Clear cell renal cell carcinoma (ccRCC) is the most common presentation of kidney cancer. The emergence of several approved targeted agents over the past 10 years has significantly improved outcomes in this patient population; however, according to Lucia Nappi, MD, PhD, and colleagues, treatment optimization has been hampered by the lack of predictive biomarkers. In other tumors, circulating tumor DNA (ctDNA) has proven to be an effective and minimally invasive alternative to tissue for profiling tumor genome.
Blood samples from patients with metastatic ccRCC were collected for next-generation sequencing of cell free DNA and germline DNA. The Roche Human Oncology Design panel of 981 genes to a median depth of 937x unique reads was used to perform targeted. Matched formula-fixed paraffin-embedded (FFPE) tissue was available from 14 patients and profiled using the same assay. Results were reported in conjunction with the ASCO 2019 Annual Meeting in an abstract titled Detection of Circulating Tumor DNA in Patients with Metastatic Clear Cell Renal Cell Carcinoma.
The researchers analyzed samples from 52 metastatic, treatment-naïve patients. Germline mutations were detected in 11% (n=6/52) of the patients. The most frequent abnormalities affected ATM, PALB2, RAD51D, CHEK2, BRCA1. Median ctDNA fraction was 3.9% (range, 2% to 40%), with a median of two mutations per patient. Somatic mutations were detected in 56% (n=29/52) of the samples. Of those, 51% (n=15/29) of the patients harbored RCC-related genes mutations; 10% (n=3/29) had non-coding mutations; and 34% (n=10/29) had alterations in non RCC-associated genes.
Median variant allele frequency was 1.9% (range, 1% to 22%). The most frequently altered genes were VHL, BAP1, PBRM1, and TP53, consistent with tissue-based reports. A fully concordant mutation profile was shared in 50% of the patient-matched FFPE tissue samples.
The researchers said, “We confirmed a high prevalence of germline mutations in patients with ccRCC. The rate of ctDNA detection in metastatic ccRCC appears to be lower than in other metastatic solid tumors. Furthermore, it is not yet clear whether all the detected somatic alterations are strictly ccRCC-ctDNA dependent. Nevertheless, a quarter of patients exhibited clinically informative ccRCC associated alterations in their liquid biopsy. These findings suggest that ctDNA is a promising tool for genomic profiling in a subset of patients with metastatic ccRCC.”
Source: Nappi L, Bacon J, Annala M, et al. Detection of circulating tumor DNA in patients with metastatic clear cell renal cell carcinoma. Abstract published in conjunction with the American Society of Clinical Oncology 2019 Annual Meeting, May 31-June 4, 2019, Chicago, Illinois.