4565 Background: Circulating tumor DNA (ctDNA) assessment is a non-invasive approach for genomic interrogation of solid tumors. As a novel tool, key benchmarks for applications in metastatic clear cell renal cell carcinoma (mccRCC) are yet to be determined. To understand the utility of ctDNA, we performed a large cohort analysis using a comparative genomics approach integrating matched primary tissue and ctDNA genomic data. Methods: Pts with prior tumor mutational profiles generated via next generation sequencing (NGS) from nephrectomy or metastatic specimens underwent single-time point plasma collection. Targeted NGS sequencing with MSK-IMPACT was performed on tumor and ctDNA with subsequent bi-directional cross genotyping using Waltz 2.0. All pts had matched germline comparison from peripheral blood; clinical data was extracted from medical record. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of < 30% allele frequency to remove germline mutations. Results: 111 mccRCC pts, of whom available IMDC-risk was favorable (35%), intermediate (60%), and poor-risk (5%) were included for analysis. The median time between tissue and ctDNA collection was 23 months (R: 1-177), and 96% of patients had undergone nephrectomy prior to ctDNA collection. In primary tissue sequencing, 64/111 (58%) from nephrectomy and 42/111 (42%) from metastatic sites, 569 unique alterations were identified across the whole cohort, with a median of 4 mutations/pt (R:1-23). RCC-specific alterations included VHL (88%), PBRM1 (48%), SETD2 (34%), KDM5C (17%), TP53 (14%). Across the cohort, 176 alterations were identified in ctDNA. With cross genotyping, ctDNA alterations concordant with primary tumors were detected in 20% (22/111 pts, 28 unique alterations) using stringent criteria with a median of 1 mutation/pt (R:1-2). Using liberal criteria, concordance with primary tumors was 59% (66/111 pts, 142 unique alterations) with a median of 2 mutations/pt (R: 1-8). Conclusions: This large cohort study matching oncogenomics from tumor and ctDNA highlights complexities and challenges of applying liquid biopsy in biomarker development in mccRCC.
MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors