Colon cancer: surround it to defeat it

A cure tailored to the person. It is the promise of personalized oncology that finds its first confirmations also in colorectal cancer. We have learned that there is room for a different treatment depending on the type of disease with breast cancer, in some cases very difficult to attack, in others not very aggressive and therefore manageable. We begin to see it in the lung, where molecular characteristics direct therapies. And colorectal cancer confirms this, in which not only the mutations present or not, but also the anatomical location of the primary tumor play an important role. This is why the new and always personalized treatment strategies were among the protagonists of the congress of theAmerican Society of Clinical Oncology which just ended in Chicago.

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On the other hand, if it is true that, thanks to screening, it is possible to identify tumors at the initial stage that are more likely to be cured, as shown by the increase in survival; it is also true that colorectal cancer still remains the second most frequent neoplasm in the Italian population after that of the breast and that in about 20% of cases it is diagnosed when it is already in an advanced stage.

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Select patients well

Many patients therefore, and often already with a serious illness. But even in this case, if the different tumor subtypes are carefully selected, it is possible to administer effective therapies. First of all by dividing those who have a primary tumor on the left side of the colon from those who have it on the right side.

“An important difference because we know that depending on the site we can use drugs and not others. For example, on the right it is useless to use anti EGFR molecules, we must instead use a triple aggressive chemotherapy and bevacizumab”, explains Chiara Cremolini, associate of Medical Oncology at the University of Pisa, which in Chicago presents an independent study on the different strategies to be used according to the characteristics of the tumor. Results valid for a good portion of metastatic patients, about a third: those who have neither the Braf nor the Ras mutation, nor do they have the so-called satellite instability.

The Triplete study, promoted by the GONO foundation, a cooperative group created precisely to promote non-profit research, has shown that in tumors that arise on the left, as opposed to those that develop on the right, the best strategy is to use a drug hitting the EGFR target with a lighter chemo. “In particular, we compared the chemo plus bevacizumab triplet to the chemo doublet plus panitumumab and saw that intensifying the therapy does not lead to better results,” Cremolini explains.

What is called a negative result – the study did not prove the starting hypothesis – which actually confirms that the careful selection of patients makes it possible to avoid aggressive chemotherapy with all its load of side effects. Another way to improve the quality of life without compromising the effectiveness of the treatments is to reduce the administration of chemo, as demonstrated by a study coordinated by the Cancer Institute of Naples.

News for mutated patients

They are a small slice of metastatic sufferers, but their characteristics make them susceptible to being treated with drugs that target the mutations. For example, tumors in which the Ras gene is mutated, which represent 5% of cases, can be treated with target therapy: in particular, the G12C mutation has been the focus of several studies presented in Chicago.

“This gives us hope: for a long time we thought it was not possible to hit Ras, but these results show that it can and in the future I hope we can do it for other mutations as well”, Cremolini emphasizes. In the future of mutated Braf tumors, which are 8-10%, there will instead be an increasingly precocious use of the target therapy which today is used only in the second line.

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The unstable cases

Another small group of patients – equal to 5% – is the one that has the so-called microsatellite instability that is, has a deficit of functionality of the DNA repair system. Well, for these patients, immunotherapy gives an extraordinary benefit, which in some cases can lead to recovery, as was reported in a study presented at the congress. A result that the researchers would like to extend to other patients as much as possible. This is therefore the meaning of some studies, also conducted in Italy, which have tried to understand if there are and what are the signals that could make us understand which “stable” tumors are more susceptible to immunotherapy.

In Chicago, Angela Damato, from the USL-IRCCS Reggio Emilia company, presented the results of the Nivacor study which demonstrates how the nivolumab immunotherapy is added to a course of aggressive chemo, there is some activity even in tumors that do not show instability.

In the same direction, a research published two weeks ago in Lancet Oncology by Cremolini’s group that used another immunotherapy, atezolizumab, demonstrating not only a signal of activity in the “stable” but also identifying a biomarker. “The hottest tumors, in which the microenvironment is rich in Cd8 lymphocytes and PD L1 positive cells, are those in which chemotherapy works in activating the immune system which are therefore more susceptible to the administration of the immunotherapy”, concludes Cremolini. All that remains is to conduct a study to demonstrate just this, selecting patients who express a lot of biomarker and recording the activity of immunotherapy even if they are stable.

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