Guideline-directed medical therapy for the prevention and treatment of cardiotoxicity is improving quality of life and oncologic outcomes associated with breast cancer treatment, according to Jean-Bernard Durand, MD, FACP, FCCP, FACC, FHFSA, Professor of Medicine at The University of Texas MD Anderson Cancer Center and Medical Director of Cardiomyopathy Services. Dr. Durand discussed the latest findings in this area at the 2022 Miami Breast Cancer Conference sponsored by PER.1
“In the treatment of breast cancer, the goal from the perspective of cardiology is very simple: to keep our patients alive, keep them feeling well, and keep them out of the hospital,” Dr. Durand said.
Potentially cardiotoxic agents in breast cancer mainly include anthracyclines; tyrosine kinase inhibitors; trastuzumab; and, most recently, pembrolizumab.
Jean-Bernard Durand, MD, FACP, FCCP, FACC, FHFSA
Cardiotoxicity is defined by an absolute 10-point drop in left-ventricular ejection fraction (LVEF) from baseline. Although echocardiography is often used in this evaluation, its intraobserver variability is high, ± 10. This drops to ± 5 with three-dimensional (3D) echocardiography, which most centers now have, but cardiac magnetic resonance imaging (MRI) is even better, with an intraobserver variability of ± 1. Dr. Durand therefore advised listeners: “You want to ask for a 3D echocardiogram or, if you have the capability, an MRI.”
Years ago, nonselective beta-blockers became established for preventing cardiotoxicity from anthracycline-based therapies after showing they could prevent the 10-point drop in LVEF. Beta-blockers are not typically prescribed at the start of breast cancer therapy, but they should be initiated at least within a 6-month window of time to be effective.
“The treatment has to be very aggressive and very early on,” he said.
Most patients respond, but those who fail to fully recover normal LVEF have a high cardiac event rate.
Cardiologists use a staging system for risk stratification. Group A includes patients receiving a cardiotoxic drug but maintaining normal LVEF and lacking symptoms. However, since many within this group also have other high-risk features, such as diabetes, hypertension, and underlying coronary artery disease, it can be difficult to know which are truly at higher risk for cardiac problems, he said.
Shift in Paradigm
“There has been a shift in the paradigm for guideline-directed medical therapy initiation,” he said. Medications—including angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and a few others—are now considered
only as patients approach euvolemia, with uptitration as needed, he said.
The benefits of guideline-directed medical therapy for heart failure are clear, with low numbers needed to treat and high relative risk reductions for hospitalizations: for beta-blockers, a number needed to treat of 9 and a 41% relative risk reduction; for hydralazine/isosorbide dinitrate, 7 and 33%, respectively; and for aldosterone antagonists, 5 and 25%, respectively.
“Those numbers needed to treat are usually unheard of in cardiovascular disease,” he noted, “highlighting the importance of medical therapy to get your patients successfully through their cancer treatment and through left-ventricular dysfunction.”
Antidiabetic Agents for Cardiomyopathy
The class of antidiabetic agents known as sodium-glucose co-transporter 2 (SGLT-2) inhibitors are now being evaluated as cardioprotective agents in patients with cancer. There is strong rationale, he said, for incorporating these “pseudo–sodium-glucose transporters”: diabetes and heart failure have similar pathophysiology, the mechanistic effects of SGLT-2 inhibitors are seen in persons with and without diabetes, and the cardiovascular benefits of the drugs are largely independent of glucose levels.
Evidence of their benefit was shown in a recent study by Kato et al.2 Compared with placebo, cardiovascular-related deaths and hospitalizations, and all-cause mortality, were significantly reduced by 36% to 45% in patients receiving the SGLT-2 inhibitor dapagliflozin.
“In the next 2 years, you’re going to be overwhelmed by the data for these antidiabetic glucose-transporting agents and their beneficial effects on cardiotoxicity and heart failure,” Dr. Durand predicted. “We are even at the point of wondering whether it’s unethical to do a heart failure trial without including them.”
Use of Trastuzumab
Under the current treatment algorithm,3 patients can immediately receive trastuzumab if they lack left-ventricular dysfunction at baseline, although there is a “gray area or messy middle,” he said. That would be the asymptomatic patient with a LVEF between 40% and 49%. Trastuzumab can be continued provided they receive some cardioprotective agent.
These patients should be followed closely, and if the LVEF drops to less than 40%, “that’s absolutely a hard stop,” Dr. Durand emphasized. “We are much more accepting nowadays that we can give life-saving chemotherapy and then manage these patients, so they have a good outcome.”
Use of Immune Checkpoint Inhibitors
The newest cardiotoxic drugs are immune checkpoint inhibitors, which in the treatment of breast cancer predominantly means pembrolizumab. With this agent, he said, “we see a mixed picture” that includes myocarditis, myositis, and the two conditions together, sometimes also including myasthenia gravis of rapid onset. “Patients can develop severe muscle weakness, and the transition can be very rapid, meaning they can look fine in the morning but by the end of the day, we’re putting them on a respirator,” he said.
Case studies have documented that 20% to 30% of patients respond to checkpoint inhibitors, 70% to 90% have an adverse event, and 12% to 24% of these events are considered serious. Cardiac side effects are rare but can be life-threatening. For example, fulminant myocarditis occurs in less than 1% of patients but carries a high mortality rate—30% to 50%, and possibly even higher—when pembrolizumab is combined with ipilimumab.
Myocarditis is diagnosed by histologic, immunologic, and immunohistochemical criteria after endomyocardial biopsy reveals a T-cell infiltrate and myocyte necrosis. The disease is not only T-cell–mediated, however, but is marked by B-cell clonal expansion with antibody production. The antibodies are not initiating factors, but they can modify the disease, he noted.
Workup of Suspected Myocarditis
Dr. Durand described his workup of a patient with breast cancer who presents with a noncardiovascular immune-related adverse event while taking pembrolizumab. If her troponin T level is less than 100 ng/L, and she lacks clinical symptoms, she receives no further workup for myocarditis. If her troponin T level is more than 100 ng/L, she proceeds to the diagnostic and treatment algorithm for possible myocarditis.
For clinically suspected myocarditis, the patient discontinues the checkpoint inhibitor and starts on steroids upfront (with plasmapheresis considered) while undergoing a full diagnostic workup over 3 to 5 days. If the patient develops myocarditis-type symptoms, the patient starts on rituximab, which is given at 0, 2, 4, and 6 weeks. If the patient exhibits signs of myasthenia gravis, Dr. Durand considers giving high-dose steroids and further considers plasmapheresis.
Besides prednisone or methylprednisolone, immunosuppression for myocarditis includes intravenous immunoglobulin, antithymocyte globulin, infliximab, and mycophenolate mofetil. These agents are incorporated under certain circumstances, depending on the patient’s response.
“We also do a subtype of T cells because we want to know what these cells are doing there. Are they in any way predictive of whether these patients will survive?” he said. He noted that CD3, CD8, and CD68 can be expressed within the heart.
Finally, Dr. Durand advised listeners to “develop a team” for addressing cardiotoxicity. “Those teams are going to include an oncologist, cardiologist, pathologist, and possibly a rheumatologist,” he said.
DISCLOSURE: Dr. Durand reported no conflicts of interest.
REFERENCES
1. Durand JB: Cardiotoxicity in 2022: Algorithms and Treatment Options. 2022 Miami Breast Cancer Conference. Presented March 4, 2022.
2. Kato ET, Silverman MG, Mosenzon O, et al: Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 139:2528-2536, 2019.
3. Jafari L, Akhter N: Heart failure prevention and monitoring strategies in HER2-positive breast cancer: A narrative review. Breast Cancer Res Treat 186:295-303, 2021.
