The term "Liquid Biopsy" describes the examination of any tumor-derived material present in the blood or any other bodily fluid. As the tumour is frequently difficult to access and may need an invasive surgery that could be hazardous, this idea is especially pertinent to lung cancer. Furthermore, the variety of anticancer medications and their sequential application emphasise how crucial it is to carry out an iterative assessment of tumour biology. With the help of liquid biopsies, regional and temporal heterogeneity can be overcome while monitoring treatment response and examining the genetic changes at resistance, as well as noninvasively detecting any targetable genomic alteration and directing matching targeted therapy. Liquid Biopsy has the potential to assist in the management of non-small cell lung cancer at all stages of the disease, including screening, the identification of minimal residual disease to direct adjuvant therapy, early relapse detection, the initiation of systemic treatment and monitoring of response (targeted or immune therapy), and resistance genotyping. The therapy landscape for advanced non-small cell lung cancer has changed as a result of targeted medicines and, more recently, immune checkpoint inhibitors (ICIs) (NSCLC). Using companion biomarkers, response to these drugs can be anticipated. The development of minimally invasive or noninvasive procedures, which yield small tissue samples with extremely small amounts of DNA, creates a dilemma between the necessity to gather large samples for repeated analysis for an increasing number of molecular indicators. In 10–20% of patients, cytological samples from procedures like endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are insufficient for a thorough molecular analysis. Furthermore, a demand for quick, noninvasive, repeatable assays to evaluate and track tumour biology through therapy has arisen as a result of a better understanding of the resistance to matching targeted therapies. In light of this, there has been a resurgence in interest in Liquid Biopsy, a term used to describe any tumor-derived material that is present in the blood or any other body fluid. The two most extensively researched substrates in the field of NSCLC, circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), have diverse benefits and drawbacks, and may even work in tandem. Liquid biopsy can noninvasively probe a tumour's molecular landscape (taking into account different clones present within all metastatic sites) and can follow subclonal evolution through iterative blood draws, whereas tissue only provides a snapshot of the tumour at a specific time and location. Whole-exome sequencing offers the capacity to both identify and investigate novel molecular mechanisms of resistance while simultaneously detecting predicted oncogenic drivers or mechanisms of resistance. The majority of clinically significant fusions, however, take place in noncoding areas and are not detected by the whole-exome technique. The use of panels of primers/probes targeting hotspots or exons of specified genes seems to be the most reasonable method in the context of liquid biopsy, given the trade-off between the depth and volume of the genome covered, given the extremely low proportion and amount of cancer DNA. Combined capture NGS is a well-known strategy in the Liquid Biopsy industry. Hybridization to biotinylated probes "captures" predetermined DNA sequences. The leftover DNA can be removed since the biotin is attached to streptavidin beads. These approaches can accurately estimate copy number changes because they avoid using prior amplification. One drawback of hybrid capture for plasma genotyping is the inherent low input DNA, necessitating systems with a high depth of sequencing. Thus, the possibility of sequencing mistakes and false positives exists. For instance, a recent study found that, using tissue as a reference, specificity was 63.5%. For pre-treatment and post-treatment specimens, the concordance rates between cfDNA and tissue were only 64.7% and 48.9%, respectively.
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