Despite the recent implementation of novel targeted therapies, the 5-year survival rate for metastatic renal cell carcinoma (mRCC) remains dismal. Prognostic and predictive biomarkers are urgently required to avoid unnecessary patient morbidity and financial toxicity. Exploratory studies leveraging archival primary tumor tissue are considered suboptimal in this setting due to the considerable heterogeneity of metastatic lesions. Circulating tumor DNA (ctDNA) permits the noninvasive characterization of metastatic cancers using a simple blood draw. In this study, we sought to establish the utility of a ctDNA-based assay as a tool to profile the somatic genome of patients with mRCC. We collected whole blood from 55 progressing mRCC patients. All patients were systemic therapy naïve at the time of sample collection. Plasma cell-free DNA (cfDNA) and matched leukocyte DNA were subjected to targeted sequencing across 981 cancer-associated genes. Matched tumor tissue from 14 patients was also analyzed. The median cfDNA sequencing depth for this cohort was 938x. 33% of patients had evidence for RCC-derived ctDNA above 1% of total cfDNA; this was significantly lower than prostate or bladder cancer patients analyzed using the same approach. Among ctDNA-positive patients, ctDNA fraction averaged only 3.9% and showed no association with clinical variables or cfDNA yield. In these patients, the most commonly mutated genes were VHL, BAP1, and PBRM1, and matched tissue concordance was 77%. Evidence of somatic expansions unrelated to RCC, such as clonal hematopoiesis of indeterminate potential (CHIP), was detected in 43% of patients. Pathogenic germline mutations in DNA repair genes were detected in 11% of patients. Patients with ctDNA above 1% had shorter overall survival and progression-free survival on first-line therapy. Patients with evidence of CHIP but not ctDNA had an intermediate prognosis compared to ctDNA-positive and ctDNA-negative patients. CfDNA sequencing enables characterization of the somatic RCC genome in only a minority of metastatic RCC patients. Due to low ctDNA abundance and presence of non-RCC derived somatic clones in circulation, cfDNA sequencing may not be a simple pan-patient alternative to tissue biopsy in metastatic RCC.

Citation Format: Jack V. W. Bacon, Matti Annala, Maryam Soleimani, Jean-Michel Lavoie, Alan I. So, Martin E. Gleave, Ladan Fazli, Kim N. Chi, Christian K. Kollmannsberger, Alexander W. Wyatt, Lucia Nappi. Plasma circulating tumor DNA is scarce and confounded by clonal hematopoiesis in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A18.

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.