Circulating tumor DNA (ctDNA) as a detection method for renal cell carcinoma (RCC) was investigated in a new review that summarizes evidence on ctDNA use and potential.
Because levels of circulating tumor DNA (ctDNA) are low in kidney cancer, very sensitive methods need to be utilized for its detection, report the authors of a new study published in European Urology Open Science. In particular, tumor-guided analysis facilitates the ctDNA detection rate and cell-free methylated DNA immunoprecipitation and high-throughput sequencing may be highly sensitive at detecting ctDNA.
“The presence of cell-free DNA in the bloodstream of patients and changes in the levels of these circulating nucleic acids are associated with tumor load and progression,” the authors wrote. “Over the past decade, there has been increasing interest in the potential of liquid biopsies and systematic biomarkers in the diagnosis and management of kidney cancer, as they may provide a tool for early detection of disease and monitoring of treatment response.”
RCC, they added, has been increasing most years, and its diagnosis and treatment can be extremely challenging because early-stage disease can be asymptomatic and metastatic disease does not respond well to radiotherapy or chemotherapy.
The authors’ review of studies from PubMed, MEDLINE, EMBASE, and Cochrane Library included findings published up to January 15, 2021. The final analysis encompassed 19 studies, 1237 patients with renal cell carcinoma (RCC), and data on sensitivity and specificity of ctDNA detection, method of ctDNA detection, and main study findings. These 19 studies covered 5 areas of ctDNA analysis, examining their advantages, downsides, and detection rates: tumor-guided plasma analysis, targeted sequencing of plasma, global sequencing of plasma, targeted methylation analysis of plasma, and global methylation analysis.
Tumor-guided plasma analysis has very high technical sensitivity in the face of known tumor mutations but does not identify new mutations. The overall ctDNA detection rate of the 5 included studies that used this method was 17% to 54%.
Targeted sequencing of plasma, because it does not require a tissue sample—sequencing is performed without prior analysis of tumor tissue DNA—is less invasive, marking an advantage to this method. In addition, the overall ctDNA detection rate of the 8 studies that used this method was between 19% and 100%, with total mutations in ctDNA showing high correlation with tumor burden. However, it is less sensitive than tumor-guided analysis.
Global sequencing of plasma, used by 2 studies, has low sensitivity for single-base mutations and is untargeted, but it also has high potential to detect large deletions and duplications and is inexpensive. Detection rates were 65% for RCC, pancreatic cancer, and glioma in one study and ranged from 23% to 33% in the second study. Optimization for this method is required, the authors noted.
Targeted methylation analysis of plasma using polymerase chain reaction, used by 5 studies, is inexpensive vs sequencing and has high specificity. However, because it analyzes few genes, ctDNA-negative results are possible when those genes lack mutations. Sensitivity is also low when comparing patients with cancer and healthy counterparts. More sensitive methods, as well as those that target larger genomic regions, might improve mutation detection for patients.
Global methylation analysis, a method that investigates epigenetic aberrations, provides more tumor-specific alterations, the authors noted. “Epigenetic alterations are more abundant than genetic alterations in RCC,” they said. Two of the 3 studies that used this method had ctDNA detection rates of 97% and 100%, with corresponding specificity rates of 100% and 88%. Detection in the third study, however, ranged from 12% to 21%, with specificities of 99.3% and 99.8% respectively. Larger studies are needed to validate this method, the authors determined.
Overall, ctDNA analysis for RCC has potential to overcome genetic heterogeneity, to provide prognostic information, and to identify genetic aberrations that lead to therapeutic resistance. However, its use in RCC needs to be investigated in more studies with larger patient populations, the authors concluded.
“The number of studies investigating ctDNA in RCC patients is still low and the number of patients included in these studies is limited, although larger studies have appeared in the past few years,” they wrote. “More studies are needed to determine the potential applications of ctDNA analysis in RCC and to improve methods for these applications.”
Geertsen L, Koldby KM, Thomassen M, Kruse T, Lund L. Circulating tumor DNA in patients with renal cell carcinoma: a systematic review of the literature.Eur Urol Open Sci. 2022;18;37:27-35. doi:10.1016/j.euros.2021.12.006