Managing Cardiac AEs in HER2-Positive Breast Cancer

Jean-Bernard Durand, MD

Certain treatments for patients with HER2-positive breast cancer can increase the risk of cardiovascular events or injury, but there are strategies for protecting patients’ hearts from anthracyclines and HER2-targeted therapies, Jean-Bernard Durand, MD, said in a presentation during the 2018 Annual Miami Breast Cancer Conference.

One of the simpler preventative measures Durand implored community oncologists to do is encourage their patients to continue with an exercise routine during cancer treatment as it strengthens the heart. More importantly though, he says, is recognizing the symptoms as soon as possible by conducting a complete medical exam and history during the first appointment with a new patient.

In a second presentation, Durand discussed the possibility of repairing cardiac damage in patients with HER2-positive breast cancer. He assured that with proper management of comorbidities, as well as using a multidisciplinary approach, extending the survival of these patients is possible.

OncLive: What are the main points of your presentation on protecting patients' hearts from anthracyclines and HER2-targeted therapies?

Is there a way to predict whether a certain patient is going to experience these toxicities?

In an interview with OncLive during the meeting, Durand, a professor in the Department of Cardiology at The University of Texas MD Anderson Cancer Center, discussed prevention, recognition, and treatment of patients with HER2-positive breast cancer who experience cardiac-related events prior to or during treatment.Durand: The take-home message is the importance of continuing HER2/neu therapy with minimal to zero toxicities. There has not been a lot of clinical data on how we can prevent toxicities from occurring. We have learned that routine heart failure therapies, such as ACE inhibitors and beta blockers, may have some protective role that could allow a patient to complete therapy without cardiovascular adverse events (AEs). Other things that we learned are the importance of giving a continuous infusion of doxorubicin, rather than giving a bolus infusion, in the amount of time that a patient is free of treatment. In other words, when anthracycline-based therapies are followed by HER2/neu therapies within 30 days, the incidence of injury to the heart is much higher than waiting 60 to 90 days.We know that 25% of these patients will express HER2 in the heart. Of the individuals who do express it, we know that they may have a predisposition to develop some sort of entry to the heart, which we now know is reversible. There may be predispositions, such as the presence of hypertension that is not adequately treated, diabetes that is not aggressively treated, a previous heart attack or any structural heart disease. If we can treat these prior to starting HER2/neu therapy, we can lower the incidence of toxicities. These are simple everyday measures that we can do.

What advice can you provide to community oncologists if their patients are experiencing these types of symptoms?

If these patients are reporting these toxicities early enough, or physicians are catching them early enough, then the patient does not need to discontinue their HER2-targeted therapy, correct?

Are there specific HER2-targeted therapies that may cause these toxicities more than others?

Most importantly, what we have learned over the last 2 years is the importance of exercise. Patients should continue their exercise programs throughout the course of their treatment. That not only lowers the incidence of injury to the heart, but it also may be complementary to the ability to respond to anticancer therapy.The most important thing is recognition. We always start with a complete history and physical exam. As an oncologist is going through their patient's history and physical exam, they can discuss the risk of hypertension and diabetes and previous structural heart disease with their patients. One avenue can be to initiate therapies while they are in the office, or to refer them to one of their colleagues; that is a specialist in the field of cardio-oncology who can manage all of the comorbidities for them. This will limit the amount of time for that portion of treatment, so that we can then move onto anticancer therapy.That is absolutely correct. One of the most important lessons that we have learned, only in the past 2 years, is that starting and stopping chemotherapy mid-cycle can actually have a detrimental effect on the ability of the patient to successfully complete and receive all of the benefits from their therapy. In other words, we have to find ways as colleagues to minimize or avoid stopping chemotherapy. That is where having a multidisciplinary approach is important, so that a patient can get through treatment event-free with minimal toxicities. We know, from all of the data published in the late 1990s and early 2000s, that 25% of patients with HER2-positive breast cancer developed either symptomatic and/or asymptotic declines in the chambers of their heart, specifically in the left ventricle. We are aware of that number; however, we also have learned that with treatment, these patients do very well, and they can fully recover.

How else can we prevent injury from occurring during treatment?

We also learned that focusing on these comorbidities plays a great role in preventing these "modifiable risk factors." A modifiable risk factor would be high cholesterol levels, diabetes, high blood pressure, previous heart attack(s), previous bypass surgery, or previous stents. If we simply practice good medicine, we can do a great job of allowing these patients to finish a therapy event-free. That is still under intense investigation. There have been a number of small studies, ironically, that have shown that starting patients on these same medical therapies used when an injury occurs has some preventive role, such as an ACE inhibitor or a beta blocker. When we use these therapies, we can stop an injury from occurring. What other things are we capable of doing? If you believe that someone is a high-risk patient, meaning that they have previous structural heart disease, they can undergo a continuous infusion over 24, 48, or 72 hours to lower their incidence of injury versus giving them a bolus infusion.

We have also learned of an agent called dexrazoxane (Zinecard), which is FDA approved to protect the heart. However, this agent is for women who have received over 350 mg/m2 of doxorubicin. Now, the current protocols are between 200 mg/m2 and 300 mg/m2 [of doxorubicin]. But, [dexrazoxane] could be an option as well.

Are there any AEs of giving an infusion over such a short amount of time?

At the rate that systemic therapies are being developed, will there be a point where these kinds of AEs will no longer be of concern?

Lastly, there is the importance that exercise and keeping patients on a good exercise regimen can keep their heart healthy as well. Yes, there is a very low incidence of developing an allergic reaction. The continuous infusion would require an admission to the hospital. Which means that this is not for every patient. Part of the multidisciplinary approach is to identify the high-risk patients. The low-risk patients, who make up a large percentage of our population, are unlikely to develop these problems. A lot of our resources and healthcare dollars are directed to identifying high-risk patients, so if we can identify them early, we may be able to intervene and lower the cost for the patient and delivery of healthcare. Wouldn't it be wonderful if we could also prevent them from any kind of injury to the heart along the way? That is a very good question, and it is our hope. An example that I gave in my talk was from data from the pharmaceutical industry stating that there are over 800 drugs that are currently in development for all types of cancers. Of those 800, roughly 50% of them have been identified as having some sort of cardiovascular AE. There is a tremendous amount of work left to do, but we cannot forget good medical practice, which is doing good due diligence and practicing guideline-directed therapies. With everything that we know about diabetes, hypertension, and structural heart disease, it is our responsibility to treat patients with those ailments as best we can prior to treatment for cancer.

How could the vaccine developments in HER2-positive breast cancer impact the prevalence of cardiac AEs?

Are there any studies related to this topic that you would like to share?

One of the evolving classes of drugs that we have our eyes on very closely is immunotherapy. Immunotherapy is a very promising therapy and it looks fantastic. However, there is a less than a 1% incidence of developing inflammation of the heart, which we call myocarditis. The morbidity, if that occurs, can be very high. We are trying to find strategies where we can identify these patients and how their immune system is working. Additionally, we want to make sure that these therapies are just attacking the tumors, and that the T cells are not redirected toward the heart. That looks very promising. We have not seen the level of [toxicity] signal with the vaccines, and we are very encouraged by what we are seeing from the cardiovascular side. Maybe that is the magic bullet. Maybe these vaccine approaches are just specific enough that they will identify the tumor cells and will bypass the other organs. That would be a wonderful story if that holds true, but we still have more work to do in that area. There are several studies that are ongoing. There are now prospective studies where we are identifying patients who are destined to receive agents such as anti-HER2/neu therapy or anthracycline-based therapy. These are being started either on an angiotensin II receptor blocker, or a beta blocker and being followed prospectively. The 2 areas of question are how many times therapies have to be stopped, and the heart function at the beginning and end of the trial.