Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

Abstract

In recent years, detection of cell‐free tumour DNA (ctDNA) or liquid biopsy has emerged as an attractive noninvasive methodology to detect cancer‐specific genetic aberrations in plasma, and numerous studies have reported on the feasibility of ctDNA in advanced cancer. In particular, ctDNA assays can capture a more ‘global’ portrait of tumour heterogeneity, monitor therapy response, and lead to early detection of resistance mutations. More recently, ctDNA analysis has also been proposed as a promising future tool for detection of early cancer and/or cancer screening. As the average proportion of mutated DNA in plasma is very low (0.4% even in advanced cancer), exceedingly sensitive techniques need to be developed. In addition, as tumours are genetically heterogeneous, any screening test needs to assay multiple genetic targets in order to increase the chances of detection. Further research on the genetic progression from normal to cancer cells and their release of ctDNA is imperative in order to avoid overtreating benign/indolent lesions, causing more harm than good by early diagnosis. More knowledge on the sources and elimination of cell‐free DNA will enable better interpretation in older individuals and those with comorbidities. In addition, as white blood cells are the major source of cell‐free DNA in plasma, it is important to distinguish acquired mutations in leukocytes (benign clonal haematopoiesis) from an upcoming haematological malignancy or other cancer. In conclusion, although many studies report encouraging results, further technical development and larger studies are warranted before applying ctDNA analysis for early cancer detection in the clinic.

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

“…Molecules of cfDNA are rapidly cleared from the circulation, with a half-life ranging from minutes to several hours. Healthy individuals have cfDNA levels of 1-10 ng/ml which can increase by intense exercise, trauma, infections and inflammatory conditions [83]. Due to the small size it is expected that cfDNA can also be analyzed in urine, but concentrations will be influenced by the glomerular filtration rate [84].…”

Tumor-Based Genetic Testing and Familial Cancer Risk

“…Although cfDNA is common even in healthy people, patients with cancer have higher blood levels of cfDNA (Leon et al 1977;Stroun et al 1987;Schwarzenbach et al 2011). The average proportion of mutated DNA in plasma is very low, 0.4% in even advanced cancers (Barbany et al 2019). Analysis of ctDNA is known as liquid biopsy.…”

“…Somatic alterations were identified in 85% of the patients overall, with a range of 51% to 93% represented across various tumor types (Zill et al 2018). The posited applications of ctDNA include identification of disease progression (i.e., ductal carcinoma in situ to invasive ductal breast cancer), cancer screening in high-risk populations (i.e., prostate cancer in men over 70), and distinguishing benign from malignant disease (Barbany et al 2019). In addition to single-gene variants, it is possible that large CNVs or chromosomal disorders may be identified (Barbany et al 2019).…”

“…The posited applications of ctDNA include identification of disease progression (i.e., ductal carcinoma in situ to invasive ductal breast cancer), cancer screening in high-risk populations (i.e., prostate cancer in men over 70), and distinguishing benign from malignant disease (Barbany et al 2019). In addition to single-gene variants, it is possible that large CNVs or chromosomal disorders may be identified (Barbany et al 2019). Additionally, there are a number of clinical trials using liquid biopsy in known variant carriers to detect early onset of tumors (Barbany et al 2019).…”

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

“…In recent years, liquid biopsy to detect cfDNA or circulating tumor DNA (ctDNA) has emerged as an attractive non-invasive methodology to discern cancerspecific genomic aberrations in plasma. Numerous studies have reported the utility of ctDNA in advanced cancer [194][195][196][197]. In particular, ctDNA assays can capture a more global portrait of tumor heterogeneity than that provided by tissue DNA (which reflects the small piece of tissue that is biopsied rather than DNA shed from both primary and multiple metastatic sites [198]); therefore, ctDNA can be exploited to monitor tumor response and resistance.…”