miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

Abstract

Approximately 20–30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment.

Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy

“…Thus, all these expression particularities and further the characteristics of uncorrelated differential expression in relation to conventional clinicopathological factors are specific for orthogonal biomarkers [47]. Consequently, new information can arise from the application of such biomarkers in clinical practice [48]. Indeed, multivariate Cox regression analysis showed that the RNA signatures developed with circEGLN3, circRHOBTB3, and linRHOBTB3 proved their hypothesized prognostic value for all three clinical endpoints (Table 5).…”

MiR-376b-3p Is Associated With Long-term Response to Sunitinib in Metastatic Renal Cell Carcinoma Patients

“…Successful independent validation of potentially predictive miRNAs remains a challenge. Overlap of results is rare in published studies of miRNAs as predictors of response to sunitinib in mRCC (8,(28)(29)(30). This could be partly due to tumor heterogeneity, various technologies used for miRNA analysis, limited numbers of enrolled patients, and failure to include a validation cohort.…”

Circular RNAs and Their Linear Transcripts as Diagnostic and Prognostic Tissue Biomarkers in Prostate Cancer after Prostatectomy in Combination with Clinicopathological Factors

“…In contrast, this expression of RNAs mostly independent from clinicopathological variables and the other mentioned particular correlations is a key characteristic of orthogonal biomarkers [ 96 ]. Biomarkers of this kind are a real prerequisite for gaining information additional to that derived from established variables and for improving, for example, the prediction accuracy of a clinical outcome endpoint [ 97 ].…”