Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications

Abstract

IntroductionTumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary.ResultsWhen controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways.Materials and MethodsResults of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer's exact test was used to compare the incidence of mutations in selected molecular pathways.ConclusionsWhen controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

“…Second, some mutations could be detected in both cfDNA and gDNA from tumor tissue using the ddPCR platform. In RCC patients, the concordance rate of genomic alterations between plasma and tumor tissue using NGS was 8.6%, likely as a result of the heterogeneity of tumor tissue . Ability of the ddPCR platform to detect rare mutations might overcome the disparities between mutant allele detection in cfDNA and gDNA from tumor tissue in our study.…”

“…In RCC patients, the concordance rate of genomic alterations between plasma and tumor tissue using NGS was 8.6%, likely as a result of the heterogeneity of tumor tissue. 42 Ability of the ddPCR platform to detect rare mutations might overcome the disparities between mutant allele detection in cfDNA and gDNA from tumor tissue in our study. These observations are of special importance as there is increasing interest toward integrating ctDNA applications into medical practice, and clinical practice will require precise, standardized methods to detect and characterize ctDNA.…”

Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients

“…Discordance observed between cfDNA and tumour tissue may be due to the subclonal presentation of drivers in the tumour in later stages of the disease, which can affect the detectability of these drivers in cfDNA and impact concordance rates [86]. A multitude of studies across the field of solid tumours (i.e., prostate, NSCLC, breast, neuroblastoma, renal, gastrointestinal, pancreatic, thyroid and melanoma) focus on individual ( Table 2) or multiple malignancies (Table 3) and report a trend for high agreement between cfDNA and tumour tissue with respect to actionable driver alterations, but with notable exceptions [70,[89][90][91][92][93][94]. In Tables 2 and 3, we have included studies that compare the extent to which cfDNA reflects driver and actionable driver alterations of the primary or metastatic tumours.…”

Cell-free Circulating Tumor DNA (ctDNA) in Metastatic Renal Cell Carcinoma (mRCC): Current Knowledge and Potential Uses

“…Some have hypothesized that liquid biopsy will more accurately reflect the genomic landscape of mRCC by capturing tumor heterogeneity. In a hypothesis-generating study of 19 patients with mRCC, we performed matched tumor tissue and liquid biopsy NGS to assess concordance, and whether a liquid biopsy was capable of detecting tumor heterogeneity [23]. When controlling for genomic segments tested by both platforms, we noted a low concordance (8.6%) in detected GAs between platforms, this may suggest that liquid biopsies are more capable of detecting tumor heterogeneity.…”