Circulating tumor DNA (ctDNA) analysis is a minimally invasive genomic assessment tool utilizing targeted next-generation sequencing of peripheral blood. At the ESMO Virtual Congress 2020, Zengin et al reported genomic results from a large cohort of patients with metastatic renal cell carcinoma undergoing ctDNA assessment (Abstract 701O). According to the analysis, genomic alterations were detected in the ctDNA of a majority of patients.

ctDNA Analysis

A total of 847 consecutive patients with metastatic renal cell carcinoma underwent ctDNA testing using a clinically validated, commercially available 73- to 74-gene panel (Guardant360). This targeted next-generation sequencing assay included analysis of sequence alterations, small insertions/deletions, amplifications, and fusions.

Among the 600 male and 247 female patients with metastatic renal cell carcinoma analyzed, one or more genomic alterations were detected in 78.8% of ctDNA samples. The ctDNA analysis identified TP53 (37%), VHL (22%), and EGFR (6%) as the most frequently altered genes. DNA damage repair alterations were seen in approximately 6% of patients, and alterations in the mTOR pathway—including PTEN, PIK3CA, and NF1—were also commonly reported.

Cumulative Concordance Rate

Further analysis compared the ctDNA genomic profile to tissue-based sequencing approaches in a subset of this cohort. Tissue-based genomic testing was performed on archived tissue using either a whole-exome sequencing platform (Ashion Analytics) or targeted next-generation sequencing (Foundation Medicine) platform. These tissue test results included variants of unknown significance.

In tissue DNA analysis of 46 patients, VHL (63.8%), PBRM1 (44.7%), and SETD2 (31.9%) emerged as the most frequently mutated genes; PBRM1 and SETD2 were not included in the ctDNA assay. The median time between tissue and ctDNA assays was 15 months.

The cumulative concordance rate between ctDNA and tissue DNA samples was 96.2%. When analysis was restricted to the genes included in both the ctDNA and tissue DNA assays, 158 genomic alterations were detected across both assays. Of these, 47 (29.7%) genomic alterations were determined to be exclusive to blood, 90 (57.0%) as exclusive to tissue, and 21 (13.3%) were found in both platforms. When only the alterations covered by the ctDNA panel were considered and patients who did not have alterations in their ctDNA panel were excluded, concordance of genomic alterations between platforms increased to 22.6%. Exclusive mutations were more prominent when there was an increased time between the tissue and ctDNA testing events.

Sequential ctDNA assessment was also performed in 39 patients. Results of this analysis showed that there was an increased frequency of mutation in EGFR and PTEN over time.

Findings from this study demonstrated that ctDNA analysis is highly concordant with tissue-based sequencing approaches in patients with metastatic renal cell carcinoma. The researchers noted that ctDNA is a useful minimally invasive approach for revealing potentially actionable mutations in metastatic renal cell carcinoma, including mutations in VEGF, DNA damage repair mechanisms, and the mTOR signaling pathway. Exclusive alterations found on both ctDNA and tissue-based sequencing platforms suggest an evolution of metastatic renal cell carcinoma tumors over time and treatment course, which may be useful in guiding treatment sequence for patients.

Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org.