic renal cell carcinoma, biomarkers, long-term responders, primary refractory Received: December 22, 2016 Accepted: February 24, 2017 Published: March 23, 2017 ABSTRACT 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.