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HIF pathway and c-Myc as biomarkers for response to sunitinib in metastatic clear-cell renal cell carcinoma

Authors Maroto P, Esteban E, Fernández Parra E, Mendez-Vidal MJ, Domenech M, Pérez-Valderrama B, Calderero V, Pérez-Gracia JL, Grande E, Algaba F

Received 22 March 2017

Accepted for publication 6 July 2017

Published 20 September 2017 Volume 2017:10 Pages 4635—4643

DOI https://doi.org/10.2147/OTT.S137677

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati

P Maroto,1 E Esteban,2 E Fernández Parra,3 MJ Mendez-Vidal,4 M Domenech,5 B Pérez-Valderrama,6 V Calderero,7 JL Pérez-Gracia,8 E Grande,9 F Algaba10

1Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, 2Department of Oncology, Nuevo HUCA, Oviedo, 3Department of Oncology, H. U. Nuestra Señora de Valme, Sevilla, 4Department of Oncology, H. U. Reina Sofía, Córdoba, 5Department of Oncology, Hospital de Althaia Xarxa Asistencial Manresa, Barcelona, 6Department of Oncology, H. U. Virgen del Rocio, Sevilla, 7Department of Oncology, H. Fundación Miguel Servet, Zaragoza, 8Department of Oncology, Clinica Universitaria de Pamplona, Pamplona, 9Department of Oncology, H. Ramón y Cajal, Madrid, 10Pathology Unit, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain

Background:
Clear-cell renal cell carcinoma (ccRCC) is a heterogeneous disease with a different clinical behavior and response to targeted therapies. Differences in hypoxia-inducible factor (HIF) expression have been used to classify von Hippel–Lindau gene (VHL)-deficient ccRCC tumors. c-Myc may be driving proliferation in HIF-2α-expressing tumors in a growth factor-independent manner.
Objective:
To explore the HIF-1α, HIF-2α and c-Myc baseline expression as potential predictors of sunitinib outcome as well as the effectiveness and safety with sunitinib in patients with metastatic ccRCC in routine clinical practice.
Methods:
This was an observational and prospective study involving 10 Spanish hospitals. Formalin-fixed, paraffin-embedded primary tumor samples from metastatic ccRCC patients who received sunitinib as first-line treatment were analyzed. Association between biomarker expression and sunitinib treatment outcomes was evaluated. Kaplan–Meier method was applied to measure progression-free survival (PFS) and overall survival.
Results:
Eighty-one patients were included: median PFS was 10.8 months (95% CI: 7.4–13.5 months), median overall survival was 21.8 months (95% CI: 14.7–29.8 months) and objective response rate was 40.7%, with 7.4% of patients achieving a complete response. Molecular marker staining was performed in the 69 available tumor samples. Significant association with lower PFS was identified for double c-Myc/HIF-2α-positive staining tumors (median 4.3 vs 11.5 months, hazard ratio =2.64, 95% CI: 1.03–6.80, P=0.036). A trend toward a lower PFS was found in positive c-Myc tumors (median 5.9 vs 10.9 months, P=0.263). HIF-1α and HIF-2α expression levels were not associated with clinical outcome.
Conclusion: These preliminary results suggest that predictive subgroups might be defined based on biomarkers such as c-Myc/HIF-2α. Further validation with more patients will be needed in order to confirm it. Outcomes with sunitinib in metastatic ccRCC in daily clinical practice resemble those obtained in clinical trials.

Keywords:
c-Myc, clear-cell renal cell carcinoma, HIF, sunitinib
 

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