METASTATIC BREAST CANCER TREATMENT

Dr Carlos Barrios is a medical oncologist from Brazil. He has dedicated his career to breast cancer research and clinical trials,  and coordinates the Latin American Cooperative Oncology Group in Brazil, which congregates investigators from 16 different countries in the region.

His main interest is to establish collaboration between institutions across different countries, to further breast cancer research.

He was a guest speaker at our 2024 Annual Scientific Meeting and we spoke to him about the sequencing of antibody drug conjugates and what to do after metastatic breast cancer patients progress on CDK4/6 inhibitors.

“Well, I’m here to discuss a number of things in two different talks. One of them, is going to address antibody drug conjugates. We need to realize that we are facing three different revolutions at the present time in the management of cancer in general, but breast cancer in particular. One is immunotherapy that has a broad impact in oncology in general, and it’s starting to have a larger impact in breast cancer.”

“The second one is the CDK4/6 inhibitor revolution, where we are changing the treatment of patients with hormone-receptor positive disease, with survival benefits we have never seen before. And the third revolution is the antibody drug conjugate.”

“Antibiotic drug conjugates are different complex drugs, where you put together an antibody that is directed to a specific antigen, you put a linker that actually links that antibody to a cytotoxic, such as a chemotherapy, and that conjunct of components actually has demonstrated to be much more effective than standard chemotherapy whenever it has been tested.”

“So, these drugs are revolutionising the management of breast cancer in different arenas. Particularly in HER2-positive disease, but also in hormone-receptor positive disease and triple-negative breast cancers.”

“So, I presume, or I predict that these drugs are going to be more and more impactful in what we do in our everyday life in clinical practice. And we’ll have a significant impact on outcomes for patients whenever the drugs are indicated.”

So, essentially, it allows the chemotherapy to more effectively target the tumour, is that correct?

“Well, the mechanism of action of the antibody drug conjugates remains, in my opinion, to be elucidated. We discuss the principle that by linking the drug to the antibody, you will prevent some of the toxicity that cytotoxic drug will have. However, that’s not necessarily what we see. We see significant amount of toxicity still when you give these drugs, but they are much more effective.”

“And at the same time, these drugs are more effective than most of the chemotherapies that have been tested against. So, I think that the idea of the mechanism of action, still remains to be clarified. There are a number of different potential mechanisms of action, not necessarily just protecting that particular toxic drug from causing toxicity.”

“However, the process still has some caveats we need to recognize importantly. We do not study very well the mechanism of resistance to these drugs. We just define that they work better than we had before. But why they stop working remains, in most cases, still a black box.”

“We know some of the mechanisms, but not necessarily all. And that’s critical for one reason as we have these drugs now into the market, and as we benefit more patients, after the patients actually progress, or the drugs stop working, what do we do next?”

“So, sequencing these drugs that seem to be a better way of delivering chemotherapy remains something that we have not been able, from the academic point of view and from the industry point of view, to study the best way possible. So that remains an unmet need and that’s what’s going to be reflected in my presentation.”

What options are there available to patients when they progress on CDK4/6 inhibitors?

“Well, the presentation I’m going to address, is a very interesting scenario that actually represents a change in what we have been doing for over the last 40 years.”

“For the last four decades, we have been treating patients with hormone receptor positive disease as if we’re all the same, giving them endocrine therapy. We have learned over the last couple of decades, that the pathways involved in endocrine signaling are much more complicated and complex.”

“And the issue, as a consequence of that, is that when we start combining drugs with endocrine therapy, we get better results. And this is what happened with the introduction of CDK4/6 inhibitors. And these are not going to be the only drugs. There are going to be other drugs that will be playing into that field. The point is that after the introduction of CDK4/6 inhibitors, we now have revolutionary survival amounts of time for patients with hormone receptor positive metastatic disease in excess of five years.”

“That’s absolutely fantastic, but the question is most of these patients actually progress at some point and what we’ll be addressing which represents again a consequence of our understanding or better understanding over the last 15 years of how complex hormone receptor positive disease is, what do you do after progression?”

“And the fact is that a number of different alternatives have been generated that actually call our attention to the fact that first we need to identify different patient populations that before we treated as if we’re all the same. Now, we must identify different subgroup of patients that have different biological characteristics, that have different biological outcomes or rhythms.”

“The disease may be more or less aggressive. And all these factors do have an influence on how you treat these patients after progression of the CDK4/6 inhibitors. And I kind of make a joke that that’s the scenario, where breast cancer is going to ever be as similar as lung cancer is. In lung cancer, we were able to, after the year 2000, identify different subgroup of patients with different diseases that are characterized by different molecular abnormalities.”

“This is not exactly the same, but similar. Breast cancer is different from lung cancer. But this is what we’re facing at the present time. So, there are three, four, five different categories, clearly identifiable categories of patients that actually deserve different treatment approaches. And this is what we’re going to be discussing in the other presentation.”

For those who aren’t familiar, why do we need to explore different sequencing options for treatment?

“Well, what we have been able to do in some cases is to cure the disease, even if it is disseminated. But that’s a minority of patients. What we do most of the time is control the disease for a period of time, but inevitably after a certain period of time, the disease becomes resistant to the therapy we give, and we need to select new alternatives.”

“So, what we do in patients that have disseminated disease, we sequence different therapies in order to prolong the life of the patients. In that very difficult process, we need to consider how long we do that in each step. And we need to consider quality of life with the toxicities patients actually have, which is each line of therapy.”

“So, sequencing remains a very important issue mainly because of efficacy and the toxicity and the consequences that these two elements have in the physician’s decision. I need the patient’s decision on how to select one treatment after the other.”

What are the benefits of antibody drug conjugates when treating breast cancer?

“The antibody drug conjugates represent a revolution because they are very elegant molecules, that are difficult to build, and they have been developed over the last 30 to 40 years. So, the concept is not new. But once we used this drug in practice, the initial idea was to prevent the very toxic chemotherapy we attach to the antibody to cause toxicity.”

“And we would have the idea that these drugs would be more tolerable.” “What we have learned is not that the toxicity is the same. We have learned, and this is the main advantage, these drugs are much more effective and in certain circumstances are leading to prolonging the survival time of some of the patients.”

“So, I think that the idea is that we have learned in this process, even though we don’t have less toxicity. We have much more effective drugs to prolong the treatment control and maybe some of these patients in certain subgroups may be cured of the disease and I’m sure that’s going to happen.”

“For example, in HER2-positive disease. We know we can cure HER2-positive disease with chemotherapy and antibodies against the disease. Certainly we have found significantly much better results and the perspective or the idea that we can cure more patients, even in the metastatic setting, in this situation is something that is keeping us very enthusiastic with the clinical applications of these drugs and clinical practice.”

How do we ensure new treatments like these are safe and effective for patients?

“Well, I think that’s part of the clinical trials and Breast Cancer Trials is actually doing that. It’s obviously critically important to recognise that we need research. We need the support for research. I think that it’s extremely critical for us to realize that support for research is scarce. We can only do limited trials from all the things that we need to investigate.”

“Certainly, we are generating a number of different alternatives for treatment over the last 5 to 6 to ten years that is absolutely impressive, but we need to do more. There are still questions we need to answer and support for research that will be well defined, well designed, and directed specifically to the populations that need treatment.”

“It’s going to be critical for us to move forward. So, I guess the final message on this issue is the fact that research is something we should all be involved with. From the patient, their physicians, society, government. In pharmaceutical industry, everybody involved in clinical research actually gains something from their participation.”

“So, I think that supporting clinical research is absolutely a must for all of us in order to improve cancer outcomes even further.”

What advice would you give to a patient who was exploring new breast cancer treatment options, such as antibody drug conjugates?

“I think that patients are a critical aspect, and they are actually the most critical aspect of all we do. Involvement of patients in the whole process is obviously mandatory. So, the patient is central in this process. But in research, we cannot do research without patients and certainly involvement of patients in research is obviously critical.”

“So, I think that that we should envision a situation where patients, when facing a situation on changing therapy or starting therapy, should ask their doctors, is there a clinical trial? Is there something I can do in order to improve knowledge and participate, gain benefits from participation of your generating information.”

“I think that in that setting, patients are obviously also very, very critical because their involvement with clinical research is absolutely mandatory in order for this to move forward.”

What excites you about the future of breast cancer treatment?

“I think that we have many challenges. And I look forward to what I can expect in the next 5, ten, twenty years. I think cancer is not going away. It’s something that we’re going to have to face together. It’s a big challenge.”

“So, we’re going to have to build a big group of people involved. In order to challenge all the issues that we need to solve, leading with cancer. Personally, I think that when you look at the results that we have today, they are better than what we had, but there’s a lot of room for improvement.”

“I think that one of the most critical things that touches me, and that I have been trying to get more and more involved in, is with the issue of access and the issue of not having equal availability of treatments all over the world. Most new drugs that are launched into the market are only available for less than 10 percent of the world’s population.”

“That’s a very big discrepancy. And that explains why the outcomes are so different in different countries and different regions. So, we need to fight against that. And there are many issues related to that. But certainly, that’s one of the things that I feel we all should be involved with. The second aspect is to stimulate more research.”

“I think that we need to build that group of people. Concentrated in trying to answer the most important questions. And having all the players actively involved. Industry, patients, governments, physicians, societies, research groups. All these need to be sitting at the table and discussing what the best ways forward will be.”

“And that probably is context dependent, in terms of what could be a solution in Australia may not necessarily work for the US or for the UK or the rest of Europe, or certainly not for South America or Africa. So, I need to see that these groups of players meet and get together within their context with specialists that know their reality in order to be practical and find the solutions that actually will help people in each different region.”