Rome, 21 February 2023 – Almost 8,000 lung cancer patients are thought to qualify for a liquid biopsy each year in Italy in order to determine the best course of treatment. But in the not-too-distant future, the number of cancer patients for whom a simple blood test will choose the optimum course of treatment will grow dramatically. A blood sample enables continuous, real-time monitoring of the neoplasm’s development, much like in a video. An image of the tumour at the time of diagnosis can only be captured by a conventional biopsy, which is performed on tumour tissue. Also, even if it doesn’t currently reflect clinical practice, the difficulty is in using a blood test to make an early cancer diagnosis. The study, which is presented in the book “Liquid Biopsy: New Challenges in the Age of Immunotherapy and Precision Oncology,” by Antonio Russo, Ettore Capoluongo, Antonio Galvano, and Antonio Giordano, Ed. Elsevier brings up truly innovative views on the use of liquid biopsy, which was presented today at a press conference in the Chamber of Deputies and has signatures from the top international experts.
“Twenty years ago, in 2003, there were fewer than 50 publications in oncology that used the term “liquid biopsy,” but today there are more than 10,000, making it a real “hot topic,” states Antonio Russo, COMU President, Full Professor of Medical Oncology at DICHIRONS – University of Palermo, and Treasurer of AIOM (Italian Association of Medical Oncology). The “Liquid Biopsy” manual serves as evidence of both the prominence of Sicily, specifically the University of Palermo, and the brilliance attained in this subject by Italian scholars across the globe.
“Up to this point,“ continues Professor Russo, “the applications of liquid biopsy that have been shown effective in clinical practice involve advanced-stage non-small cell lung cancer, for the assessment of the EGFR gene mutational status. In two clinical contexts, the method is suggested in these instances as a possible alternative for tumour tissue examination.
First of all, in patients who have just received a diagnosis and prior to beginning any kind of treatment, when the quantity or quality of tissue available is insufficient to perform the anticipated molecular analyses, when the molecular analysis of tissue has been found to be insufficient, or when it is impossible to obtain biopsy tissue due to the patient’s poor clinical conditions. It should be kept in mind that, even when used for histological diagnosis, the tissue sample is not acceptable for molecular characterization in roughly 30% of instances. 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, i.e. with first and second-generation EGFR inhibitors. In these cases, blood sampling is very useful for searching for a specific resistance mutation and directing the change of cure, i.e. treatment with the third-generation EGFR inhibitor. The latter, in light of the robust overall survival data, has now become a solid option on 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 liquid biopsy has undoubted advantages over the traditional approach consisting of the analysis of tumor tissue – says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Sien, and Founder and President of the Sbarro Health Research Organization (SHRO). “It is minimally invasive, low-cost, has very fast reporting times and is practically free of complications because it can be performed with a simple blood sample. 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.”
“The liquid biopsy has undeniable advantages over the conventional method that involves the study of tumour tissue,” says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Siena, “It is less invasive, inexpensive, has extremely quick turnaround times, and is essentially complication-free because it can be carried out with a simple blood sample. Furthermore, serial sampling is used to highlight the development of therapy resistance in real-time and, if necessary, change the treatment. It is characterized by a high level of patient acceptability and can be repeated without issues.
Instead, very few patients opt to have a second tissue evaluation, in part because the general clinical circumstances often exclude it. Moreover, the tissue biopsy sample, particularly when it is obtained through fine-needle aspiration, may not necessarily be an accurate representation of the entire tumour. This is not the case with the liquid biopsy, which solves the issue of the heterogeneity of the tumour tissues by analyzing the tumour DNA discharged into the circulation.”
The predominant biopsy method currently utilized in clinical practice today is the examination of circulating tumour DNA, or ctDNA (circulating tumour DNA), which is a fraction of circulating free DNA (cell-free DNA, or cfDNA), isolated from peripheral blood (particularly from plasma).
“The chance of success is dependent on the quantity of ctDNA in the peripheral blood, which may impact the test’s sensitivity,” underlines Ettore Capoluongo, Full Professor of Clinical Biochemistry and Clinical Molecular Biology and SOC Director of Clinical Pathology and Genomics, Cannizzaro Hospital of Catania, “One drawback is that, depending on the volume and locations of the disease, the amount of ctDNA in the context of cfDNA is frequently limited, and this might result in “false negative” results on the liquid biopsy sample. The size and stage of the tumour are really connected to the concentration of ctDNA in plasma, with advanced-stage neoplasms releasing more ctDNA than early-stage ones. Exosomes, platelets, circulating tumour cells, circulating tumour RNA and microRNA, as well as other biological fluids like urine, saliva, ascitic fluid, and pleural could all be used in clinical practice in the future to provide additional information beyond that provided by the analysis of ctDNA isolated from plasma.” It is crucial that the measurement of these molecular tumour markers be as consistent as possible; for this reason, using liquid biopsy as part of the diagnostic process is the perfect scenario for clinic and laboratory collaboration.
“Due to its capability to swiftly translate laboratory discoveries into clinical applications, the liquid biopsy must only be examined in laboratories that pass quality controls and serves as a key illustration of translational medicine,” explains Marcello Ciaccio, Full Professor of Clinical Biochemistry, Dean of the School of Medicine and Surgery of the University of Palermo, Past President and President-elect of SIBioC (Italian Society of Clinical Biochemistry and Clinical Molecular Biology), “which enables the simultaneous identification of all forms of genetic changes in several genes during a single liquid biopsy study. NGS is more cost-effective than a single gene method, according to cost analyses. This advantage becomes even clearer once a threshold of patients has been evaluated in order to fully realize the potential of NGS technologies, which enable the simultaneous profiling of several individuals while optimizing costs and turnaround times. The subsequent step will be to make NGS approaches accessible and convenient to utilize. Building a real network is important to accomplish this goal.”
“The liquid biopsy definitively establishes the importance of multidisciplinarity,” says Saverio Cinieri, National President of AIOM (Italian Association of Medical Oncology), “The Molecular Tumor Boards, interdisciplinary committees where various talents are combined to govern the clinical and decision-making processes of appropriateness, are responsible for selecting the material to be exposed to molecular analysis. Yet it’s important to make a distinction between regular clinical practice and research. Although if research efforts are in the right direction, it is not yet possible to diagnose cancer from a blood sample. Nowadays, liquid biopsy plays a significant role as a predictor of response to therapy in lung cancer. An investigation based on a novel strategy, namely the methylation signatures of circulating free DNA, was presented at the most recent Congress of the European Society of Oncology. There were more than 6,000 participants who were over 50, appeared healthy, and had never been given a cancer diagnosis. In 1.4% of the participants, the test revealed changes in the methylation profile, which are common to more than 50 distinct forms of neoplasms. Among these individuals, the oncological diagnosis was confirmed in around 40% of the instances. Yet, in more than 60% of cases, no oncological illness diagnosis was made after the positive test results.”
“The sensitivity of the liquid biopsy, in a context of early diagnosis, is therefore still conditioned by a high rate of false positives, the causes of which are being studied,” continues the AIOM President, “The emerging clinical applications of this procedure mainly concern colorectal, breast and advanced melanoma cancers. Indeed, there is solid and reproducible information regarding the characterization of RAS and BRAF genes for colorectal, PIK3CA for breast, BRAF and NRAS in melanoma. It is likely that plasma analysis for this type of alteration will soon be recommended in clinical practice”.
“In order to personalize treatment, a very active area of study is the use of liquid biopsy in immunotherapy. This field has the potential to produce “dynamic” and reproducible biomarkers in the near future,” highlights 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 crucial to keep moving in this direction. “.
“One of the roles of Patients’ Associations is to support the scientific community with regard to research progress, adopting a rigorous, but informative and easy to understand the method,” continues Adriana Bonifacino, President of the IncontraDonna Foundation, “It is essential that patients are increasingly involved in trials, including those on liquid biopsy. Quality of life is becoming a central element in the evaluation of the innovativeness of treatments and the liquid biopsy fits into this context. Being able to monitor the evolution of the tumor in real-time with a simple blood sample also represents an element of reassurance from a psychological point of view for the patient, as well as avoiding the invasiveness of traditional procedures on tumor tissue”.
“The “Liquid Biopsy” book is distinguished by the special focus on educational aspects and by the inclusion of the so-called “expert comments,” authored by internationally known experts,” concludes Professor Russo, “Our group of researchers from the University of Palermo has been conducting experiments on liquid biopsy since the early 2000s and is at the forefront in this sector, today with further studies on exosomes and on the determination of circulating immune checkpoints. The exciting data from studies may also lead to changes in the parameters used to classify cancer stages. To the TNM system, where T describes the extent of the disease, N the status of the lymph nodes and M the possible presence of metastases, B, such as blood, should be added, which provides information on circulating tumor DNA.”
About the Sbarro Health Research Organization
The Sbarro Health Research Organization (SHRO) is a non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes, and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org