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John Leonard, MD (Host):  Welcome to Weill Cornell Medicine, CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today we will be talking about cancers' impact on the heart. I'm really happy to have our guest today, Dr. Syed Mahmood, who's a cardio-oncologist at Weill Cornell Medicine and New York Presbyterian Hospital. Dr. Mahmood specializes in helping cancer patients tolerate the cardiac side effects of cancer therapy, caring for cancer patients with heart disease and optimizing the heart health of cancer survivors. So, Dr. Mahmood it is really great to have you here. Thanks for taking the time. You are a cardiologist who specializes in the field of cardio-oncology, which is an important, and I think an emerging area in cardiovascular medicine. So, maybe we can start by asking you to describe the cardio-oncology field to our audience

Syed Mahmood, MD (Guest): well, thank you very much for having me on the podcast. Let me start by saying that I'm a fan and a subscriber, and I have learned a lot by listening to the podcasts and just as you said, cardio-oncology is a brand new sub-specialty within cardiology and really the field exists because of the substantial advances that our oncology colleagues have made in the care of cancer patients. I'm just blown away by the fact that the number of patients who would be called cancer survivors has continued to increase over the years. As you know, in 2019, there was an estimate of about 17 million, cancer survivors in the United States and that's expected to grow to 22 million.

And this is really a marker of the tremendous success and advances that have been made in the management of these cancer patients. And so with the novel, the new cancer therapies that have been developed that have made this success possible, there's also been a growing recognition that we have to help these patients tolerate these cancer therapies, including any effects that may happen on the heart. And that's where the role of the cardio-oncologist comes in. So, physicians will train in cardiovascular disease and then we'll do additional training in the management of cancer patients who have heart disease.

Host: So, typically when someone is diagnosed with cancer, they're obviously very concerned about the diagnosis and they want to do their best to eliminate or control the disease. And so, typically the thing that's front of them, and foremost often is dealing with a cancer and taking care of that. But there are clearly scenarios where patients given that heart disease is common and cancer is common. There are a fair number of people that come into a cancer diagnosis, having a history of heart problems and treatments for cancer in some cases can affect the heart. And so how do you approach that? Or how does one think about this when one is diagnosed with cancer and thinking about how to approach their treatment?

Dr. Mahmood: That's a terrific question. And yes, there certainly is a overlap between heart disease and cancer. In fact, many of the risk scores that we use to quantify the risk of heart disease also have been shown to be associated with the occurrence of cancer. And so there are shared risk factors between heart disease and cancer. The role of the cardio-oncologist is to manage preexisting heart disease that the patient may have before the cancer diagnosis and also manage any heart disease that is uncovered during the course of the cancer treatment. Because I do agree with you that the focus that I share is that the focus should be on the management of cancer.

So, for instance, patients who have cancer can have high blood pressure, can get exacerbated during their ongoing cancer therapy. And so it will be the role of the cardio-oncologist to help control that so that they can continue with their cancer therapy. Similarly patients may, as you were saying, have other risk factors like heart failure, which is a weakening of the heart muscle. And so, our job is to help strengthen that muscle through medical therapy as well as close monitoring of the patients so that they can continue with their cancer therapy. And so there's a whole host of cardiovascular conditions that can overlap in patients who have cancer and we have many tools available to help manage these comorbid conditions so that patients can focus on their getting better from their cancer therapy.

Host: So, there are a number of different cancer therapies, whether it be chemotherapy, radiation therapy, immunotherapy that can affect the heart. What are some of the key categories or types of drugs or treatments that do affect the heart? And why do these agents damage the heart as kind of a by-product in some cases, of their cancer treatment process.

Dr. Mahmood: So, the cancer therapies, especially the new ones that exist today are remarkable in their on target effect. And are really responsible for the significant advances in cancer care that has been achieved over the last several years. But the human body is obviously quite complex and there can be off target effects from these cancer therapies. So, if I were to list off target effects that we would be concerned about they would be that patients can experience higher blood pressures as a result of their cancer therapy. We can see these in the patients who have say prostate cancer and are getting androgen targeting therapies. We can also see worsening blood pressure in patients who are getting tyrosine kinase inhibitors, which a remarkable category of medications which are oral treatments for cancer. Similarly, there can be a weakening of the heart muscle, and that can happen in patients who say have breast cancer and are getting targeted therapy which is targeting the HER2 receptor.

It can also happen in patients who are getting anthracyclines for various forms of cancer. And then again, can happen in patients who are getting tyrosine kinase inhibitors. The other broad categories of heart illnesses that can occur would be changes in heartbeats that can ,occur with several oral therapies that are out there. There can be blockages in the blood supply of the heart or the limbs that a patient may already have before a cancer diagnosis and could accelerate during the course of their cancer therapy. And we know this can happen from cancer therapies particularly immunotherapies, such as immune checkpoint inhibitors.

Or the patients who are undergoing treatment with agents such as 5FU. The other two categories that I think are worth talking about of cardiovascular illnesses that can occur is the impact on heart valves. So, for instance, a patient who was getting radiation to the chest area, that radiation, particularly in older protocols of radiation can impact heart valves, which can down the road lead to stiffening of the heart valves. And then finally cancer therapies can also impact inflammation within the body. And of course, cancer in and of itself is a pro inflammatory state, but particularly with the newer agents particularly with immunotherapy agents, there can be an inflammation of the heart.

And so the mechanisms for each of these side effects varies depending on the agent but what I would like to highlight to your listeners is that we as cardio-oncologists have many medications that we have available to us, which help us control these side effects, these off target effects so that the patient is able to complete their life prolonging cancer therapy.

Host: Some of these side effects or toxicities happen early and in the middle of the treatment some of the arrhythmias that you referenced with some drugs, others happen decades later in some cases. So, it's clearly something that may depend exactly on the treatment that the patient is getting, but in general, can you tell us a little bit about some of the tools that you and your colleagues use either before starting cancer therapy, in the middle of starting cancer therapy and then in followup, as patients might be in a situation where they need to be monitored years later. What are some of the things that you do as you assess patients?

Dr. Mahmood. : That's a great question. And my standard practice for patients who are proceeding to cancer therapy is to really understand how their heart is doing before they are exposed to any cancer therapy. And the reason that we do this is because once we know the baseline, you're less likely to attribute any changes that you notice incorrectly to the cancer therapy. So, patients who come into a cardio-oncology clinic before the initiation of the cancer therapy should get an EKG, which is way for us to assess the heart's electrical circuitry. We have a detailed discussion with the patient to understand their baseline exercise capacity, because often before there are any obvious cardiovascular manifestations, the first thing the patient will start noticing is a decrease in their exercise capacity.

So, to understand that well in advance helps us to understand how the patient is doing when they are getting cancer therapy. I also will get an ultrasound of the heart. And the reason I do that in some cases is because that allows me to visualize the heart structures, to get a baseline assessment of how the heart has been doing till that point. And it also allows us then to be able to compare what's happening to the heart during cancer therapy compared to the baseline before they started cancer therapy. Another new tool that we have available to us is called the cardiac MRI. And this is really the state of the art non-invasive method of understanding what's happening within the heart muscle, what we call tissue characterization.

So, that'd be have a really good understanding of how the patient is doing before the start of the cancer therapy and also during the cancer therapy. Regarding monitoring patients as they're undergoing cancer therapy, what I tell patients is to keep in mind how they're feeling. And if they find that they are having fatigue that is out of proportion to what would be expected during their cancer therapy, if they are finding themselves unable to walk as far as they could, and maybe having more shortness of breath; then that's really a reason to reach out to us because then we would repeat this cardiac testing that I just went through, the EKG, the ultrasound, we can do certain lab works to see how the heart is doing, to really try to understand whether they are having some side effects from this life prolonging cancer therapy that involves the heart. And as I mentioned, we have many medications that are available to us to help patients tolerate these side effects.

Host: One of the side effects or one of the challenges cancer patients have relates to some of the symptoms you just cited. Patients can have fatigue. They might be anemic. They may be tired just as an effect of the treatment, unrelated to the heart. They may not be able to walk as far or climb stairs as much. It seems to me like the degree of their symptoms and perhaps some other associated findings such as leg swelling or cough or pain, that might trigger whether or not, they should not just attribute things to the cancer treatment or the cancer itself, but maybe chase after the heart. Is that a fair statement or are there other kind of red flags that you would say to a patient? Yeah, don't blame this on the cancer treatment. We really should take a look at what's going on with your heart.

Dr. Mahmood. : Yes. I think that's a very accurate description which is that in patients who are having above expected, shortness of breath, leg swelling, decreased exercise tolerance; we want to be very thorough in understanding whether these symptoms are simply related to their cancer therapy or could it be due to the cancer therapy's impact on the heart. And in this discussion, we always keep in mind, one, what is the cancer that the patient has and more importantly two, what is the actual cancer therapy that they're getting? So, an illustrative example, maybe a patient who say is having breast cancer and is undergoing treatment with HER2 receptor targeting therapy which as, you know, as a life prolonging cancer therapy. In these patients, we already know that some patients would experience a reversible weakening of the muscles of the heart. And so, for patients who are undergoing this sort of breast cancer therapy, I always tell them that please be aware of any changes that you notice because if you do start having any of these symptoms, then we would do an ultrasound of the heart to see whether the squeezing function is down.

And one of the bigger advances in cardio-oncology is also understanding when do we continue with the cancer therapy? Because we can support the patient with the symptoms that they're having. So, for instance, for these breast cancer patients who are getting Herceptin also called trastuzumab or other agents in that drug category, we know that some patients will have a mild weakening of the muscles of the heart and that these patients, once we start them on heart protecting medications, such as beta blockers, ACE inhibitors, these patients can actually tolerate the life prolonging cancer therapy despite this mild weakening of the heart. And we can actually help them complete their cancer therapy which we know is associated with better outcomes. And then after they've completed the cancer therapy, we continue them on these cardioprotective medications, over time, allowing the heart to recover to its normal functioning in most cases, and then eventually take them off these cardioprotective medications that we started because of the effects of the cancer therapy.

Host: One of the questions that comes up is who should see a cardiologist who specializes in cardio-oncology? There are clearly lots of oncologists. There are lots of cardiologists. There are relatively few physicians like yourself who specialize in cardio-oncology. Clearly you can't see every patient with cancer getting cancer treatment. And clearly many patients have cardiologists from their pre-existing history. Are there certain categories of patients who you would recommend specifically see someone with your expertise because of specialization required and the knowledge required of   their particular situation?

Dr. Mahmood. : Yeah, so I think that's a terrific question. And what I would tell your audience is that if there is a patient who has pre-existing risk factors for heart disease, so for instance perhaps advanced age above 65, or they have high blood pressure or they have diabetes or obesity, then we start thinking about these patients as being at relatively higher risk for the development of cardiovascular disease. And so patients who are at relatively higher risk should see a cardio-oncologist. And the purpose of seeing us would be that we would focus on really managing the preexisting heart disease and optimizing it. So, for instance, if the blood pressure is not well controlled, we would get better under control. The cholesterol is not well controlled. We would try to get that controlled as well. We'd work with the endocrinologist to control the diabetes because the better shape these risk factors are in, the better the patients are going to do when they have this added stress of undergoing treatment for their cancers.

I would also say that certain patients who are getting cancer therapies that we know are associated with cardiovascular side effects and these include anthracyclines that we know can weaken the heart muscle in some cases, or who are getting HER2 receptor targeting therapies or getting certain types of tyrasine kinase inhibitors, such as ibrutinib or osimertinib which have been associated arrhythmia as well as weakening of the heart muscle or are getting medications that can accelerate atherosclerosis, a buildup of plaque within the blood supply of the heart and legs such as checkpoint inhibitors. Patients such as these should also be referred to the cardio-oncologist so that we can continue to monitor them and put them on any protective medications that help control their risk factors.

Because ultimately, the goal is that we live in this wonderful era of these amazing advances in the treatment of cancers. And by in advance controlling these cardiovascular risk factors, we can help ensure that the focus is on completing the cancer therapy which most of our patients are able to do.

Host: You highlighted the fact that there are so many new agents and advances, and I think that's one of the reasons why a cardio-oncologist may be particularly helpful in that a general cardiologist may not keep up with the changes in drugs and medications. And I think this is really an advantage of being treated at a multidisciplinary center where you can avail yourself of experts amongst all the areas of medicine involved with cancer patients and cardio-oncology is one of those among some others.

I want to ask you about your research interests around the immunotherapies, the immune checkpoint inhibitors and CAR T-cells. And I know that's a research area for you and an area of special expertise. I know that many in our audience are familiar with the advances of immune checkpoint inhibitors activating the immune system to fight the tumor as well as CAR T-cells, a way of engineering, the immune system to fight certain types of tumors. We have them available in lymphoma, in certain types of leukemia and multiple myeloma. They're being researched in other areas. It might be surprising to people that these immune based drugs can affect the heart. Can you explain a little bit about how that works and why patients getting them these treatments need to be monitored for cardiac issues?

Dr. Mahmood. : Yeah, I think you've raised a very important point about immunotherapy. You know, as a cardiologist, I'll often joke with my cardiology colleagues that the the biggest thing that's happened in medicine is not within the field of cardiology, but rather within the field of oncology with immunotherapy. And just as you were saying, the two most exciting categories in my mind are immune checkpoint inhibitors which incidentally, the 2018 Nobel Prize in Medicine and Physiology was given to the scientists who identified these checkpoint inhibitors. So, I have to underscore how breakthrough this new technology has been.

And the second is CAR T therapy also for relapsed refractory cancers. And what we have found over the last several years since these therapies have become food and drug administration, FDA approved for treatment and their use has been more widely adapted; is that in fact they do have an effect on the heart. And speaking about immune checkpoint inhibitors, this is by far a life prolonging breakthrough cancer therapy. But in a very small number of patients, I would say less than 1% of patients, what we find is that immune checkpoint inhibitors activate the immune system of the patient and the immune system is then able to successfully target the cancer. But the immune system can also cause inflammation in the heart. And part of my research has been on understanding how these patients do, who develop this very rare adverse event of an otherwise remarkable life-prolonging cancer therapy. And we have been able to, I hope advance our understanding of one, how to manage these patients so that we can control this inflammation. And get them out of the hospital as soon as possible. So, they can return to their oncologist and resume additional avenues of cancer therapy. And two, we also focus on risk stratifying. So, we're working very hard and trying to understand who these patients are, who will have these sorts of adverse events as well as understanding that once we identify this adverse event, this inflammation ongoing in the heart, who is at risk of a bad outcome.

And so we've been able to use echocardiography as well as cardiac MRI to look at the heart and identify things such as a strain, which is a particular way of assessing how the heart is doing. It picks up subclinical dysfunction in the heart and use these modalities and these measurements to try to understand who's going to be at risk, that we can do a really good job in taking care of those patients and prevent them from getting more sick from this adverse event related to immune checkpoint inhibitors. The other line of therapy that I'm very excited about is CAR T therapy, as you mentioned.

And I'm amazed by the advances that have been made in the use of CAR T therapy. And of course all of us in the field of our cardio-oncology are reporting seeing more and more of these patients because their use has been expanded significantly since FDA approval. And so what our research and the research of others has shown, is that again, similar to immune checkpoint inhibitors, CAR T therapy can be associated with inflammation in the body because the CAR T cells are doing what they're supposed to do, which is targeting the cancer. But there can be more generalized inflammation in the body. And what we have found is that in a small minority of patients who have a greater degree of inflammation that sets up the mileau where the heart really is asked to bear the burden of sustaining the body during that inflammation.

So for instance, there can be changes in blood pressure. There can be fevers. There can be more difficulty breathing in patients who are having this inflammation. And so the heart is really called upon to sustain the body during that time. And in a minority of cases, we can see a weakening of the heart muscle. And so my research has really focused on following these patients to one, understand what is the burden of this cardiomyopathy, this weakening of the heart muscle. And two, try to understand who is at risk of developing this weakening of the heart muscle, the arrhythmias that can happen.

Because once we understand that, the cardio-oncologist can really do a better job of risk stratifying patients who are about to get CAR T therapy, as well as get involved in the management, after the infusion of this life prolonging cancer therapy, to do surveillance on who is going to develop these cardiovascular events and then manage them because again, the shared focus of all this effort, should be on the treatment of this cancer.

And by managing these cardiovascular effects and controlling them so that they don't get out of hand, we can work with the oncologists and with our patients to have this undivided attention on treating the cancer that the patient is having.

Host: So, in our last couple of minutes, I want to just touch on the fact that which is great news, that cancer patients are living longer and doing better. There are tens of millions of cancer survivors in the US. People that have either had cancer and are doing well in remission or cured. And some of whom are living for many, many years with their cancer diagnosis also in many cases doing well.

But a number of these individuals, some of whom may be in our audience need to think about their cardiovascular risk in the long-term and potentially be monitored for these risks and to try to prevent any problems down the line. How do you advise someone who was treated for cancer, say five or 10 years ago or longer? How should they be monitored and cared for in order to try to prevent any longer-term problems?

Dr. Mahmood. : I think that's a terrific question and I completely concur with you that the real breakthrough story here is the improved survival. I mean, we live in a wonderful era where there are multiple cancer therapeutics available and we are seeing more and more cancer survivors. And so, as I had alluded to before, I would say that it is very striking, that there are common risk factors for the development of cancer, as well as for the development of heart disease.

So, for the ever expanding cancer survivor population in the United States, we have to do a really good job in controlling these cardiovascular risk factors. There is data to show that for instance, that in patients who have undergone STEM cell transplant, they have a higher rate of diabetes, high blood pressure, increased cholesterol, than the general population. So, there's something about that post-cancer condition which increases the occurrence of these risk factors. However, we have many, many medications that we can use to control these cardiovascular risk factors. And so what I tell cancer survivors that I see in clinic is that this is a time for celebration of the successes of oncology and they should enjoy their lives, and they should check in regularly with their cardiologist or cardiac-oncologist so that we can monitor their cholesterol, so that we can do a really good job of controlling their blood pressure.

So, that we can do a really good job working with the endocrinologist to control diabetes. And by investing upfront in controlling these risk factors, we're really investing in their health 20, 30, 40 years down the line. So that, yeah even if they are an accelerated risk for these cardiovascular risk factors, by putting them on a statin, by putting them on blood pressure control medications, by encouraging them to be cardiovascularly fit, by going out for regular walks, by being active in the gym, we're investing in their health decades down the line, despite their prior exposure to cancer and cancer therapy.

So overall, I would say that, you know, the real success story is that it's been a privilege to work with so many cancer survivors because of the advances made in cardiology. And by continuing close followup with your heart doctor, we can ensure health many, many years after cancer therapy.

Host: Well, I want to thank you for these insights today. I think that they've been very helpful to our audience and certainly provided some thoughts for people out there who may not have had their cardio vascular health front and center. And I think, again, as I mentioned earlier, this is a really important part of the idea of a multidisciplinary team, where you can get expertise in all of the different aspects of cancer care, some of which might not be as obvious to you, but for some people can make a big difference in the longterm. So, thanks for your work and thanks for what you do for our patients.

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