Background: The clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) and IO.
Methods: Consecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.
Results: 91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in (64%), (38%), (24%), (17%) and (12%). promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of promoter mutations and mutations were found to be mutually exclusive. While mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.
Conclusions: Our analysis found that promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with loss-of-function mutations.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359179 | PMC |
| http://dx.doi.org/10.1136/jitc-2020-000953 | DOI Listing |
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