Michal Eid: "Precision therapy is suitable for a third of patients in oncology and the number is increasing."

Increasingly, we are encountering the terms "precision medicine" and "personalised medicine". What is the relationship between them?
Precision medicine can be seen as a higher level of personalised treatment. Generally speaking, it is tailor-made treatment. It is a relatively new approach, where we do not just define a specific tumour in a specific location in a patient, but name it much more precisely, based on molecular genetic testing (panel sequencing using next-generation sequencing). Just as no two people have the same fingerprint, no two people have the same type of tumour. We try to find such uniquenesses, and if there is a targeted therapy for them and evidence of effectiveness, then we treat these patients in a targeted manner. In other words, it is not enough for us today to know what the location of the tumor is and what the histological type is.

So if I recall the well-known statement that there is not just one cancer, but hundreds of them, with this approach this number increases by another order of magnitude...
Let's say that we have over a hundred different types of cancer, and by further subdividing these types according to the presence or absence of a given gene aberration, we get into the high hundreds to thousands of different subtypes of cancer diagnoses and we try to treat them individually. This is a principle that has been known for ten to fifteen years, or even longer for some diagnoses. However, precision oncology is currently experiencing a huge boom. If you were to attend an oncology conference, a large part of the announcement deals with precision oncology.

So how non-universal is cancer treatment?
Thirty years ago you were diagnosed with colon cancer and treated with one type of treatment common to all patients. Today, for the vast majority of patients, we are not satisfied with information like "it's colon cancer". We want to know what type of cancer it is, what subtype it is, what mutations it has, and ideally we would like a hundred colon cancers to be treated a hundred times differently. We are somewhere completely different than we were ten years ago, and in another ten years we will be somewhere completely different than we are now. According to the latest data, a precision approach in oncology is appropriate for one third of all cancer patients, and this number will undoubtedly continue to rise.

How is the diagnosis done in practice and how do you decide whether to treat the patient as standard or to proceed with personalised treatment?
For some diagnoses, personalised treatment makes more sense, for some it makes less sense. For example, it makes a huge difference for bile duct, lung, breast, colon or neuroendocrine tumours. However, the European Society for Medical Oncology has recently issued a new guideline suggesting that certain types of sarcomas, thyroid tumours, rare tumours - those with an incidence of less than six per 100 000 per year, tumours of unknown origin and gastrointestinal stromal tumours (mesenchymal tumours of the wall of the digestive tract - author's note) should also be tested. Another indication is for patients who can be considered for targeted therapy regardless of histological diagnosis and localisation, but only with regard to whether they have a given targetable gene variant. Thus, this therapy is administered based on the molecular profile of the specific tumour. This is called tumour-agnostic therapy and we have six products registered for this type of therapy today and a seventh in the approval process. There will undoubtedly be more to come. The above indications for molecular genetic testing are much broader now than they were, say, five years ago.

At what stage of the disease is personalised treatment indicated?
The basic parameter is that the patient is in a good clinical condition to allow further treatment. The whole process takes time. The result of the panel sequencing is known in two to three weeks after the indication by the treating oncologist, and negotiations with the insurance company take about a month. It takes approximately two months from the physician's indication to the potential initiation of targeted therapy based on the panel sequencing results and the molecular tumor board recommendation. It is therefore a big mistake to refer patients for this type of treatment who are significantly overtreated, exhausted and frail, when they would have difficulty tolerating any further treatment. The second prerequisite is that the patient must have a disease that cannot be cured, i.e. it must be palliative cancer therapy. In the Czech Republic, the reimbursement of new targeted drugs in oncology is set in such a way that the patient should have exhausted the standard cancer therapy options in order for the drug to be reimbursed by the insurance company. Of course, this is often at odds with the results of phase II and III clinical trials, where targeted drugs are administered earlier in the earlier stages of palliative cancer treatment.

And it's also something that's often the subject of discussion in publicized cases...
I can't say it's something I like to respect. Because it's the patient who has already exhausted the standard therapy options that tends to be significantly overtreated and usually frail and may not have a great survival time anymore, unfortunately. And there are aggressive diagnoses like biliary tract tumors or pancreatic tumors where we have to act quickly. That's why I don't completely agree with the last condition of the insurance company, and we try to test selected patients earlier so that we have information about further therapy options early and can negotiate with the insurance companies early.

What is the proportion of patients you refer to the personalised treatment programme at your workplace?
As of May 2021, we have 500 patients tested. We are currently at an average of sixteen patients tested per month. Suitable patients for testing are selected by the treating oncologist who sends me the patient's records for review. It is a condition of the insurance company that the testing is first approved by the so-called molecular tumour board, which I chair, and within which we discuss individual patients. Only absolutely isolated cases are not recommended for further testing.

How does your workplace stand in terms of facilities?
In terms of standard equipment, we are quite comparable to workplaces in Western Europe. Precision oncology in adulthood itself is not something that is done only in Brno. The molecular tumor board has multiple Comprehensive Cancer Centers. However, at the University Hospital Brno we also deal with paediatric patients, rare and ultra-rare diseases in childhood and vascular malformations. Within the Centre for Precision Medicine, we currently have four sub-centres and commissions, which is already unique in the Czech Republic. In addition, the plan is to involve other specialties such as neurology, cardiology or haematooncology, and the purpose of the Centre is to coordinate all precision medicine across disciplines.

Can you describe the progress that precision medicine has made in recent years?
The progress is truly incredible. What we learned a year ago may not be true today. Virtually every day, new studies or case reports appear that take knowledge a step further. In 2023, the number of patients suitable for targeted therapy, regardless of diagnosis, was 30%. In 2017, the figure was 17%. This percentage has almost doubled in six years. Our vision is that precision medicine and precision oncology should be available to every suitable patient with advanced cancer. However, there is already talk that by 2030 every patient with a metastatic tumour will be sequenced at the start of their treatment. And it is likely that in such a decade we will sequence any patient at any stage of the disease. Indeed, the cost of sequencing is steadily decreasing. Currently, the cost of one such panel sequencing (high tens to hundreds of genes under investigation) is approximately equal to four different predictive PCR assays, which is now the standard for many diagnoses. It is then preferable to perform one comprehensive test at a time from a single biological material.

Ideally as early as possible...
Exactly. But it's important to remember that all clinical trials that are done on targeted therapy start by testing a patient who has exhausted all treatment options and has more or less nothing left to offer. Then that therapy is offered to patients in an earlier line of treatment, and when it is found to work, it is tested in an even earlier line. We are now in a period where targeted therapy is beginning to be offered not only in the first line of palliative treatment, but also in the pre-operative or post-operative period. And this is logical, because it is the only way to ensure that more people get access to this treatment, and this treatment is often more effective when given earlier. The dark side of this is that it is not clear how these drugs will be financed.

How do health insurance companies even keep up with precision medicine?
Medicare reimbursements are, of course, inadequate. But this is a reality that was already in place before precision medicine. The reimbursement systems cannot even logically keep up with all the research, its results, the changing guidelines... Finances are what they are, and I think we are doing quite well in the Czech Republic, and thanks for the oncology we have. However, we cannot be satisfied with the fact that there is a targeted treatment for a given patient based on a discovered gene variant that we strongly believe will work, but we cannot apply it because the insurance company will not reimburse us. It is too much of a financial burden for the insurance company, and it has to take into account that there is money left over for other patients as well.

How well is therapy keeping up with diagnosis? Isn't it doubly true in the field of precision medicine that every new answer raises more and more questions?
It is important to monitor the field and know what clinical trials are taking place, whether within the country or in the Central European region. I am just a little bit concerned that the supply of clinical trials for our patients is decreasing. Virtually none of our sequenced and treated patients have been enrolled in a clinical trial. Yet these trials are extremely important, because they can offer our patients medicines that we would not have access to for several years. The newly established CREATIC centre can help us in many ways.

How can this assistance be imagined in practice in the future? Could you give examples of ongoing projects within faculty research teams from whose findings the Centre for Precision Medicine can benefit in the future?
There are a number of research projects underway at Masaryk University that should have an impact in the future in the precision medicine approach to patients, and not only cancer patients. For example, we are currently cooperating in the Institute of Histology and Embryology, the Department of Surgery and the Internal Hematology and Oncology Clinic on an AZV grant that focuses on the development of ex-vivo cell models for pancreatic adenocarcinoma. These should be applied specifically in the precision treatment of patients with this serious disease. In terms of cancer genomics and implementation of new technologies for precision oncology, there is a long-term collaboration with Prof. Slaby's team from the Institute of Biology, Faculty of Medicine, MU and the Central European Institute of Technology (CEITEC).

The Centre for Precision Medicine brings together four sub-centres, with the aim of coordinated and efficient development so that scientific knowledge can be applied to patient care as soon as possible. How does this coordination work in practice?
We are in daily contact and all members of the executive board of the Centre for Precision Medicine meet regularly. We discuss further development, the obstacles we encounter and how to overcome them. We share with each other the latest publications on precision medicine and try to implement everything into our practices as much as possible. And, as I mentioned, the goal is to assign additional medical specialties to further develop the center.

Am I right in thinking that one of the advantages of such a connection is the possibility to respond more effectively to the development of treatment?
It's just as you say. I've already mentioned that the field of precision medicine and specifically oncology is moving forward in an incredible way. I will give you an example of a patient who was treated for a metastatic bowel tumour. The patient had multiple liver and lung metastases. He received chemotherapy, biological treatment, surgery for the metastases, radiation and radio-interventional procedures. However, repeatedly the disease returned until finally it was extensive with multiple metastases. The procedure described so far was quite standard. During the course of treatment, as he was beginning to approach the last standardized therapy, we decided to refer the patient for panel sequencing to give us hope of administering a therapy that has not yet been standardized but for which there is already evidence that it works. From the tumor sample, we found what we call an amplification in the ERBB2 gene that can be targeted with therapy. Back then, we did not have the modern therapeutic products that we have today, but even those, let's say basal ones, which are approved by the insurance company as generics, were given to the patient. Today, it's been over two years since he was treated with this very simple and relatively inexpensive therapy, and his largest metastasis has shrunk from eight centimeters to two. His oncomarkers have dropped in an extreme way and have virtually normalized. The patient goes for three-quarter hour drips every three weeks and is extremely happy because no one is poking him, no one is cutting him, and no one is irradiating him. This is how I want to demonstrate how we can change the course of therapy and the overall prognosis during treatment. Just to give you an idea, metastatic colon cancer has a median overall survival of about 34 months. This patient is now five years from diagnosis. We're essentially making cancer a chronic disease. In addition, we have recently added another study that demonstrates the effect of a modern targeted drug that is clearly a good fit for this patient. We have other treatment options.

What are the biggest challenges in precision medicine today?
That's an amazing question... (laughs). There are several challenges. One is the availability of panel sequencing for the right patients at the right time. Next, it is certainly the availability of drugs recommended by the molecular tumor board, but this is a problem not only in the Czech Republic but throughout Europe. Another challenge is the correct handling of panel sequencing data. Some molecular tumor boards for adult patients in the Czech Republic, including ours, are perhaps a bit more adventurous and recommend treatment based on preclinical research or case reports. On the other hand, there are cancer centers that really only go after hard data, such as data from phase II and III trials, without which they will not recommend treatment. Maybe it's good that it's so heterogeneous. We are trying to meet within the country and exchange experiences. Also, within the country, all the collaborating molecular tumor boards share data to show what makes sense and what doesn't. Part of the challenge is that there are labs that do panel sequencing but don't have a molecular tumor board, which I think is a big mistake. But the situation is one in the Czech Republic, another in France, or perhaps in Scandinavia or the Baltics. In some countries to the west, there is worse access to the therapy recommended by the molecular tumour board than in the Czech Republic. Few people know that. So once again, let's be happy for Czech oncology.

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