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

作者：Maroto P^*; Esteban E; Fernandez Parra E; Mendez Vidal M J; Domenech M; Perez Valderrama B; Calderero V; Perez Gracia J L; Grande E; Algaba F

来源：OncoTargets and Therapy, 2017, 10: 4635-4642.

DOI：10.2147/OTT.S137677

• c-Myc
• clear-cell renal cell carcinoma
• HIF
• sunitinib

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-2 alpha-expressing tumors in a growth factor-independent manner.
Objective: To explore the HIF-1 alpha, HIF-2 alpha 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-2 alpha-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-1 alpha and HIF-2 alpha 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-2 alpha. 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.

• 出版日期2017