The Liquid Biopsy

Abstract

The liquid biopsy is one of the most compelling concepts in cancer diagnosis and treatment as it offers an opportunity for both early diagnosis of cancer and for an oncologist to be able to monitor cancer progression during treatment. The liquid biopsy is where cancer biomarkers are monitored in biological fluids such as blood, urine or plural effusions to provide the same diagnostic information derived from a tissue biopsy. The ability to easily and repeatedly access blood and urine means diagnostic tests can be performed with minimal discomfort to the test subject. As such, during treatment, the impact of treatment on the cancer, and how the cancer might change, could be monitored on a molecular level. This is in some ways a major departure from current practice where the impact of molecular tools such as chemotherapeutics is mostly monitored by changes in cancers determined from imaging tools. The challenges to the liquid biopsy becoming routinely used are however considerable and revolve around identifying the biomarkers, fully understanding how the changes in biomarkers relate to how the cancer is responding to treatment and actually being able to measure changes in the very low concentrations the biomarkers are typically found. The last two challenges relate to the fact that the sample is collected remotely from a cancer. Being able to monitor change in the levels of biomarkers at ultralow concentrations is a considerable analytical challenge. (1) The common biomarkers investigated in the liquid biopsy are circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, microRNAs (miRNA), mRNA and protein biomarkers. As outlined by Kelley and co-workers. (2) 1 CTC in 10 mL can be diagnostically and prognostically important, ctDNA needs to be detected in the atto- to femtomolar range, miRNA is typically in the atto- to picomolar range where changes within this range need to be monitored and protein biomarkers can be between the femtomolar to the micromolar range. (2) These low levels of biomarkers are a challenge with regards to both the sensitivity of the transducer of the sensor and in terms of mass transport in bringing the analyte to the sensor. (1) The challenge of detecting such low concentrations of biomarkers is exacerbated by also being required to detect these species in complex biological fluids. It is important to keep in mind that for the liquid biopsy, any sensing technology must compete with quantitative PCR which is incredibly robust. This speed and ease of operation are two of the key attributes a sensor will need to provide an advantage over the incredible power of PCR. This Collection highlights papers published in ACS Sensors and Analytical Chemistry in the past few years that seek to address these challenges. The remoteness of the sample from the cancer can to some degree be addressed by selectively detecting biomarker levels from extracellular vesicles (EVs) that are derived from the cancer. Many authors have risen to this challenge by collecting and detecting EVs. The collection includes a perspective article (3) on detecting EVs as well as several primary research papers on methods for collecting and detecting EVs. (4−11) To address the challenge of selecting EVs, microfluidic technologies come to the fore (4,5,11) while many papers focus on ultrasensitive detectors for the payload of EVs, including down to the level of detecting single molecules. (4,6−8,12,13) Single molecule sensing has also been used to detect other biomarkers such as microRNAs. (7,9,13) Other papers also looked at approaches to capturing biomarkers and selectively detecting them. (14−16) Of these, the major challenge in some ways, at least in terms of finding an analyte which is exceedingly rare, is the circulating tumor cells. Even with this ultimate analytical challenge, one cell in a billion of more, authors have come up with a multitude of solutions. (17,18) This Collection represents just a small subset of some of the really exciting papers that have addressed the considerable challenge of selectivity and detection limit that is so necessary for the liquid biopsy. The solutions being developed for the liquid biopsy will both help in cancer diagnosis, prognosis and in devising a treatment plan. The authors that have risen to these challenges are also of course paving a path for the development of ultrasensitive sensors for other applications as well. Where once nanomolar detection limits were a major challenge, now authors are presenting methods with femtomolar and even attomolar detection limits. The papers in this Collection present some of the approaches to achieving such incredible sensors. This article references 18 other publications. This article has not yet been cited by other publications.