A Darwinian approach to find the right therapy and spare patients unnecessary treatments. This is based on the concept of tumor evolution of drug resistance to direct therapy selection, analyzing in real time the circulating tumor DNA in search of resistance mutations. In short, choosing the right therapy, for the right patient, at the right time: a goal that seems closer for metastatic colorectal cancer, thanks to the liquid biopsy that allows to analyze the circulating tumor DNA through a blood sample and thus to select patients on the basis of the molecular characteristics of the tumor at that time, regardless of previous therapies and the interval of suspension. This was revealed by the Chronos interventional clinical study, published today in Nature Medicine and coordinated by the Irccs Candiolo of Turin and the Niguarda Hospital of Milan, with the collaboration of the University of Turin and the University of Milan and the clinical participation of the National Cancer Institute of Milan, the Institute Oncologico Veneto of Padua and the IRCCS Candiolo.
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Resistance to therapy
The study was made possible thanks to funding from the Piedmontese Foundation for Oncology Irccs Candiolo in the context of an Airc 5×1000 research funding. “In patients with metastatic colorectal cancer, many molecularly targeted therapies are based on monoclonal antibodies against Egfr growth receptors, which can only be used in patients without mutations in Ras / Braf,” he explains. Alberto Bardelli, co-author of the Candiolo Irccs study, Department of Oncology and professor at the University of Turin. “Although the therapy is effective, most patients undergoing this treatment may develop resistance to the drug over time and the disease progresses.”
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When to do the ‘rechallenge’
These patients can be administered a second cycle of therapy, the so-called ‘rechallenge’: “It consists – explains Bardelli – in resuming anti-Egfr therapies after a period of suspension, once the mutated genes have disappeared and the disease has become sensitive again. to the treatment. The difficulty, however, lies in understanding when to initiate a rechallenge ”. Until now it was not possible to establish it except in an empirical way, based on a statistical time interval since the previous therapy.
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Lo studio Chronos
The Chronos study fits into this context which, for the first time, exploits the potential of liquid biopsy to monitor tumor progress in real time and guide therapy, allowing it to be excluded in patients with mutated genes for which treatment does not it would work. “The approach of the Chronos study – underlines Bardelli – is based on liquid biopsy which, through the analysis of a simple patient’s blood sample, allows to obtain valuable information on the tumor and its development, ‘hunting’ for traces molecules released by cancer cells circulating in the bloodstream or DNA. The laboratory analysis of these traces can reveal, for example, the presence of specific alterations in the tumor’s DNA that can affect the sensitivity or rather the resistance of the tumor to various therapeutic treatments “.
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How the study took place
The Chronos clinical study took place in the Oncology of the Niguarda Hospital in Milan under the direction of Professor Salvatore Siena, of the University of Milan and director of the Niguarda Cancer Center who coordinated the other participating clinical centers. In patients for whom a rechallenge therapy with anti-EGFR was considered suitable, a liquid biopsy was performed and the circulating tumor DNA was analyzed at the Candiolo Institute. In the absence of resistance mutations, therapy with panitumumab, the drug used for rechallenge, was started. “We observed that multiple resistance gene alterations were frequently present, probably arising after the first exposure to anti-EGFR drugs and still in circulation,” he explains. Andrea Sartore Bianchi of the University of Milan, lead author of the Chronos study and oncologist at the Niguarda Cancer Center.
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Zero molecular tolerance
Applying a concept of ‘zero molecular tolerance’, the researchers administered the therapy only to patients who had a complete clearance of these mutations: “By doing so – continues Sartore Bianchi – we obtained an objective tumor response rate of 30% and a control of oncological disease of 63%. These data – he continues – represent a step forward in clinical situations where therapeutic alternatives are often absent, and this targeted strategy improves the therapeutic index of this ‘chemo-free’ treatment for colorectal cancer ”. Therapy with the panitumumab monoclonal antibody was, in fact, well tolerated and tumor responses occurred regardless of the line of treatment and the type of therapy received prior to the rechallenge. Furthermore, the longitudinal study of circulating DNA under treatment has shown that other genetic mutations arise again upon progression to this therapy.
The impact of precision medicine
Therefore, thanks to the liquid biopsy among the patients without mutations, enrolled in the study, 30% showed an objective response, a value higher than that observed with the selection of patients according to clinical criteria only.. “Overall – says Bardelli – this clinical trial represents the first integration of the liquid biopsy into the therapy process in a big killer tumor such as colorectal cancer. From a drop of blood it is possible to decipher the vulnerability to a molecularly targeted therapy and the Chronos study opens the way to studies that take up this emerging challenge in the field of personalized medicine. The most important thing that Chronos has demonstrated is precisely the positive impact of precision medicine on the quality of life of individuals. In patients with very advanced tumors, preserving the quality of life is just as essential as identifying a treatment that ‘chronicizes’ the tumor. Having a diagnostic tool that excludes treatments that are certainly ineffective saves unnecessary toxicity and suffering ”, concludes Bardelli.