Cancer: towards a treatment specially adapted to each patient

Just imagine: when the patient arrives at the hospital, the laboratory immediately performs a biopsy of his tumour, then analyzes it in order to establish its genetic and immune characteristics. Armed with this “molecular identity card”, the oncologist prescribes one or more appropriate treatments, which will certainly counter all the survival mechanisms specific to the patient’s tumour… Nothing can then prevent healing. This ideal scenario is what personalized medicine, the Holy Grail of the fight against cancer, is trying to achieve. It is she who will finally make it possible to overcome the status quo, where 50% of cancers still thwart conventional treatments, such as chemotherapy, radiotherapy and surgery.

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Certainly, over the past twenty years, notable successes have brought new hope to the battle waged by medicine against this scourge. Including the development of specific drugs, as was the case for chronic myeloid leukemia, a cancer of blood cells. The condition is associated, in 95% of cases, with a particular genetic anomaly: the translocation – ie the movement of a gene between two non-homologous chromosomes – of the BCR-ABL gene. Research has led to the development of a drug capable of directly targeting this anomaly, leading to a spectacular increase in the life expectancy of patients. This is just one example: to date, the National Cancer Institute has identified 144 personalized drugs – 107 molecules for targeted therapy and 37 specific immunotherapies.

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A COMPLEX COMBAT

But then, faced with so many targeted treatments, so many improved therapies, so many new strategies, why does cancer resist us again and again? Simply because it is multiple. Already, “Faced with a genetic anomaly, we do not always have an effective treatment” , recalls Gérard Milano, specialist in oncopharmacology at the Antoine-Lacassagne Center in Nice. Some existing drugs are only effective on a very limited population of patients who nevertheless have cancer affecting the same organ.

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In the lung, for example, the mutation of the EGFR gene, for which an inhibitory and therefore therapeutic molecule exists, is present in the tumor of only 11% of patients. The same cancer therefore sometimes requires totally different therapeutic approaches. The opposite is also true: the same drug can be effective against different tumors if the latter have identical molecular mechanisms. “The KRAS gene mutation is already well treated in the context of lung cancer, and large clinical trials are currently aimed at transposing drugs for pancreatic cancers, which are also 90% endowed with this same mutation”illustrates Gérard Milano.

To add complexity, the tumor itself is not physically homogeneous! “Today, we know that a tumor is made up of very different cellspoints out Fabrice Barlesi, director of the Gustave-Roussy Institute. If the treatment kills some, others can resist and multiply. ” To circumvent this problem, new so-called “per-cell” sequencing techniques (single-cell, see our main file in S&V #1242) make it possible to finely characterize this “tumor heterogeneity”. “This type of analysis consists of sequencing the tumor cell by cell – up to 10,000 – to get a good overview of its composition”, explains Patrick Mehlen, director of the Center for Cancer Research in Lyon. With this ultra-detailed identity card, doctors can combine different specialized treatments, which will attack the tumor on all fronts.

Cancer: improving diagnostics…

… by systematizing screening campaigns

Early detection is one of the best ways to reduce mortality. This is why national programs have been encouraging the population, for about twenty years, to screen for cancer of the breast, colon or uterus. Pilot studies are also evaluating the value of systematic screening for other tumours, using medical imaging and artificial intelligence tools.

… by increasing the resolution of visual techniques

In the context of breast cancer, two new technologies are tending to become more popular: angiomammography – which combines digital mammography and intravenous injection of an iodinated contrast medium – and tomosynthesis – which produces a 3D image of the breast. According to a Norwegian study, the latter technique would identify 27% more cancers than conventional mammography.

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… by creating new, more efficient tests

A lot of current research is aimed at designing and evaluating blood diagnostic tests: thanks to a simple blood test, doctors would detect the presence of tumors at a very early stage – only a few millimeters – by simply identifying tumor biomarkers.

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Finally, the ultimate pretense of cancer: not all patients react in the same way to therapies. Scientists are therefore trying to better predict each person’s responses and resistance to medication. “We have been trying to do this for a long time by growing cancer cell lines in Petri dishes, or grafting tumors onto mice explains Fabrice Barlesi. But these models only imperfectly represent the complex interactions between the tumor and the patient’s organism. ”

As an alternative, several cancer centers are now developing “organoids”, 3D reconstructions of tumors obtained by culturing cancer cells taken from the patient. Objective: to be able to compare this living model with the various therapeutic molecules and observe its evolution. “Today, we are still evaluating these organoids by comparing their response to that of the patient after treatment continues the researcher. But tomorrow, if it works, we can use it predictively to select the best treatment to administer!”

As we can see, in this battle against cancer, it is as much a question of treatments as of their personalization for each patient. Other more down-to-earth obstacles will therefore have to be overcome, starting with unequal access to care. “Today, only specialist cancer centers or teaching hospitals have the means to characterize the molecular profile of the tumour, which then determines eligibility for innovative treatments” underlines Simone Mathoulin-Pelissier, director of clinical research at the Bergonié Institute in Bordeaux.

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“Depending on whether you are treated in a dedicated cancer center or 200 km away, the difference in life expectancy can be drastic” , abounds Patrick Mehlen. It is only by improving the information given to patients, and to the doctors who refer them, that this inequality can be reduced. It is also dependent on the availability of sequencing centres, which are set to multiply as part of the ministerial plan “Médecine France génomique 2025”. “Ultimately, the development of so-called liquid biopsies, aimed at analyzing tumor DNA circulating in the blood, should greatly facilitate the sending and receiving of samples for non-expert centers” also provides Simone Mathoulin-Pelissier.

Target the right treatments

By testing the different therapies on organoids – laboratory reconstruction of the patient’s tumor – the most effective treatments can be determined. By combining several of them (immunotherapy and targeted therapies), it is thus possible to attack the various survival mechanisms of the tumor and to minimize the risks of relapse.

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MADELINE LANCASTER/MRC-LMB/UK – FLOWJEM – SHUTTERSTOCK

Perfecting and systematizing the identity card of tumors

The genetic and immune profiling of tumors is destined to be refined: this technique makes it possible to characterize the diversity and distribution of the cells making up the tumor, and no longer just an average sample. Moreover, it will soon no longer be the prerogative of certain specialized hospitals: indeed, the number of sequencing centers is set to increase considerably in the coming years.

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MADELINE LANCASTER/MRC-LMB/UK – FLOWJEM – SHUTTERSTOCK

Accompany the patient until complete recovery

By benefiting from personalized consultations – nutrition, sport and adapted psychological support – patients would see the side effects of treatments reduced and their remission would be faster. They would also become actors of their treatment thanks to complete information on their disease and their therapies.

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MADELINE LANCASTER/MRC-LMB/UK – FLOWJEM – SHUTTERSTOCK

There remains the ever-high cost of increasingly specialized treatments. Immunotherapy can cost up to €100,000, compared to just a hundred euros for chemotherapy. “A proven therapeutic innovation will hardly be refused reimbursement in the French system analyzes Valérie Paris, economist at the High Authority for Health. This means that we will either have to find savings elsewhere, or increase the overall health budget. ” A vision tempered by some doctors: “The additional cost generated by innovations is not immutable: within ten years, the patents corresponding to the first immunotherapies will fall into the public domain” emphasizes Patrick Mehlen. “The personalization of care will make it possible to avoid unnecessary treatments, and therefore to reduce costs”, argues Gérard Milano. This is the example given by Oncotype DX® and MammaPrint® two tests approved in the context of breast cancer to detect patients for whom chemotherapy does not provide any benefit compared to hormone therapy. “For these people, we can therefore be satisfied only with the second option” points the researcher .

More treatments, better predictability of their response, combinations of therapies depending on the patient: medicine promises to cure more cancers and stabilize the toughest ones. “A growing number of patients will live more or less normally with cancer with treatment, as some are coping with diabetes today”, predicts Simone Mathoulin-Pelissier. Defeat cancer, therefore. Or tame it while waiting to overcome it definitively.

Prevention, a weapon not to be neglected

This is the other front of the battle against cancers: up to 40% of them are due to behavioral factors – smoking, alcohol, diet, physical inactivity, etc. – which can be fought. “While treatment is important, health promotion is also a key issue”, says Simone Mouthoulin-Pelissier. The Institut Gustave-Roussy has designed the “Interception” program for this purpose, which consists in directing, thanks to general practitioners, patients exhibiting one or more risk factors to rapid diagnosis centres. First tested in the context of lung cancer and, soon, colon cancer, this strategy should become widespread. Objective: reduce by 30% the number of diseases evaluated at stage 2 or higher.

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Cancer: towards a treatment specially adapted to each patient


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