Circulating tumor DNA: current challenges for clinical utility

Abstract

Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.

Real-life disease monitoring in follicular lymphoma patients using liquid biopsy ultra-deep sequencing and PET/CT

“…The minimum quantity of cfDNA sequenced was 15ng. Considering that a genome equivalent (GE) has a mass of 3pg (31), 15ng is enough to screen 5,000GE and therefore achieve a sensitivity of 2 • 10 − 4 VAF (0.02%). In addition, ve samples with less than 15ng of cfDNA but high disease burden and positive MRD value were included in the study.…”

Circulating Histones to Detect and Monitor the Progression of Cancer

“…Circulating tumor DNA liquid biopsy has been studied most extensively in patients with established metastatic disease and has been applied in some routine clinical applications using next-generation sequencing (NGS) technologies [ 1 , 2 ]. Very often, tumors are characterized by specific genetic mutations: ctDNA assays revolutionized the field, being able to routinely assess somatic alterations of interest (point mutations, chromosomal aberrations, epigenetic modifications, and DNA fragmentation size), moving the monitoring approach from tumor tissue-based to blood-based testing.…”

Development of a novel NGS methodology for ultrasensitive circulating tumour DNA detection as a tool for early-stage breast cancer diagnosis

“…Importantly, we also found mutations in 8 plasma samples whose corresponding tumours bore no detectable mutations (Additional le 2: Table S6). This observation highlights the tumour heterogeneity as well as the commonly mentioned liquid biopsy's capacity to provide a more complete tumour genetic landscape as compared to solid biopsy, which is limited by the tumour tissue captured by core needles [18,19].…”