Abstract
INTRODUCTION – Circulating tumor DNA (ctDNA) sequencing complements tissue-based next-generation sequencing (NGS), offering noninvasive and serial testing. We explore the mutational landscape of renal cell carcinoma (RCC) using matched tissue and ctDNA data to assess complementarity and clinical significance of molecular alterations.

METHODS – From the Tempus multimodal database, we retrospectively analyzed de-identified data from patients with RCC with concurrent tissue (Tempus xT) and ctDNA testing (Tempus xF). Patients with xT and xF matched samples (collected +/- 90 days of one another) were included. We evaluated socio-demographic and clinical characteristics and selected pathogenic somatic short variants (PSSVs) and copy number variants (CNV). Analyses were restricted to the 104 genes shared by all assays.

RESULTS – Among 392 patients, 66% (n = 259) had metastatic disease. The median time from tissue to blood collection was 21 days. The most common tissue sites were kidney (49%, n = 189) and bone (11%, n = 43). Frequently altered tissue-tested genes were: VHL (59%), PBRM1 (32%), and SETD2 (23%). Most frequently altered genes in ctDNA were TP53 (23%), VHL (18%), BAP1 (6%), and PBRM1 (5%); notably, 176 patients did not have any pathogenic or likely pathogenic variants detected in the 104 genes analyzed. Complementary ctDNA and tissue testing detected 6% more alterations than tissue testing alone, with greater concordance in metastatic cases.

CONCLUSION – ctDNA testing offers complementary insights to tissue NGS in RCC, particularly in metastatic disease, suggesting the potential utility of ctDNA in advanced RCC. Longitudinal analysis may enhance delineation of biomarkers of response and resistance at mutation and ctDNA fraction levels.

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