The choice of 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 based on the molecular characteristics of the tumor at that time, regardless of previous therapies and the withdrawal interval. This was revealed by the Chronos interventional clinical study, coordinated by the IRCCS Candiolo of Turin and by 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 Veneto Oncological Institute of Padua and the IRCCS Candiolo.
The study, published today in
Nature Medicine,
was made possible thanks to funding from the Piedmontese Foundation for Oncology IRCCS Candiolo in the context of an AIRC 5x1000 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"
explains
Professor Alberto Bardelli, co-author of the study of the
IRCCS di Candiolo Department of Oncology
and professor at the University of Turin
-
Although the therapy is effective, most patients undergoing this treatment can develop resistance to the drug over time and the disease progresses
.
To these patients
- adds Bardelli -
it is possible to administer a second course of therapy, the so-called “rechallenge”, which consists in resuming anti-EGFR therapies after a period of suspension, once the mutated genes have disappeared and the disease has become sensitive to treatment again.
The difficulty, however, lies in figuring out 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.
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 in whom the treatment wouldn't work.
THE CHRONOS STUDIO
"The approach of the Chronos study 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 the molecular traces released by the cells tumors circulating in the bloodstream or DNA
-
underlines Bardelli
-
The laboratory analysis of these traces can reveal, for example, the presence of specific alterations in the DNA of the tumor that can affect the sensitivity or rather the resistance of the tumor to different treatments therapeutic ".
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 is directly integrated into the therapy decision process for patients with metastatic colorectal cancer”,
comments Bardelli
.
“Just as in the Darwinian paradigm, we have applied
- he continues -
the concept of tumor evolution of drug resistance to the direct selection of therapy, analyzing in real time the circulating tumor DNA in search of resistance mutations.
In colon cancer, resistance to anti-EGFR drugs, which are used as a standard of therapy in advanced disease, is associated with the onset of specific mutations that 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 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,"
explains Professor
Andrea Sartore Bianchi of the University of Milan, lead author of the Chronos study and oncologist at Niguarda Cancer Center
.
“By applying a concept of 'zero molecular tolerance', we administered the therapy only to patients who had complete clearance of these mutations and in doing so we obtained a tumor objective response rate of 30% and a cancer control 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 the circulating DNA under treatment has revealed that other genetic mutations arise again upon progression to this therapy.
"Overall
-
says Bardelli
-
this clinical trial represents the first integration of 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 paves the way for studies that address 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.
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