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.
Highlights
The introduction of targeted therapy agents has significantly improved the overall survival of patients with metastatic renal cell carcinoma [1]
The aims of this study were (a) to identify typical miRNA profiles in nephrectomy specimens from two groups of metastatic renal cell carcinoma (mRCC) patients under first-line tyrosine kinase inhibitors (TKIs) treatment, (b) to explore the most discriminative miRNAs as predictive biomarkers of primary resistance to first-line TKI therapy by reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) using the sophisticated droplet digital PCR technique and (c) to validate the predictive capability using different evaluation approaches such as receiver-operating characteristic curve analysis (ROC), decision curve analysis and univariate and multivariate analyses in comparison to that for conventional clinicopathological variables
An area under the ROC curve (AUC) of 0.75 was defined as the required discrimination criterion considering a 2 to 1 ratio of responder to non-responder in the study cohort
Summary
The introduction of targeted therapy agents has significantly improved the overall survival of patients with metastatic renal cell carcinoma (mRCC) [1]. A recent large sunitinib global expanded-access trial with 3353 evaluated mRCC patients reported an objective response rate of approximately 20% (defined as the sum of complete and partial responses according to RECIST criteria) and a clinical benefit (sum of objective response plus stable disease ≥3 months) of approximately about. 20–30% of patients are primarily refractory to sunitinib treatment This phenomenon of non-responsiveness is termed primary or intrinsic resistance, in contrast to the secondary or acquired resistance that often develops after 6–15 months of treatment [7]. In both cases, the mechanisms are obviously multifactorial and have not yet been satisfactorily examined [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
