Protecting Breast Cancer Patients From Cardiac Adverse Effects of Treatment With Anthracyclines and HER2-Targeted Therapies

Jean-Bernard Durand, MD

As part of our coverage of the Miami Breast Cancer Conference, held March 8–11 in Miami Beach, Florida, we spoke with Jean-Bernard Durand, MD, about protecting against serious cardiac adverse events in patients who are being treated with anthracyclines and human epidermal growth factor receptor 2 (HER2)-targeted therapies. Dr. Durand, a cardiologist and medical director of cardiomyopathy services at the MD Anderson Cancer Center, discussed this topic in a talk at the conference.

-Interviewed by Anna Azvolinsky

Cancer Network: What are the data on anthracyclines and HER2-targeted therapies that make cardiologists such as yourself concerned about patients who are receiving these drugs as treatment for their breast cancer?

Dr. Durand: Our biggest concern has been partly the incidence [of cardiac problems]. Between 7% and 16% of patients have a heart function issue, based on a dose of anthracyclines between 200 and 300 milligrams/m², which is the typical dose. Our concern is that, although these patients have completed their treatment and are free of disease, cardiac effects may negatively impact their quality of life. They spend a lot of their time going to emergency rooms or being admitted to the hospital for symptoms of heart failure, which are shortness of breath, fatigue, and fast heart rate. The patients survive their cancer only to have a very different life based on these side effects, so we are concerned about how these therapies affect our patients’ lives. Oncologists are doing such a wonderful job in treating patients and getting them to survive their cancer that they now have, in some cases, switched one disease for another. Hopefully, through work that we are doing in conjunction with oncologists and patients, we can change this so patients can benefit from the treatments they receive for their cancer and have a better quality of life.

Cancer Network: Is it only specific anthracycline-based regimens or the combination of regimen type and treatment duration that can lead to these heart issues after the patient has completed her breast cancer treatment regimen? And are there patients whom you and your colleagues have identified who are at highest risk for cardiovascular adverse events following these treatments?

Dr. Durand: We have learned that the modifiable risk factors play an incredibly important role. If a patient has diabetes or hypertension or high cholesterol, or has had any kind of [invasive procedure performed on her] heart, she is at higher risk for developing cardiovascular problems as a result of these treatments. If you think about the patient flow, it makes sense to us now that our focus should be to deal with these cardiac issues and treat them as best we can before the patient receives her treatment, rather than wait to intervene to address this in the middle of treatment or afterwards. We need to pay attention to these modifiable risk factors, which we can usually treat prior to initiation of [breast cancer therapy].

Cancer Network: What are some approaches to mitigate the risk of adverse cardiovascular events in patients who are receiving anthracycline-based regimens? Are there patients who should not be given any of these drugs despite their diagnosis of HER2-positive breast cancer?

Dr. Durand: That is a very good question. In considering whether an anthracycline chemotherapy is appropriate, we have to balance the risk of adverse cardiac events and against the potential clinical gain from the use of anthracycline-based regimens. Anthracycline-based therapies are still utilized in about half of pediatric patients and in patients with breast cancer, and they have excellent response rates. So, we don’t want to deny patients [the potential benefits of anthracycline-based treatment], except in cases where we start to worry that their heart function, as determined by the ejection fraction, is less than 40%. That is a red flag. Even then, however, we might consider an alternate relatively slow infusion over the course of 48 or 72 hours, because these drugs are still highly effective [when administered this way]. In addition, with new drugs coming to the forefront of treatment, and the availability of new combinations of therapies, we are seeing that these patients may have other options that they did not have in the past.

Regarding HER2-positive targeted breast cancer therapies, aside from the anthracyclines, we know cardiac adverse events that are experienced are reversible, so there is an opportunity to administer protective therapy to these patients that can mitigate the cardiac events. In particular, agents in the beta-blocker drug class can work well, and these drugs have been around for more than 60 years. We have accidently discovered that when patients receive these drugs, they have a protective effect on the heart-even though we do not understand the mechanism of how that works. The frequency of toxicity from beta-blockers is minimal, with less than 1% of patients actually having to stop taking this medication. These drugs have a very low risk and the potential to help and protect the heart throughout the patient’s course of breast cancer treatment. There is some recent evidence that there may be an anticancer effect as well, such that patients who regularly take a beta-blocker have a much better response to their cancer therapy, meaning they have less cancer recurrence and survive longer if they are on this therapy. So we try to find every way that we can to help these patients, and beta blockers, in particular, have a great potential to help them.

Cancer Network: Are there best practices for monitoring patients who are being treated with anthracyclines? What should patients look out for themselves, when they are on these therapies?

Dr. Durand: There are best practices. Most of us still follow recommendations from the makers of HER2-targeted therapies, including that patients receive an echocardiogram every 3 months while on therapy and then in the first year after they complete therapy. The timing of when heart function should be checked after that is still unclear. So, those guidelines are still being reviewed. There was a recent set of guidelines from ASCO [American Society of Clinical Oncology] that discuss how frequently imaging of the heart should be done and make recommendations on starting these beta-blockers in our patients. We are quite encouraged by these guidelines, although they are not backed by that much evidence yet because we have not done these large randomized placebo-controlled randomized trials. My suspicion is that it will be another 10 to 20 years before we have better evidence. In the meantime, we go with best practice and ask what we can do that is reasonably safe and will help our patients now. So, we try to initiate beta-blockers, especially if the patient is at higher risk of heart issues. What we don’t know yet is whether there are low-risk patients with no comorbidities but who still may be at risk. What we are hoping is that either blood tests or imaging will be able to identify patients with normal function and minimal or no risk factors, and yet have a higher risk for developing some sort of injury to the heart.

Cancer Network: You mentioned future clinical trials to study the heart effects of these drugs. Are there studies being planned or now ongoing to address these issues-with supportive therapy, observational approaches, or other approaches to replace some of these drugs that are associated with adverse cardiac events?

Dr. Durand: There are, indeed. Several trials, both imaging and medical therapy trials, are underway. A relatively large trial is testing an angiotensin receptor blocker, which is a cousin of an ACE [angiotensin-converting enzyme] inhibitor, with a beta-blocker in patients prior to starting their cancer treatment. Similar prior trials were all small, and this is now a larger trial to address whether this therapy will help to reduce heart issues. There are trials being done where patients with breast cancer are given beta-blockers prior to starting their treatment, and we are eagerly waiting to see what those studies show. There are also imaging trials looking at a new modality of ultrasonography which measures the rotational forces of the heart. There are promising data indicating that, long before there is significant injury to the heart, we might be able to identify these issues early using ultrasonography to identify markers of which patients were at risk of developing heart problems. We are very eager to learn the results of these trials, and hope some of the findings will allow us to better serve our patients.