Circulating DNA in solid organ cancers-analysis and clinical application

Abstract

Circulating tumour DNA (ctDNA) is that fraction of circulating DNA that is derived from a patient's cancer. For a number of years, patients with haematological malignancies have had their disease diagnosed or monitored using tests based on detecting specific cytological or molecular biomarkers in blood. It has long been appreciated that the more common epithelial malignancies also shed DNA into the blood and that this tumour-derived DNA generally contributes a minor percentage of the overall cell-free DNA burden in peripheral blood. The biotech revolution has transformed our ability to detect, quantify and interpret genetic events. This has led to a renewed interest in the potential of using a simple blood test to both diagnose cancer and longitudinally monitor the response to medical interventions in patients with solid organ malignancies.In this review we provide a summary of the literature to date and describe the main attributes of the current analytical approaches to ctDNA. We then focus on the potential clinical applications. There is increasing evidence to support the routine analysis of ctDNA in clinical decision-making for certain subgroups of patients with so-called hotspot mutations, particularly in lung and colorectal cancer. With continued refinement and technological progress, non-invasive molecular biomarkers including of ctDNA may be clinically useful at all stages of cancer management from diagnosis to disease progression.

Figure 1

Schematic of potential application of ctDNA in clinical practice. A person may present with an advanced cancer bearing a mutation (red) that means the cancer is sensitive to a particular drug. However the tumour may harbour a subclonal population (orange) with a separate mutation conferring resistance to the drug. Therefore during initiation (b) and maintenance (c) therapy the dominant clone will respond while the subclone will be resistant and can metastasise (c), but may not initially cause symptomatic disease. Eventually the patient will become unwell with a high tumour load (d) with the now dominant clone (orange) and potentially other subclonal populations (blue, magenta). It should be possible to use cfDNA analysis at all stages of the patient’s management. At diagnosis the original dominant clone (red) should be readily detectable in cfDNA. The resistant subclone may be detectable with more sensitive technologies at diagnosis and following initial treatment, as well as on clinical progression (a–c). The earlier detection of the resistant subclone in plasma could influence therapeutic decision-making e.g. instituting treatment with a second-line drug with activity against both clones, if available. Irrespective of treatment modality the rise in cfDNA titre could predict subsequent clinical relapse (d) and prompt imaging investigations and a therapeutic re-evaluation.