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Data from a Large Cohort of Patients with mRCC Demonstrate the Feasibility of ctDNA Analysis and High Concordance with Tissue Genomic Analysis

Identification of the most frequently mutated genes in metastatic renal cell carcinoma
21 Sep 2020
Genitourinary cancers;  Translational research

Circulating tumour DNA (ctDNA) is a minimally-invasive genomic assessment tool utilising targeted next-generation sequencing (NGS) of peripheral blood. Dr. Zeynep Zengin from the City of Hope Comprehensive Cancer Center in California has reported genomic results from the largest cohort of patients with metastatic renal cell carcinoma (mRCC) undergoing ctDNA assessment to date. In an oral presentation at the ESMO Virtual Congress 2020, Dr. Zengin reported that genomic alterations (GAs) are detected in ctDNA of a majority of patients with mRCC.

Sequencing of ctDNA in patients with mRCC provides clinically relevant genomic data in a high proportion of patients

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

Among the 600 male and 247 female patients with mRCC analyzed, ≥1 GAs 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.

Comparison of ctDNA and tissue DNA samples showed a high 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 NGS (Foundation Medicine) platform. These tissue test results included variants of unknown significance (VUS).

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 GAs were detected across both assays. Of these, 47 (29.7%) GAs were determined to be exclusive to blood, 90 (57.0%) as exclusive to tissue, and 21 (13.3%) GAs were found in both platforms (as shown on Figure). When only the alterations covered by the ctDNA panel were considered and patients who did not have GAs in their ctDNA panel were excluded, concordance of GAs between platforms increased to 22.6%. Exclusive mutations were more prominent when there was an increased time between the tissue and ctDNA testing events.

Data-from-a-Large-Cohort-of-Patients-with-mRCC-Demonstrate-the-Feasibility-of-ctDNA-Analysis-and-High-Concordance-with-Tissue-Genomic-Analysis-701O

Genomic alterations detected on both ctDNA and tissue-based sequencing platforms.

© Zeynep Zengin.  

Sequential ctDNA assessments reveal temporal evolution of mRCC

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 the course of time.

Conclusions

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

No external funding was reported for this study.

Reference

701O – Zengin ZB, Weipert C, Hsu J, et al. Assessment of circulating cell-free tumor DNA (ctDNA) in 847 patients (pts) with metastatic renal cell carcinoma (mRCC) and concordance with tissue-based testing. ESMO Virtual Congress 2020.

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