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Liquid Biopsy: New Challenges in the Era of Immunotherapy and Precision Oncology

Updated: May 16

First published in Italian,

Translational research has recently opened revolutionary options for the application of liquid biopsy, as described in the book "Liquid Biopsy. New Challenges in the Era of Immunotherapy and Precision Oncology" edited by Antonio Galvano, Antonio Giordano, Ettore Capoluongo, and Antonio Russo. Until 2003, there were fewer than 50 oncology articles including the term "liquid biopsy". However, there are currently more than 10,000 scholarly contributions, making it a real "hot topic."

Almost 8,000 lung cancer patients in Italy are possible candidates for liquid biopsies each year to determine the best course of treatment. The majority of liquid biopsy uses in clinical practice today is used for the assessment of the EGFR gene's mutational status in advanced stages of non-small cell histotypes.

In the clinical setting, the method is suggested as a potential substitute for tumor tissue analysis: in patients with a new diagnosis who have never received any systemic treatment, when the quantity or quality of the tissue is insufficient to perform the intended molecular analyses (in about 30% of cases, tissue material is not suitable for molecular characterization), or when obtaining biopsy tissue is impossible due to patient's poor clinical condition. In addition, this test is strongly recommended for patients presenting with disease progression following the first line of treatment with first or second-generation TKIs. In these settings, blood collection is very helpful for identifying specific mutations generating resistance to third-generation TKI treatment, or direct therapeutic switching.

Due to its high efficacy, the latter has now surpassed the use of liquid biopsy for resistance mutation research as a secondary alternative in light of strong overall survival results.

As a result, liquid biopsy has undeniable benefits over the conventional method of studying tumor tissue. because it can be carried out with just a quick blood draw and it is minimally invasive, inexpensive, and has very quick reporting times (TAT). it is also characterized by high patient acceptance and is reproducible. Serial sampling is done to monitor the development of therapy resistance in real time and, if necessary, adjust the therapeutic method used.

Currently, a high proportion of false positives limits the sensitivity of liquid biopsy for early diagnosis. Newly developed therapeutic applications of this methodology are available for advanced-stage colon-rectal, breast, and melanoma malignancies. Results for the characterization of RAS and BRAF genes for colon-rectal cancer, PIK3CA for breast cancer, and BRAF and NRAS for melanoma are already available, and they are all extremely promising. It is therefore expected that plasma analysis for these kinds of abnormalities will be soon suggested in clinical practice. Currently, the primary method for liquid biopsy in clinical oncology practice is the examination of circulating tumor DNA (ctDNA), extracted from peripheral blood and/or other biological fluids. The likelihood of success is correlated with the amount of circulating ctDNA, which can affect the accuracy of the results of the genetic study. In reality, "false negative" results from the liquid biopsy sample can occur due to the limiting amount of ctDNA, which depends on the volume and location of the disease as well as the stage of the disease. Other blood components, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, exosomes, and other biological fluids, like urine, saliva, ascites, and pleural fluid, could be used one day in clinical practice to gather additional data in addition to the one obtained from the analysis of ctDNA extracted from plasma.

The diagnostic approach employing liquid biopsy represents an ideal scenario for collaborations between the clinic and the laboratory as it is important to standardize the techniques on which is based to evaluate the molecular "traces" of the tumor. Liquid biopsy is a crucial example of translational medicine for its capacity to rapidly translate laboratory findings into clinical applications, and it should be only performed in molecular biology facilities that pass quality standards.

Another very active field of research is the use of liquid biopsy in immunotherapy, which has the potential to identify in the near future "dynamic" and reproducible biomarkers with an eye towards therapeutic personalization. Many research efforts are conducted to determine whether cfDNA, ctDNA, and soluble immune checkpoint forms can be used as predictive indicators of response. Applications for liquid biopsy have recently drawn more attention as the clinical practice has begun to vastly use sequencing. The Next Generation Sequencing (NGS) technology enables the simultaneous detection of genetic changes in several genes within a single analysis. NGS is more cost-effective than a single-gene method, according to cost assessments. A certain number of patients must be enrolled to fully utilize the promise of NGS approaches, which enable the simultaneous profiling of numerous individuals while maximizing costs and time.

Liquid biopsy unequivocally proves the value of multi-disciplinarily. Molecular Tumor Boards, interdisciplinary groups integrating numerous professional competencies are currently in charge of the discussion and selection of the diagnostic/clinical pathway for oncology patients to establish appropriate clinical and decision-making procedures.

This article was originally published in, here's the link!

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