Intra-individual genomic diversity between circulating tumor cell-free DNA (cfDNA) and tumor tissue testing in metastatic renal cell carcinoma (mRCC).

Abstract

444 Background: Multiple approved targeted therapies are available for treatment of mRCC. Though some clinical trials guide treatment selection, there are many gaps without high-level evidence. Both tumor tissue and cfDNA based next-generation sequencing (NGS) testing are frequently performed to help guide treatment. Our objective was to assess type and number of genomic aberrations among tumor tissue and cfDNA. Methods: 14 sequential pts with both tissue and cfDNA NGS testing were selected and genomic profiles were compared. The total number of aberrations detected was statistically evaluated using comparison of the means. The Mann-Whitney test was used to compare the incidence of mutations in identified mutation pathways. Results: There was a discordance in the genetic aberrations detected among tumor versus cfDNA NGS tests, confirming intra-individual genetic diversity. Specifically, alterations in the DNA repair, PI3K, and epigenetic pathways were more common in tissue based testing (Table). Additionally, the median number of mutations identified was significantly lower for cfDNA based NGS testing (median 1.5) compared to tissue based NSG testing (median 10.0) (p < 0.0001). Conclusions: Discordance in the type of genomic aberrations in tissue versus cfDNA testing suggests intra-individual genetic diversity and may have implications in treatment selection when using these tests. Lower number of aberrations detected by the cfDNA testing may have occurred due to lower sensitivity of NGS by cfDNA compared to the tissue based NGS. The higher frequency of aberrations on tissue based testing suggests that tissue based testing should be used preferentially in clinical trials and practice. This data is hypothesis generating and needs further investigation in a larger cohort. [Table: see text]