Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy

Abstract

Considerable interest surrounds the use of immune-checkpoint inhibitors in patients with solid tumours following the demonstration of the impressive clinical efficacy of anti-programmed cell death protein 1 and anti-programmed cell death 1 ligand 1 antibodies in several tumour types. However, the emergence of unexpected tumour response patterns, such as pseudoprogression or hyperprogression, might complicate the management of patients receiving these agents. Analysis of circulating tumour DNA (ctDNA) has been shown to have prognostic value by enabling the detection of residual proliferating disease in the adjuvant setting and estimation of tumour burden in the metastatic setting, which are key stratification biomarkers for use of immune-checkpoint inhibition (ICI). Furthermore, examinations of ctDNA for genetic predictors of responsiveness to immunotherapy, such as mutations, tumour mutational load, and microsatellite instability provide a noninvasive surrogate for tumour biopsy sampling. Proof-of-concept reports have also demonstrated that quantitative changes in ctDNA levels early in the course of disease are a promising tool for the assessment of responsiveness to ICI that might complement standard imaging approaches. Other applications of this technology are also currently under investigation, such as early detection of resistance to immunotherapy and characterization of mechanisms of resistance. The aim of this Review is to summarize available data on the application of ctDNA in patients receiving immunotherapy and to discuss the most promising future directions.

Whole exome sequencing of cell-free DNA – A systematic review and Bayesian individual patient data meta-analysis

“…Goodall et al [21] demonstrated this discovery-capacity of WES by identifying frameshifts in germline and somatic DNA repair mutations as mechanisms of resistance to PARP inhibitors in prostate cancer. For estimation of TMB, large targeted sequencing panels can be used [48]. However when taking estimation of TMB by whole genome sequencing (WGS) as reference, 30% of patients were misclassifiedeither false negative or false positive -when targeted sequencing panels were used.…”

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

“…Predictive biomarkers can help identify patients who may respond to or develop resistance to specific therapies [67,68]. However, ctDNA has not been standardized as a biomarker, which means that the results of the ctDNA analysis may not be comparable due to technological differences [69]. To fully incorporate liquid biopsies into clinical practice, there is a glaring need to standardize methods, such as the way blood samples are collected and stored, the technical specifications of the assays, and ctDNA isolation [58,63,70,71].…”

“…Despite recent progresses, there are several important technical challenges to the wider use of ctDNA: insufficient knowledge of the tumor microenvironment and the immunologic response to ctDNA release in liquid biopsy samples; diagnostic tools must be further refined to detect small amounts of tumor-derived components in the circulation; the analytical sensitivity of sequencing methods must be increased [72]. In addition, ctDNA analysis is generally limited to fragments of DNA and requires a priori knowledge of specific DNA aberrations [60,69]. With the development of detection technology, a new ctDNA sampling technology is urgently needed to overcome the disadvantages of existing methods, such as high cost, slow speed, low sensitivity, and complexity.…”

Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in Non‐Small Cell Lung Cancer

“…The level of circulating tumor DNA (ctDNA), a surrogate of tumor burden, can be used to estimate clinical responses in patients receiving anti‐tumor treatment. [ 5–8 ] In a longitudinal assessment, the baseline concentration and early mutational dynamics of ctDNA were correlated with radiological and survival outcomes in response to ICB treatment in multiple solid tumor types. [ 9–15 ] Typically, commercially available panels for ctDNA mutation profiling cover a limited set of genes, such as known oncogenes, tumor suppressor genes, immune‐related genes, and other targets of actionability and/or research interest.…”