A study, published in “Nature Medicine”, helps to understand the right time to administer a second course of therapy to metastatic patients
Choosing the right therapy, for the right patient, at the right time: a goal that seems closer to metastatic colorectal cancerthanks to the liquid biopsy that allows to analyze the circulating tumor DNA through a blood draw and thus to select patients on the basis of the molecular characteristics of the tumor at that time, regardless of previous therapies and the withdrawal interval. This was revealed by the interventional clinical study Chronos, published in the scientific journal Nature Medicine
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 and the Institute Oncologico Veneto of Padua.
When to administer the second course of treatment
“In patients with metastatic colorectal cancer, many molecularly targeted therapies rely on monoclonal antibodies against EGFR growth receptors, which can only be used in patients without mutations in RAS / BRAF – explains Alberto Bardelli, co-author of the study, oncologist at the IRCCS of Candiolo and professor at the University of Turin -. Although the therapy is effective, most patients undergoing this treatment can develop over time drug resistance and the disease progresses. In these cases it is possible to administer a second course of therapy, so-called rechallengewhich consists of the resume anti-EGFR therapies after a suspension period, once the mutated genes have disappeared and the disease has become sensitive to treatment again. The difficulty, however, lies in figuring out when to start 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 treatment. The Chronos study fits into this context (carried out thanks to the funding of the Piedmontese Foundation for Oncology IRCCS Candiolo and AIRC 5×1000) 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 in whom treatment would not work.
Lo studio Chronos
“The approach of the Chronos study is based on liquid biopsy which, through the analysis of a simple patient’s blood sample, allows us to obtain valuable information on the tumor and its development,” hunting “for molecular traces released by circulating cancer cells in the bloodstream or DNA – underlines Bardelli -. The laboratory analysis of these traces can reveal, for example, the presence of specific changes in tumor DNA which can affect the sensitivity or rather the resistance of the tumor to various therapeutic treatments “. 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. “With Chronos liquid biopsy it is directly integrated into the decision-making process for therapy for patients with metastatic colorectal cancer – continues the expert -. In colon cancer, resistance to anti-EGFR drugs, which are used as the standard of therapy in advanced disease, is associated with the onset of specific mutations which give the tumor a selective advantage of drug resistance “. 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, which coordinated the other participating clinical centers. In patients for whom a therapy of rechallenge with anti-EGFR a liquid biopsy was performed and the circulating tumor DNA was analyzed at the Candiolo Institute.
A cure for patients with few options
In the absence of resistance mutations, therapy was initiated with panitumumabthe drug used for the rechallenge. “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 Niguarda Cancer Center -. Applying a concept of “zero molecular tolerance“, We administered the therapy only to patients who had a total absence of these mutations and in so doing we obtained a tumor objective 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 monoclonal antibody panitumumab it was in fact well tolerated and tumor responses occurred regardless of the line of treatment and the type of therapy received prior to rechallenge. «Overall – concludes Bardelli – this clinical trial represents a first integration of the liquid biopsy to 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 collect this emerging challenge in the context 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 equally essential than to identify a treatment that “chronic” the tumor. Having a diagnostic tool that excludes treatments that are certainly ineffective saves unnecessary toxicity and suffering ».
August 7, 2022 (change August 7, 2022 | 18:38)
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