Mandar Aras, MD, PhD, discussed the management and prevention of cardiotoxicity in patients receiving systemic therapy for breast cancer at the 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC.
Cardiac dysfunction is a prominent concern in patients receiving therapy for breast cancer, especially those with HER2-positive disease who may receive targeted therapies and have a history of prior anthracyclines exposure.
In a presentation at the 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC, Mandar Aras, MD, PhD, of the University of California San Francisco, discussed best strategies for treating these patients, which includes consistent monitoring and proactive management when toxicity develops.
“Cardiovascular disease represents the leading cause of noncancer deaths among cancer patients at every point after their diagnosis,” Aras said. “Cardiovascular complications [associated with cancer therapies can include] hypertension, pericardial disease, cardiomyopathy, pulmonary hypertension, arrhythmias, and even sudden cardiac death.”
Patients with breast cancer who are treated with anthracyclines and HER2-targeted therapies are at an especially increased risk for developing these complications, said Aras. However, other agents that may be used in the treatment of this patient population could also lead to an increased risk of cardiac events, including immune checkpoint and proteasome inhibitors.
Some factors that can be taken into consideration when administering anthracyclines to patients with breast cancer include their age, the use of sequential cardiotoxic treatments such as radiotherapy, and pre-existing diseases such as myocardial infarctions or moderate valvular disease.
“The classic characteristics of anthracycline toxicity is that it’s dose dependent,” Aras said. Although there’s no dose that’s truly safe, we generally think of an anthracycline dose less than 250 mg/m2 as low risk.”
Cardiac toxicities associated with anthracyclines can occur both early and late in the course of systemic therapy administration. In one study of over 2000 patients with cancer who received anthracyclines—including patients with breast and hematologic cancers—the incidence of cardiotoxicities was 9%, with almost all events (98%) occurring within the first year, with a median of 3.5 months of onset.2
“On the other hand, we know from our pediatric populations receiving anthracycline therapy that they remain at higher risk of developing heart failure and cardiomyopathy, even decades after receiving a cancer cure,” Aras said.
Therapies targeting HER2 receptors also target neuregulin and downstream pathways critical for cardiomyocytes, stress response, and survival. The same risk factors for anthracyclines should be considered for these therapies, as well.
A study conducted by Hari K. Narayan, MD, and colleagues examined phenotype changes in echocardiogram parameters prospectively in a breast cancer cohort after the receipt of commonly used systemic therapies over time. What they found was that both doxorubicin and trastuzumab (Herceptin) can lead to an early decline in left ventricular ejection fraction (LVEF).3
“Doxorubicin…caused a small decrease in LVEF, but that was sustained over the course of 3 years,” Aras said. “Trastuzumab, on the other hand, led to a small decline in LVEF that was recovered after 3 years.”
He went on to say that patients receiving sequential therapy had a more pronounced and sustained decline in LVEF. Fortunately, though, most cardiac toxicities that developed were resolved within 5 years.
Treatment and Prevention
In patients developing cardiac toxicity on HER2-targeting medications, Aras said dose holds with or without cardiac medication is usually enough to lead to recovery from ejection fraction. However, not all events of ejection fraction may fully recover over time.
Preventing cardiotoxicity involves avoiding or reducing the use of systemic therapies that commonly lead to these events. Screening and actively managing cardiovascular disease risk factors such as smoking, diabetes, dyslipidemia, and obesity are also key in this endeavor.
Cardioprotective agents may also be used in patients, especially those being treated with anthracyclines, and these methods have been explored in clinical trials.
The first that Aras reviewed was the PRADA trial (NCT01434134) looking at heart failure medications such as a b blocker (metoprolol) or an angiotensin receptor blocker (candesartan) to prevent cardiac dysfunction during early breast cancer therapy. Compared with patients receiving placebo, those on active treatment had lower rates of LVEF by MRI when assessed at baseline and after therapy (P = .005).4 However, biomarkers of LVEF were not significantly affected by the use of cardioprotective therapy.
Similarly, the MANTICORE 101-Breast trial (NCT01016886) of perindopril, bisoprolol, or placebo (1:1:1) for the duration of adjuvant trastuzumab therapy failed to show a statistically significant benefit in trastuzumab-mediated left ventricular remodeling, which was the trial’s primary outcome. As with the previous trial, the rate of LVEF was improved with cardioprotective therapy.5
Another study of 468 patients with HER2-positive breast cancer receiving trastuzumab, 189 of whom also received anthracyclines, looked at both lisinopril and carvedilol for the prevention of cardiotoxicity. And while rates of toxicity were comparable for all 3 arms across the entire study cohort, patients who received both anthracyclines and trastuzumab benefited from both lisinopril (37%) and carvedilol (31%) versus placebo (47%). Cardiotoxicity-free survival was longer for both carvedilol (HR, 0.49; 95% CI, 0.27-0.89; P = .009) or lisinopril (HR, 0.53; 95% CI, 0.30-0.94; P = .015) versus placebo.6
“While this study represents the largest randomized clinical trial in breast cancer primary cardiac toxicity prevention, I think that…the primary end point calls into question how the definition of cardiac toxicity was defined in this study, and perhaps it’s related to the variability in ejection fraction as a measurement.”
In the SAFE-HeaRt study (NCT01904903), whose primary end point was the completion of HER2-targeted therapy without cardiac complication in patients with reduced LVEF who received cardioprotective medications and close cardiac monitoring, therapy was completed in 27 out of 30 participants (90%).7
“Only 2 patients developed a cardiac event and only 1 had an asymptomatic worsening of LVEF less than 35%, so they found that HER2[-targeted] therapy can be safely continued in patients with reduced ejection fraction,” said Aras.
Aras said screening for and aggressively managing cardiovascular risk factors is important in patients with breast cancer who receive systemic therapies that increase the risk of cardiac events. This involves getting an echocardiogram at baselines and at regular intervals during treatment. If changes are detected, trastuzumab should be held for at least 4 weeks and resumed if LVEF normalizes or permanently discontinued in the instance of recurrence of sustained reduction.
Aras M. Understanding and Managing Cardiac Toxicity in Breast Cancer. Presented at: 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource, LLC.
2. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981-1988. doi: 10.1161/CIRCULATIONAHA.114.013777
3. Narayan HK, Finkelman B, French B, et al. Detailed echocardiographic phenotyping in breast cancer patients: associations with ejection fraction decline, recovery, and heart failure symptoms over 3 years of follow-up. Circulation. 2017;135(15):1397-1412. doi: 10.1161/CIRCULATIONAHA.116.023463
4. Gulati G, Heck SL, Røsjø H, et al. Neurohormonal blockade and circulating cardiovascular biomarkers during anthracycline therapy in breast cancer patients: results from the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. J Am Heart Assoc. 2017;6(11):e006513. doi: 10.1161/JAHA.117.006513
5. Pituskin E, Mackey JR, Koshman S, et al. multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol. 2017;35(8):870-877. doi: 10.1200/JCO.2016.68.7830
6. Guglin M, Krischer J, Tamura R, et al. Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer. J Am Coll Cardiol. 2019;73(22):2859-2868. doi: 10.1016/j.jacc.2019.03.495
7. Lynce F, Barac A, Geng X, et al. Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study. Breast Cancer Res Treat. 2019;175(3):595-603. doi: 10.1007/s10549-019-05191-2