Abstract
Sorafenib is a tyrosine kinase inhibitory drug with multiple molecular specificities that is approved for clinical use in second-line treatments of metastatic and advanced renal cell carcinomas (RCCs). However, only 10–40% of RCC patients respond on sorafenib-containing therapies, and personalization of its prescription may help in finding an adequate balance of clinical efficiency, cost-effectiveness, and side effects. We investigated whether expression levels of known molecular targets of sorafenib in RCC can serve as prognostic biomarker of treatment response. We used Illumina microarrays to profile RNA expression in pre-treatment formalin-fixed paraffin-embedded (FFPE) samples of 22 metastatic or advanced RCC cases with known responses on next-line sorafenib monotherapy. Among them, nine patients showed partial response (PR), three patients—stable disease (SD), and 10 patients—progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. We then classified PR + SD patients as “responders” and PD patients as “poor responders”. We found that gene signature including eight sorafenib target genes was congruent with the drug response characteristics and enabled high-quality separation of the responders and poor responders [area under a receiver operating characteristic curve (AUC) 0.89]. We validated these findings on another set of 13 experimental annotated FFPE RCC samples (for 2 PR, 1 SD, and 10 PD patients) that were profiled by RNA sequencing and observed AUC 0.97 for 8-gene signature as the response classifier. We further validated these results in a series of qRT-PCR experiments on the third experimental set of 12 annotated RCC biosamples (for 4 PR, 3 SD, and 5 PD patients), where 8-gene signature showed AUC 0.83.
Highlights
Specialty section: This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal
All patients enrolled in this study have previously signed written informed consents to participate in the observational clinical investigation, and for publication of depersonalized molecular profiles and study results in the form of gene activity profiles associated with age, sex, and results of sorafenib monotherapy treatment estimated according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria (Eisenhauer et al, 2009)
47 renal cell carcinomas (RCCs) patients were enrolled in this study (21 female and 26 male patients, age range 41–74, mean 58 y.o.)
Summary
Specialty section: This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal. We found that gene signature including eight sorafenib target genes was congruent with the drug response characteristics and enabled high-quality separation of the responders and poor responders [area under a receiver operating characteristic curve (AUC) 0.89] We validated these findings on another set of 13 experimental annotated FFPE RCC samples (for 2 PR, 1 SD, and 10 PD patients) that were profiled by RNA sequencing and observed AUC 0.97 for 8-gene signature as the response classifier. Several RCC sorafenib resistance biomarkers were identified by RNA expression assays in drug responder and non-responder tumors: long non-coding Despite those important observations, no diagnostic settings were constructed to predict effectiveness of sorafenib for RCC patients
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