CARDIAC ISSUES IN CANCER SURVIVORS Jean-Bernard Durand, M.D.

Transcription

1 CARDIAC ISSUES IN CANCER SURVIVORS Jean-Bernard Durand, M.D. Hello, my name is John-Bernard Durand. I m an Associate Professor of Medicine at University of Texas MD Anderson Cancer Center, and I ve been working within the Department of Cardiology for the last 17 years. We re going to talk today about cardiac issues in cancer survivors. This is meant to specifically address those practitioners who see these sorts of patients in their practice and have to make good decisions about their treatment prior to their chemotherapy or radiation, during or after. Not only am I including evidence-based medicine, I m also including practice-based evidence so that as we go through this lecture, you can use that information to make active decisions about your patients. The objectives --- are --- today are to look at performance of differential diagnosis of acute left ventricular systolic dysfunction; to evaluate cardiomyopathy of unknown etiology, what we like to call CUE; define the role of diagnostic testing; delineate the role of standard heart failure therapy for acute left ventricular systolic dysfunction; and --- th --- discuss the role of re-challenge of chemotherapy. At our institution, we see roughly 3,000 outpatient and inpatient consults per year. We have over 1,000 patients that have been coded as a diagnosis of heart failure. We perform now over 16,000 echocardiograms per year, and over 60,000 EKGs per year. For a point of emphasis, in our institution and in our practice, we look at a survivor. That definition occurs at the time of their diagnosis of their cancer. Why would we do that in our institution? Because we recognize the importance of recognizing that problem very early on during the course of treatment of a cancer patient, rather than wait until they have severe symptoms after they are cured and then addressing the issue. So, a lot of our conversation will deal with the issue of how we can prevent these complications from occurring as well as treating them. At our approach, we have a multidisciplinary approach. This cannot be done in a vacuum or in a silo. There are many team members that interact and play an important role in patient care and prevention of cardiotoxic effect, having a medical director, a clinical pharmacist who can help with drug-drug interaction, a nurse practitioner, and a physician s assistant, and of course, a radiation oncologist, a thoracic surgeon, an adult and pediatric oncologist as well. We use multi-modality imaging, understanding that one single imaging modality may not give you all the necessary information you need so that you can make an educated decision about your patient during your treatment. And then, lastly, the very important role of physical therapy and rehabilitation, to keep patients active, and performance status at a high level, to minimize complications that may occur. So, the goal of a cardio-oncology clinic is the prevention, management, and treatment of cancer patients at high risk of cardiovascular complications prior, during, and long after

2 their treatment. Number two is to promote the development of new chemotherapy radiation regimens and new drug therapeutic options for cancer patients. The scope of the practice is really focused on all the different toxicities that can occur from a number of different therapies that can be given to a cancer patient. For example, we know that tyrosine kinase inhibitors are associated with the development of hypertension. That has a fairly high incidence. We also know the tyrosine kinase inhibitors (TKI) and anthracyclines can cause heart failure and cardiomyopathy, as can TKI and QTc prolongation, acute coronary syndrome, atrial fibrillation, and arrhythmias. Radiation is known to cause valvular disease and peripheral artery disease that can occur from TKI, and then, lastly, HDAC inhibitors which can cause pericardial disease and/or pericardial effusions. This is a study that was published by Greg Armstrong from St. Jude s Children s Hospital in Tennessee, looking at data from the Childhood Cancer Survivor Study. What you see are three separations of line. In blue, you see those individuals whose --- cardi --- cumulative mortality continues to go up. This starts at five years after they have completed treatment. And, you see there s a leveling off as you get to 15 or 20 years, as opposed to, or in contrast to, the orange or yellow line that shows that there is a rapid ascent, especially after 15 years, to the point that cardiovascular or non-external causes, nononcology causes will surpass the cause of death of oncology. And then, lastly, external causes. This is to reflect causes such as suicide and mental health. This is a follow-up study by Dr. Tukenova published in Journal of Clinical Oncology, and this is a sample size of 4,000 patients that looked at two primary endpoints in cardiovascular mortality after treatment for childhood cancer. And again, look at where this starts, roughly at about five years. In blue are the observed; in gold or yellow are the expected, and what you see by these impressive curves is that all cardiovascular disease, the death rates continues to go up specifically after 15 years, until --- the point --- the slope of the graph is exponential. And, you see the same --- sories --- sort of event rates for cardiac disease. The blue is the observed and the yellow or gold is the expected. Again, a very high incidence of cardiovascular death rates compared to what would be expected for this --- pa --- cohort of patients. So as an overview, we know that cancer treatments have shifted over the last 16 years, right about the year and --- when there was a major shift in oncology treatment and oncology trials. We shifted from using four or five drugs to what we call these targeted therapies, and one of the many strategies behind these targeted therapies was the idea that if we give one single agent, we can use that agent to minimize collateral injury to innocent tissue around the cancer, much like the analogy of using a shotgun versus a sniper. Use one single bullet to kill a tumor cells. Unfortunately, we have realized there is, in fact, collateral damage in innocent bystanders, in organs that may be harmed by receiving these targeted therapies. Unfortunately, there are limited randomized control trials for prevention of cardiotoxicity. However, what is available, we will discuss in this

3 next 45 minutes. And, the treatment really is focused and based on prevention, early detection, and progression of progression of heart failure. So here is an illustration I d like to propose about determination of onco-cardiology patients, and the importance and need to identify cardioprotective therapy. So we start off with a very heterogenous population. You look out in your clinic and you see many different types of patients with many different types of diseases. And, they may have --- modif --- modifiable risk factors that coexist prior to their getting their treatment, such as hypertension, diabetes, a previous history of stroke, prior bypass surgery. We know already in the medical literature that those comorbid conditions play a very important role in their prognosis, in our patients response to drugs, and even how often they will develop toxicity. So, the question becomes, as you look out in your clinic, I cannot treat every single one of my patients this way. How can I risk stratify or identify these individuals? We would propose the following: Those patients that are high risk individual, meaning they have high blood pressure, diabetes, hypertension, high cholesterol, previous heart attacks. They may perhaps be your high risk individuals that require a lot of your resources, a lot of your attention, a lot more closer surveillance. However, the low risk patients who have minimal disease or minimal --- mod--- modifiable risk factors, those may be the type of patients that you need to do a baseline type of study and then you follow them more closely, but they do not necessarily require extensive investigation throughout the course of their treatment. And that really is the quagmire because we want to identify those patients who need all of our attention, all of our resources, and minimize our attention and resources to those individuals that would do very, very well with our treatment. Every patient that we see, we always consider all the different risk factors that can cause heart failure, such as coronary disease, hypertension, diabetes, a lot of the issues that I addressed, and some of the things you may not remember, in the audience, are simple things such as the treatment of sleep apnea and what that role plays in developing heart failure. Or just a simple low hemoglobin or anemia, or smoking, or obesity, those all contribute to development of toxicities on top of standard cancer therapy. This is a --- class --- classification study that was developed in the year 2000 by Sharon Hunt. It was published in Circulation in the year We in the cardiovascular world, we started to think more and more like oncologists. We started to understand that heart disease moves through stages. So, for example, if you are a Stage 1 patient and you have hypertension or diabetes, or you are exposed to cardiotoxicity therapy. By definition, we know that those kinds of patients will, over the course of time, progress from a Stage A to a Stage D. A Stage A patient is that patient who is at high risk, but has absolutely no symptoms and has absolutely no structural heart disease. And they have never shown signs of heart failure. We also know that, for example, the Stage B patients are patients who have structural disorders of the heart, however, have never shown symptoms. Stage C patients are those who have structural heart disease and have shown symptoms. And

4 then lastly, when we think about the Stage D patients, those are the patients who have active symptoms. They usually are in the hospital. They may not be on very powerful medicines to improve their heart function. They may be even considered for an artificial heart or a heart transplant. And if you see the corollary with the New York Heart Association Class on the right, you see that Stage B is where we start to have asymptomatic, and as we move from asymptomatic to symptomatic, we can identify those patients that are Stage B, C, or D. We are well aware from a study from Von Hoff published way back in 1978 that looked at the probability of developing impaired myocardial function and a decline in ejection fraction based on exposure to a cumulative dose of greater than 300 mg/m 2 of doxorubicin, a very active agent that s used for four very common types of cancer lymphoma, leukemias, sarcoma, and breast cancer. We still know that --- ant --- doxorubicin-based therapies occur in over 50% of children who have actually improved their survival by use of this drug. However, when you look at the incidence, what is reported for development of heart failure, 1-2% if it s 300; 3-5% if it s 400; 5-8% if it s 450; and 6-20%. And, I remind you, this is from 1978, from 4,000 patients from a retrospective study. At that time in 1978, we did not perform routine assessment with the technology of an echocardiogram. So this study was re-evaluated by Sandra Swain, who published this paper in Cancer, looking more specifically at what the new data tells us, is that when we look at the incidence of development of heart failure based on dose, when you look at a dose of 250 mg/m 2, we find that in 630 patients, the incidence was actually closer to 8.8%. And at 550 mg/m 2, the incidence goes up to 65%. So, we know that with continuous surveillance, and further looking into the possibilities, that we believe that with the new age technology, that the incidence might be, in fact, a lot higher. So we need to be prepared for that as providers that we can detect, identify, treat, and manage these individuals who have changes in their heart function. One of the most important translational studies over this past decade that has been performed has been performed by Dr. Ed Yeh and Dr. Yi Zhang from Nature Medicine. What they were able to identify are that there are two primary proteins that occur in cancer biology and in heart biology: Top2α and Top2β. We know that doxorubicin, a very common agent of chemotherapy, poisons both --- top a --- Top2α and Top2β. Proliferating cancer cells can only express Top2α. The adult human heart only expresses Top2β. So, the hypothesis is that doxorubicin-induced cardiotoxicity may perhaps be mediated by this enzyme called Top2β isomerase.

5 So, what Dr. Yeh and Dr. Zhang were able to do is create an animal model where there was the presence or the absence of Top2β, as well as a control animal. And, part of the hypothesis that we understand is that doxorubicin, in particular, can affect through Top2β isomerase, injury that is in the form of Reactive Oxygen Species (ROS). When Dr. Yeh and Dr. Zhang looked at these animals, the hearts, on terms of a biopsy, and looked at those animals who were Top2β positive, meaning they had the gene, versus a knockout, they did not have the gene. What you see in control versus doxorubicin, in this slide on your lower left, you see there is disruption and swelling of the mitochondria. There is disruption of the Z band and the cardiac myocytes. And there is vacuolization injury that occurs from exposure to doxorubicin. On your right, in those individuals who are negative for Top2β, you see that structurally, by electron microscopy, the heart cells look completely normal, i.e. preventing cardiac injury. So, this is a nice example from an animal study that perhaps Top2β plays a very important role in propagating the injury from Top2β and doxorubicin. So, when one looks at more additional --- da --- data regarding Top2 deletion, we see that those individuals that have Top2 deletion versus those with Top2β, there is a significant drop in their ejection fraction, even with the heterozygous form of these animals. In terms of treatment and drugs that are related to this particular concept, there is a medication called dexrazoxane. It has an FDA approval. The on-label approval is only for women with breast cancer who are to receive greater than 300 mg/m 2. Dexrazoxane, it is a molecule that is able to bind to iron and with iron, prevent the oxidative stress that occurs from this iron-doxorubicin complex. When this was looked at in historical data, those individuals who received dexrazoxane with doxorubicin, from historical data, had a 3% incidence of heart failure. When they did not, that incidence was nearly 22%, in historical control. That is the only known medical therapy that we know that has an FDA approval to prevent injury to the heart from doxorubicin. I now would like to share with you a number of small randomized placebo controlled trials that specifically tried to address the prevention of cardiotoxicity with doxorubicin. Study No. 1 was published in Cancer in These were a small number of patients with lymphoma that were randomized to valsartan versus placebo, valsartan in blue, versus placebo, and they measured, over the course of seven days, BNP, brain natriuretic peptide, the biomarker, a biologically active molecule that is released from the heart when the heart is under stress. And what you see in the placebo arm, this level goes up and then goes back to normal by Day 7. However, there is a blunting of the effect in those individuals that are exposed to valsartan. Valsartan is an angiotensin receptor blocker, which is an antihypertensive drug, which is also a drug that is FDA-approved for treatment

6 of known heart failure. The difficulty, however, is that this trial only lasted seven days and we probably need a lot more data to be able to incorporate that into our practice. Here is another study that comes from Istanbul, published in the Journal of the American College of Cardiology in 2011, that did a comparative analysis of an echocardiogram between two groups of individuals. Group 1 were those individuals who received a statin. In particularly, they used Lipitor 40 mg daily versus those who received placebo, measuring these following indices on an echocardiogram: The ejection fraction, the end diastolic dimension, the end systolic dimension. Why would this be so important to look at? Because we understand that the ejection fraction alone does not explain all of the changes that occur to the heart. The heart, under injury, will also enlarge, both during systole and diastole. And, what this study was able to show was though individuals who received a statin such as Lipitor, there were statistically significant differences in terms of protecting the ejection fraction, prevention of the heart from getting larger during diastole and during systole. Here s another follow-up study, also from Istanbul, Turkey, from Calais, published in the Journal of the American College of Cardiology nearly 10 years ago, that looked at a comparative analysis of patients with lymphoma, sarcoma, and breast cancer. And they were randomized to placebo versus carvedilol 6.25 twice a day, so 12.5 mg daily. What you see in the carvedilol arm was there was preservation of ejection fraction the ejection fraction never falls. However, in the control group, there is a significant drop from 68 to 52% of the ejection fraction. We know in the oncology world that a 10-point drop is significant and may warrant stopping therapy. In this particular example, because we know that 50% or more is normal, these patients may still be candidates for receiving additional doxorubicin therapy. And, then, a trial called the Overcome Trial. This is a trial that comes from Spain, published in the Journal of the American College of Cardiology, that looked at two groups of individuals, 90 patients that were given both an ACE inhibitor and a beta blocker versus placebo. And what you see over the course of time was, although this did not reach statistical significance, there appears to be greater preservation of the heart function in the groups that received dual therapy for heart failure versus those who received nothing. And when one looks at the hard data from these particular trials, what you see is that premature end of study, there were far more individuals who had to be stopped on study if they received placebo versus this combination. And if you look at a composite endpoint of death, heart failure, or final LVEF of less than 45%, 6.2 versus 24 one in four patients will have this major composite event. So, these series of three --- trials --- trials represent less than 200 patients that were done in randomized placebo control fashion. However, those were very, very compelling about how we should practice to prevent injury.

7 Here is a follow up study from Danielle Cardinale published in Circulation, looking at 700 high risk individuals who received high dose chemotherapy. Their mean age was 47. In this study, they followed them for 48 months and the endpoints they looked at were MACE Major Adverse Cardiovascular Events. And they measured serum Troponin. Troponin is a biomarker that, when the heart is injured, it will be released into the bloodstream and we can detect it, typically used for acute myocardial infarction. This biomarker, in particular, may perhaps have an important role in identifying injury to the heart, in particular from chemotherapy. When one looks at the results of Dr. Cardinale s study, we see that there were three groups. Those individuals whose Troponins increased. Those individuals whose Troponins were positive and went to negative. And those individuals (in green) who never had an elevation of their Troponin. So when she looked at the event rate in these individuals, something very interesting was found. Those individuals who have an elevated Troponin and continued to be elevated during their treatment, they had the highest event rate, 84% of that rate. Those individuals who had a negative Troponin, meaning they never released the biomarker for injury into their bloodstream. Their event rate was only 1%, suggesting that maybe, perhaps, this may play a very important role in identifying those high risk patients that we need to identify early that we can treat early and follow with greater surveillance. So she categorizes these individuals as the following: Persistent Troponin elevation, high risk; transient Troponin changes, intermediate risk; negative Troponin throughout their treatment, low risk. The negative predictive value was 99%. So she did an important follow up study of looking at 114 patients, and she randomized them. Fifty-six patients received enalapril versus 58 who were on placebo. It was started one month after completion of their therapy and they were followed for one year with physical exam, EKG, echocardiogram at one, three, six, and 12 months. And here s what she found. The total group, the cumulative event rate was 27%. However, those individuals who were on an ACE inhibitor, their event rate was 2%, versus half of the patients who received nothing, starting one month after treatment. There was a statistically significant effect that maybe, perhaps, the elevated Troponin, those may be your high-risk patients that you may have to pay a little more attention to during your practice. Here s some follow up study from Dr. Cardinale, looking at patients and time to starting treatment, looking at the following endpoints: Starting treatment from one to two months; two to four months; four to six months; and six months and thereafter. What you see is a linear relationship. The earlier one starts the therapy, the greater the effects in being able to increase the ejection fraction, the heart function, by at least 10 points. The earlier, the better. However, what also catches your attention is six to eight months, zero. So waiting until they develop symptoms or waiting six months and not seeing them back in clinic, we

8 may lose our window of opportunity where we can have the greatest impact in the improvement in their heart function, and potentially their survival. So, essence is of time to detect this problem early and to treat it early and aggressively. So she defines a responder as greater than 10-point improvement, and what you see, in terms of cardiac event-free rate, those individuals (in green) who had a response had the least amount of events. Those individuals who had at least less than a 10-point increase in heart function, they had significant effects, even the partial responders as well. This is a trial study that was conducted here at MD Anderson by one of my colleagues and myself, Dr. Oliveira. We were looking at individuals who develop a drop in their heart function and performed an analysis in those individuals survival, based on whether they recovered their heart function (in green), versus those who have no recovery, and their individual confidence interval. --- Wh--- what we were able to detect, again, was those individuals who have recovery of their heart function have far better survival than those individuals who do not. So, what about the imaging modality? Why is this imaging modality so important? We know as a diagnostic tool, we have echocardiography. We know that in the practice, we also can use a MUGA for a gating study to study the ejection fraction. What would be the advantage of one versus the other? With an echocardiogram, you can define valvular heart disease, wall motion abnormality, pulmonary pressures, hemodynamics, diastology, and strain. With the MUGA, it s incredibly accurate for detection of low ejection fraction. It can be less accurate, however, if there are rhythm disturbances such as a PVC or atrial fibrillation. It gives you no information on valvular disorders and gives you little information on wall motion abnormalities. And there s not an exposure to radiation. So, echocardiography may play an important role for your diagnosis. Here is an ultrasound of one of our patients. And, if you look at this closely, what you see is the left ventricular cavity. And this is the left ventricle that s contracting. If you were to ask a cardiologist what is the heart function of this individual patient, it s 55%, completely normal. You see the mitral valve opening and closing here. And you see the left atrium here. This looks consistent with a completely normal echocardiogram. What has changed over the last five to 10 years is now the technology of using threedimensional imaging, because now, by measuring the heart function in three dimensions, the intra-observer variability, meaning when you repeat these studies again and again by different investigators, is plus or minus three. It is far more accurate to receive a threedimensional assessment of your heart function than a two-dimensional. Why would that be so important? Because the ejection fraction is a critical marker and number that we follow in order to be able to enroll patients in our cancer clinical trials.

9 But the story does not end there. We talk about ejection fraction. There s a study that was published by Michael --- Ju --- Ewer in Journal of Clinical Oncology in What was important about this particular study was the fact that an endomyocardial biopsy was done, a biopsy of their heart, and to measure injury in patients who were given doxorubicin. They used two separate systems, the McKay and the Billingham, to measure the underlying injury. And what you see here is even patients who had very low doses of doxorubicin, or 400 or greater than 500, there was still Grade 1 injuries that occurred. Meaning that just because you see the ejection fraction is normal, that does not mean they don t have underlying metabolic injury. An echocardiogram may not be sensitive enough to detect that level of injury. But we know that ultrastructurally, under a microscope, pathologically, those injury patterns have already occurred, even when the heart function is normal. So, how do we wrap this up so that this makes sense to us as providers? This is a spectrum that we like to use in conjunction with the oncology doctors. So we take, for example, a lymphoma patient who has received treatment with R-Chop Rituxan and CHOP. At Cycle 1, we, in our group, we do a baseline EKG, an echocardiogram with strain. Strain is a measure of deformation that comes from the echocardiogram. We would measure Troponin and we would measure a BNP. Provided they are all normal, we would recommend those patients go on to get Cycle 2. As long as their biomarkers, BNP and Troponin, are normal, they would go on to get Cycle 3 and Cycle 4. However, if it s positive, then that is the time to either check an echocardiogram or to consider --- adding them --- adding to their regimen either a beta blocker or an ACE inhibitor and continue medical therapy. The only time we really have a hard stop, if you re on our practice, is when their heart function becomes less than 40%. Every cycle that they receive, we have a discussion with our patients to let them know their risk and how they re doing, and then at Cycle 4, we stop. And, that s the time that the patient, the oncologist, and the cardiologist come together to make a decision: Can you stop there because you ve received excellent response. Or are there additional cycles that are needed in this patient to reach a cure or remission? And, that s where the dialog is very, very important between oncologist, the patient, and the cardiologist. So we re going to flip now to some of the newer therapies that are called tyrosine kinase inhibitors that all came about within the early We know from the Human Genome Project, there are 500 tyrosine kinases that exist in the human genome. Over 250 of them have been cloned. There are at least, but significantly more, drugs that have now been approved that are tyrosine kinase inhibitors. Four of these tyrosine kinase inhibitors can affect 17 kinases and what is important to recognize about that is that these are very promiscuous molecules in that they can inhibit multiple sites. Even though we believe they are targeted, they can attach and affect a lot of other organs with just one single molecule. So of course, the questions becomes, from the Human Genome Project, have we learned which of these tyrosine kinase are in fact cardiac-specific, meaning they are expressed and made only within the heart?

10 Here is a study that was published in Nature Biotechnology that looked at three different compounds imatinib, dasatinib, and bosutinib. Everywhere you see a white here, that represents an inhibition of a tyrosine kinase. And, what you see in comparison to imatinib, dasatinib, and bosutinib is that there are a lot more inhibition steps in dasatinib or bosutinib, compared to imatinib which has a very low incidence of cardiovascular toxicities something to consider. Here is a study that comes from Dr. Ron Witteles who is at Stanford University, and he published this paper in Journal of the American College of Cardiology Heart Failure. Looking at their cohort of patients, the number of patients who developed at least a Grade 2 to Grade 4 hypertension, and you see that number for all the different therapies approaches 65%. But there is great variability based on which one of these tyrosine kinases you plan on using. Also, look at elevated BNP, the biomarker. You see that there is all therapies, the percent of patients is at least close to 25% but is again quite variable, based on the type of tyrosine kinase inhibitor. We know that the FDA approved tyrosine kinases and the year of their approval, we also understand their mechanism of action. When you look at green and red, vascular endothelial growth factor, platelet derived growth factor, play an important role in inhibition, and you see their respective incidence of heart failure, anywhere from 1% to 27%. There are FDA approved targeted therapies that we know can cause cardiomyopathy, which is the CMP here, and hypertension. What we do know from experience, from many investigators and clinicians, is that when you start these patients on ACE inhibitors and beta blockers, they do extraordinarily well. And, the SHF and DHF represent systolic heart failure and diastolic heart failure, and you see these two molecules here, sunitinib and bevacizumab, the ones that tend to cause a lot of hypertension. They cause both systolic and diastolic heart failure. How does this all play out in terms of real world patients? At Stanford, they looked at 247 consecutive patients that were referred. The average drop in heart function was from 60 to 41%. Eighty-four percent of them were given beta blockers, 83% ACE inhibitors, and then four patients were given what s called CRT, cardiac resynchronization therapy, a special kind of pacemaker that coordinates the right from the left side of the heart to potentially improve survival. The average EF, ejection fraction, after treatment with these drugs, increased from 41 to 53%. Three-quarters of the patients recovered their ejection fraction back to normal. Here s a follow up study from Dr. Brian Rini, who is at Cleveland Clinic, that asks a very important question: How does hypertension serve as a biomarker for efficacy in

11 treatment of cancer patients with kidney cancer who are treated with Sunitinib, an agent that is known to raise your blood pressure? He looked at outcomes by looking at objective response rate, progression-free survival, and overall survival in all individuals who had a rise in blood pressure, or no rise, both in systolic and diastolic pressure. And I focus your attention here to overall survival, in months. What you see is those individuals who have a rise in their blood pressure, their average survival is 30.9%. Those individuals who failed to have a rise in their blood pressure, their systolic blood pressure is 7.2. And, here is a graphical survival curve that looks at all the different options for these patients, dose reduction, antihypertensive drugs, both/neither, and then no hypertension. What should capture your imagination is that those individuals who develop hypertension and are treated, they do very, very well. However, individuals who do not have a rise in their blood pressure, they have a significant increase in mortality very quickly, early on, within several months. So looking for the hypertensive response is an important component of identifying these problems early on. So, there s one concept that I think is very important that audience understands, that we are starting to understand the biology of cancer and the biology of the heart much closer together. One example is the example of stress. Here is a paper that was published in Nature Review Clinical Oncology. The author is Powe. And what he proposes is that the sympathetic nervous system, that system in all of us that is our fight-or-flight, when that is activated from stress that releases our stress hormones, one of which is called norepinephrine. Norepinephrine travels through the bloodstream and interacts with a number of white blood cells called macrophages. These macrophages are responsible for interacting with cancer cells and releasing these very high pro-inflammatory chemokines. What was discovered in this model and postulated was that, in fact, beta blockers inhibit adrenergic activation of targeted therapies. So meaning these cells, they upregulate their beta 1 and beta 2 receptors. And when you inhibit them, you can potentially prevent metastasis, these cells from going other places in the human body and setting up shop. So remember, this is a model. We don t have human data yet. But I will go through some retrospective study that will help you to understand this a little bit better. So in a graphical form again, what we understand is that any injury to the heart be it hypertension, chemotherapy, diabetes, that activates these stressful systems of neurohormones that affect hypertrophy, apoptosis, arrhythmias, remodeling, fibrosis, all of those affect morbidity and mortality. That s the cardiovascular world. In the oncology world, we also understand that the growth of a tumor requires stress hormones and that involves angiogenesis, proliferation, cell growth, undifferentiation, and that contributes to metastasis, morbidity and mortality.

12 So here s a study that comes from MD Anderson, published in Journal of Clinical Oncology, and this was a study that was conducted in women with triple negative breast cancer. And why that is so important is that triple negative breast cancer is one of those few types of cancers that we really don t have a lot of option. Women don t live a long time when they have this particular agent. What the investigators did here was they looked at women who were on beta blockers with triple negative breast cancer. In blue are the group with no beta blockers. In orange or yellow or gold, those are on beta blocker. And what you see is the probability of relapse free survival. And the probability of overall survival over the course of years is much better in those women who receive the beta blocker, versus those who do not. Remember, the mechanism of action of a beta blocker is to inhibit or antagonize adrenergic receptor. However, when one looks at the progesterone and estrogen receptors, that did not seem to play an important role in affecting overall survival. Here s a follow up study, published again by this author, Powe, and --- it was --- the study was done looking at hypertensive women that were already on a beta blocker. And then looking at the probability of survival, time taken for --- are dis--- distant mets, and breast cancer-specific survival. And what you see in orange, those individuals are already on a beta blocker, they have statistically significant better survival than those who are not a beta blocker. Again retrospective data but certainly asking the question: How important are beta blockers for the anticancer effect and maintaining patients free of cancer? So, we know that the model that has been seen here by MD Anderson has been --- repl --- replicated now around the world. We now have a cardioncology partnership at Vanderbilt University. There is an International Society for Cardioncology that was based out of Milan, Italy. There is a Brazilian cardioncology program that is based out of Sao Paulo, Brazil. There is now a Canadian Cardioncology program based out of Ottawa, Canada. There are a number of ongoing studies that are happening, including the use of enalapril for Troponin-guided strategy; the use of candesartan versus placebo after treatment with trastuzumab in the Netherlands; and carvedilol versus placebo and anthracycline-based breast cancer therapy. So how do you put this all together and all the services that we have here at MD Anderson because of this multidisciplinary approach? We have a number of different cardiologists who play a role specifically geared towards --- preventin --- preventing injury to the heart, such as Interventional --- Onc --- Oncocardiologists and Electrophysiologists, Cardiomyopathy Clinic, Pacemaker Clinic, Radiation After-Effects, a Valve Clinic, a Cardiac Tumor Board, an MRI Service, Echocardiography Lab, a Carcinoid Board. We even have individuals who specifically are involved in pregnancy that occurs related to cancer and heart disease. And preoperative and pre-chemo evaluation to help our patients to be effectively and successfully treated for their cancer.

13 So, what are the challenges? The challenges that we have in our cancer patients are the following: Having an excessively fast heart rate, having a blood pressure that s too high or too low, having creatinine or kidney function that affects our ability to use many powerful drugs to treat their cancer. And what are their individual causes? Biomarkers, what are great about them, is their ease of being noninvasive. Unfortunately, they lack specificity to help confirm a diagnosis. BNP and Troponin can be elevated in other heart conditions. We need to address early sepsis and anthracyclines likely result from injury, direct myocardial injury. We know that tyrosine kinase inhibitors, they may become elevated. However, they also may be nonspecific. The one area that we know very well about is an entity of iron overload cardiomyopathy, that ferritin levels correlate very, very well with cardiac involvement. And then lastly, cardiac amyloid has established guidelines for staging with NTproBNP or BNP, and Troponin T. So in summary, ultimately the success of cardiology in clinic has its fundamental basis in the relationship between the cancer, patient, and the oncologist relationship. We know there s a lot of exciting new therapies that are being discovered. But in order to maximize their potential, we have to identify these cardiotoxicities up front and early and treat them aggressively. And --- though --- although recent clinical trial has shown significant postchemotherapy trials with toxicities, we ve also seen resolution of these by standard of care, routine heart failure therapy. And of course, more work needs to be done collaboratively with our oncology colleagues in biomarkers as well as cardiac imaging for early detection and treatment. So a takeaway is that there needs to be a commitment of cardiologists to be fully engaged to cancer treatment. We need to attend and present at local Oncology Tumor Boards. We need to commit to attending at least one major Oncology meeting every year. We need to develop protocols as collaborators in partnership with oncologists. There needs to be education of local cardiology practice and hospital metric so we can track quality of care. And we need to commit to identify translational cardiologists and oncologists to promote a better understanding of the mechanisms of the toxicities. So I d like to thank you. I ve included my as well as my Twitter account. I welcome any feedback of any sort that will help us so that we can better help you as providers. So that we can all help our cancer patients to successfully get through their chemotherapy without having any kind of cardiovascular event. Thank you.