Transcending Blood—Opportunities for Alternate Liquid Biopsies in Oncology

SIMPLE SUMMARY: Cell-free DNA—DNA that has been expelled from cells and can be isolated from blood plasma and other body fluids—is a useful tool in medicine, with applications as a biomarker in diagnosis, prognosis, disease profiling, and treatment selection. In oncology, the ease of access to the tumour genome is a major advantage of cell-free DNA, but while this has led to significant research in blood, other body fluids have not received equal attention. This review article summarises the current research into cell-free DNA in non-blood body fluids, highlighting its values and limitations, and suggesting the direction of future studies. We conclude that cell-free DNA from non-blood body fluids may provide additional information to supplement traditional biopsies, allowing informative and improved patient care across many cancer types. ABSTRACT: Cell-free DNA (cfDNA) is a useful molecular biomarker in oncology research and treatment, but while research into its properties in blood has flourished, there remains much to be discovered about cfDNA in other body fluids. The cfDNA from saliva, sputum, cerebrospinal fluid, urine, faeces, pleural effusions, and ascites has unique advantages over blood, and has potential as an alternative ‘liquid biopsy’ template. This review summarises the state of current knowledge and identifies the gaps in our understanding of non-blood liquid biopsies; where their advantages lie, where caution is needed, where they might fit clinically, and where research should focus in order to accelerate clinical implementation. An emphasis is placed on ascites and pleural effusions, being pathological fluids directly associated with cancer. We conclude that non-blood fluids are viable sources of cfDNA in situations where solid tissue biopsies are inaccessible, or only accessible from dated archived specimens. In addition, we show that due to the abundance of cfDNA in non-blood fluids, they can outperform blood in many circumstances. We demonstrate multiple instances in which DNA from various sources can provide additional information, and thus we advocate for analysing non-blood sources as a complement to blood and/or tissue. Further research into these fluids will highlight opportunities to improve patient outcomes across cancer types.