1. Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma
- Author
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María José Méndez-Vidal, Luis León, Xavier Garcia del Muro, Cristina Suarez, Mónica Martínez-Fernández, Jesús M. Paramio, Sogug, Enrique Gallardo, María Jose Juan-Fita, Laura Basterretxea, Marta Dueñas, Begoña Perez-Valderrama, Emilio Esteban, Daniel Castellano, Beatriz Suarez-Paniagua, Javier Puente, Nuria Lainez, Julio Lambea, Julián Sanz, M. Luz Samaniego, Sergio Vázquez, Luis Antón, and J. P. Maroto
- Subjects
Male ,0301 basic medicine ,Oncology ,Indoles ,sunitinib ,Kaplan-Meier Estimate ,urologic and male genital diseases ,primary refractory ,Càncer de ronyó ,Metastasis ,0302 clinical medicine ,Renal cell carcinoma ,Molecular Targeted Therapy ,Hematology ,Sunitinib ,Biochemical markers ,Prognosis ,Renal cancer ,030220 oncology & carcinogenesis ,Cohort ,Marcadors bioquímics ,Female ,Signal Transduction ,Research Paper ,medicine.drug ,medicine.medical_specialty ,Antineoplastic Agents ,macromolecular substances ,metastatic renal cell carcinoma ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Mortalitat ,Humans ,Pyrroles ,Mortality ,Carcinoma, Renal Cell ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Gene Expression Profiling ,biomarkers ,Retrospective cohort study ,Biomarker ,medicine.disease ,MicroRNAs ,Clear cell renal cell carcinoma ,030104 developmental biology ,ROC Curve ,Drug Resistance, Neoplasm ,long-term responders ,business ,Progressive disease - Abstract
[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. PPfizer; SOGUG-2011-05 Ministerio de Economía, Industria y Competitividad; SAF2015-66015-R Ministerio de Economía, Industria y Competitividad; ISCIII-RETIC RD12/0036/0009 Ministerio de Economía, Industria y Competitividad; PIE 15/00076
- Published
- 2017