It is estimated that every year, in Italy, there are over 8,000 patients with lung cancer who are candidates for undergoing a liquid biopsy to identify the most effective therapy. But the number of people affected by cancer in which a simple blood test will determine the choice of the best treatment, in the not too distant future, is destined to increase exponentially. The blood test allows continuous monitoring of the evolution of the tumor in real time, like in a video. Instead, the traditional biopsy, i.e. on tumor tissue, is only able to take a snapshot of the tumor at the time of diagnosis. And, even if it doesn’t represent clinical practice yet, the challenge is to diagnose cancer early with a blood draw. The research opens revolutionary perspectives in the use of liquid biopsy, summarized in a book (“Liquid Biopsy. New Challenges in the Era of Immunotherapy and Precision Oncology”, by Antonio Russo, Ettore Capoluongo, Antonio Galvano, Antonio Giordano. Edizioni Elsevier) in signature of the most important international experts, presented today at a press conference in the Chamber of Deputies.
Non-small cell lung cancer
«Twenty years ago, in 2003, the publications that contained the term “liquid biopsy” in oncology were less than 50, today they are more than 10 thousand, transforming it into a real “crucial issue” – explains Antonio Russo, president of the Collegio University Medical Oncologists (Comu) —. The manual is the demonstration of the excellence achieved in this field all over the world by Italian researchers. To date – continues Russo, Professor of Medical Oncology at DICHIRONS University of Palermo – the applications of liquid biopsy validated in clinical practice concern advanced stage non-small cell lung cancer, for the evaluation of the mutational status of the gene EGFR. In these cases, the procedure is recommended as a possible alternative to tumor tissue analysis in two clinical scenarios. First of all, in newly diagnosed patients and before starting any type of treatment, in which the quantity or quality of available tissue is not sufficient to carry out the expected molecular analyzes or in which the molecular analysis on tissue has been found to be inadequate, or when it is impossible to obtain the biopsy tissue due to the poor clinical conditions of the patient. It should be remembered that, even if usable for histological diagnosis, in about 30% of cases the tissue material is not suitable for molecular characterization”.
In the second scenario, the liquid biopsy provides a very important contribution during the monitoring of patients with EGFR gene mutation, in progression after first-line treatment with targeted therapies, ie with first and second generation EGFR inhibitors. «In these cases, the blood draw is very useful for the search for a specific resistance mutation and direct the change of treatment, i.e. treatment with the third generation EGFR inhibitor – continues the expert -. The latter, in the light of the robust overall survival data, has now become a solid option in the front line and, given the high inhibitory activity, has made the use of liquid biopsy for the search for the resistance mutation secondary”.
The advantages
“The liquid biopsy has undoubted advantages over the traditional approach consisting of the analysis of tumor tissue – he says Antonio GiordanoDirector of the Sbarro Institute for Cancer Research and Molecular Medicine of the Temple University of Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Siena —. It is minimally invasive, low cost, has very fast reporting times and is almost free of complications, because it can be done with a simple blood draw. Furthermore, it is characterized by a high level of acceptance by patients and can be repeated without problems, by performing serial sampling to highlight the onset of resistance to therapy in real time and, if necessary, modify the treatment. Instead, there are few patients who decide to undergo a second tissue examination, also because the general clinical conditions often do not allow it. Furthermore, the material taken from the tissue biopsy, especially with fine-needle aspiration, is not always representative of the entire neoplasm. This is not the case for the liquid biopsy which, by evaluating the tumor DNA released into the circulation, overcomes the problem of the heterogeneity of the tumor tissues”.
Circulating tumor DNA
Analysis of circulating tumor DNActDNA (circulating tumor DNA), which represents a fraction of circulating free DNA (cell free DNA, cfDNA), isolated from peripheral blood (especially from plasma), represents, today, the main liquid biopsy approach used in clinical practice. “The chances of success are linked to the amount of ctDNA present in the peripheral blood, which can affect the sensitivity of the test – underlines Ettore Capoluongo, professor of Clinical Biochemistry and Clinical Molecular Biology and SOC Director of Clinical Pathology and Genomics, Cannizzaro Hospital of Catania —. One of the limitations is represented by the fact that the quantity of ctDNA in the context of cfDNA is often limited, depending both on the volume and on the locations of the disease, and this can determine “false negative” results on the liquid biopsy sample. The concentration of ctDNA in plasma, in fact, is correlated to the size and stage of the tumor: advanced-stage neoplasms release a greater quantity of ctDNA than initial ones. It is possible that, in the future, other derivatives obtained from blood, such as circulating tumor cells, circulating tumor RNA and microRNAs, platelets, exosomes, as well as other biological fluids such as urine, saliva, ascitic fluid and pleural are used in clinical practice to obtain further information than those obtained from the analysis of ctDNA alone extracted from plasma”.
It is important that you arrive at standardize the quantification of these molecular traces of the tumor as much as possible: for this reason the diagnostic approach through the use of liquid biopsy represents an ideal scenario of collaboration between clinic and laboratory.
Laboratories and equipped and Molecular Tumor Board
“The liquid biopsy must be analyzed only in laboratories that pass quality controls and represents an important example of translational medicine, due to its ability to quickly transfer laboratory discoveries into clinical applications – he explains Marcello Ciaccio, full professor of clinical biochemistry, dean of the School of Medicine and Surgery of the University of Palermo –. Next Generation Sequencing (NGS) is the most effective laboratory technology: it allows to simultaneously identify all the different types of genetic alterations in multiple genes in a single liquid biopsy analysis. Cost analyzes have shown that NGS is more cost effective than a single gene approach. This advantage becomes even more evident when a critical number of analyzed patients is reached, so as to be able to fully exploit the potential of NGS methods, which allow the simultaneous profiling of several people, thus optimizing costs and times. The next step will be to make the use of NGS methods not only convenient, but also easy to access. To achieve this goal it is necessary to build a real network».
The liquid biopsy definitively establishes the importance of multidisciplinarity “The choice of the material to be subjected to molecular analysis is the task of the Molecular Tumor Boards, interdisciplinary groups in which multiple skills are integrated to govern the clinical and decision-making processes of appropriateness – he recalls Saverio Cinieri, president of the Italian Association of Medical Oncology —. However, it is necessary to distinguish daily clinical practice from research. To date, the liquid biopsy has an important role as a predictor of response to therapy in lung cancer, but it is not yet possible to make a cancer diagnosis based on a blood sample, even if research efforts are going to the right point. this direction”.
Liquid biopsy and immunotherapy
“The application of liquid biopsy also to immunotherapy constitutes a very active field of research, which has the potential to provide “dynamic” and repeatable biomarkers in the near future, with a view to personalizing treatment – concludes Antonio Galvano, Associate Professor of Medical Oncology at the University of Palermo -. Only a fraction of patients today show a significant response or long-term benefit with immunotherapy drugs. Individual biological and immune factors affect the heterogeneity in the response. For this reason, the identification of predictive biomarkers of response or resistance to treatment, for example, with immune checkpoint inhibitors, assumes an important role. Numerous studies are underway with the aim of evaluating the potential use of cfDNA, ctDNA and soluble forms of immune checkpoints as predictive biomarkers of response. In recent years, our research group has published studies conducted mainly on lung, pancreatic and melanoma tumors in important international scientific journals. It is important to continue in this direction”.