It is critical to balance the expected benefits of cancer treatment with cardiovascular risk and identify strategies to prevent cardiotoxicity and improve outcomes and the long-term quality of life for breast cancer survivors.
In our review paper published recently in the journal Current Treatment Options in Oncology, we provided a comprehensive update on the cardiotoxicities associated with contemporary breast cancer treatment and the latest strategies for their prevention, detection, and management. (1)
Assessing patient- and treatment-specific risk factors with appropriate cardiovascular surveillance is an essential component of cancer care. Our multidisciplinary team of specialists includes clinical cardiologists who specialize in the comprehensive management of co-existing cardiovascular disease and cancer and the cardiotoxic side effects of cancer treatment. They work closely with oncologists and radiologists to design individualized treatment plans for each patient.
Cardiotoxicities Associated with Contemporary Breast Cancer Treatments
These agents may lead to chronic, progressive, dose-dependent cardiomyopathy. Doses used for the treatment of breast cancer are typically lower than the thresholds associated with cardiotoxicity risk as defined by the American Society of Clinical Oncology (ASCO), (2) but about nine to 10 percent of patients still experience a significant decline in left ventricle ejection fraction (LVEF), and about 0.6 to 1.3 percent of patients develop heart failure. (3), (4), (5) Strategies to mitigate these adverse effects include continuous versus bolus administration, using a liposomal formulation of doxorubicin, and administering dexrazoxane, a cardioprotective agent that has been shown to lower the risk of left ventricle (LV) dysfunction by about 65 to 80 percent with no apparent impact on treatment efficacy. (6), (7) Dexrazoxane is currently FDA approved for use in patients with metastatic breast cancer who have received at least 300mg/m2 of doxorubicin and have an ongoing indication for additional anthracycline chemotherapy.
- Trastuzumab: Combination treatment of trastuzumab plus chemotherapy for adjuvant treatment has been shown to confer a two times greater risk of late-onset heart failure compared to chemotherapy alone. (8) Other risk factors include older age, concomitant cardiovascular risks, and lower baseline LVEF. (4), (5), (9) Cardiac dysfunction most commonly occurs within two years of starting treatment (4), (10) and necessitates treatment interruption in 15–20 percent of patients. (4), (11) However, partial to complete LVEF recovery occurs in up to 80 percent of patients after six or seven months of treatment interruption, either spontaneously, or with medical treatment (11), (12), (13) and some patients can tolerate “rechallenge”. (11)
- Other Anti-HER2 agents: Pertuzumab is used in neoadjuvant, adjuvant, and metastatic settings. Long-term follow-up studies show it does not increase the risk of cardiotoxicity beyond the risk associated with trastuzumab plus standard chemotherapy. (14), (15), (16), (17)Ado-trastuzumab emtansine (TDM-1), is used to treat metastatic breast cancer that has progressed after treatment with trastuzumab. (18) Recently, it has shown benefits in patients with residual disease after neoadjuvant taxane and trastuzumab therapy. (18), (19) In a Phase III trial for early breast cancer, there was only one (0.1 percent) cardiac event reported after a median follow-up of 40 months. (19)Lapatinib is used in combination with capecitabine or letrozole to treat patients with progressive metastatic HER2-positive cancer. (20) An analysis of Phase I–III trials of more than 3,600 patients found a 1.6 percent incidence of cardiac events at a mean of 13 weeks with an average LVEF decline of 18.8 percent from baseline and a partial or full recovery by 7.6 weeks in a majority of patients. (21)
Cyclin-Dependent kinase 4/6 Inhibitors
Abemaciclib, palbociclib, and ribociclib are used together with endocrine therapies to treat patients with hormone receptor-positive HER2-negative breast cancer. A meta-analysis of phase II and phase III studies found a 3.5-fold higher risk of venous thromboembolism (VTE). (22) A phase I study of ribociclib found a dose-dependent QTc prolongation starting at 600 mg/day. (23) The product label for ribociclib recommends QTc monitoring at baseline, day 14, the beginning of cycle two (day 28), and after that as necessary, with dose reduction and/or interruption for QTc prolongation. (24)
Third-generation aromatase inhibitors (AIs) including anastrozole, letrozole, and exemestane are used in long-term adjuvant settings in early disease or as first-line therapy in advanced, hormone-receptor-positive disease. (25) They confer better disease benefits and overall survival compared to tamoxifen but have also demonstrated a 19 percent increased risk of cardiovascular events in a meta-analysis of randomized controlled trials. (26) AIs are associated with unfavorable lipid changes (27), (28) and an increase of up to 13 percent in the incidence of hypertension and significant vascular dysfunction. (29) Tamoxifen has been associated with positive lipid changes but has also demonstrated an almost two-fold greater risk of thrombogenicity, up to a 5 percent rate of VTE. (23), (30)
Radiation-Induced Ischemic Heart Disease
Incident radiation of cardiac tissues can cause damage that manifests as coronary artery disease or cardiomyopathy. (31) Cancer survivors have a two to 5.9 times greater risk of radiation-induced heart disease. (32) Darby et al. found a 7.4 percent increased risk of major coronary events per Gray (Gy) of mean heart dose of radiation therapy, beginning within the first few years of exposure and continuing after 20 years. Patients who received left-sided versus right-sided radiation therapy had a 29 percent and 22 percent higher risk for coronary heart disease and cardiac death, respectively. (33) Contemporary techniques including CT-based simulation, prone imaging, respiratory gating, heart blocks, intensity-modulated radiation therapy, and volumetric modulated arc therapy have substantially reduced the radiation dose to the heart and helped to minimize adverse effects. (34)
Strategies to Prevent, Detect, and Manage Cardiotoxicities
Pretreatment evaluation of cardiovascular disease risk is recommended before patients initiate cancer treatment with known cardiotoxic effects. This includes a physical examination, taking a comprehensive health history, and baseline LVEF assessment. Patients with pre-existing cardiovascular disease or its risk factors should be screened and managed throughout treatment according to ASCO guidelines. (2)
Results have been modest and mixed for studies that have evaluated the efficacy of various renin-angiotensin system-blocking and beta-blocking agents to prevent LV systolic dysfunction associated with adjuvant anthracycline and/or trastuzumab therapy. (1) In a promising study by Guglin et al. lisinopril and carvedilol demonstrated effectiveness for preventing LVEF decline among patients treated with sequential anthracyclines and trastuzumab. (35) Statins may also be beneficial. A retrospective cohort study found that statin use during anthracycline therapy was associated with a decreased risk of heart failure. (36) The prospective PREVENT Trial, which is examining the prophylactic value of atorvastatin in patients planned to receive adjuvant anthracycline, is ongoing with an estimated primary completion date of May 2020.
Early Detection and Management of Cardiotoxicity
Current recommendations for monitoring treatment-related cardiotoxicities include routine LVEF assessments during and after anthracycline and anti-HER2 therapy, for example, at baseline and every three months during treatment. (37), (38) However, adherence to this schedule is poor at less than 50 percent, despite age or other cardiovascular comorbidities. (39), (40) The value of frequent monitoring among low-risk patients has been questioned, especially among patients who are receiving regimens with low cardiotoxic risks. Results from several small studies suggest that patients with asymptomatic LVEF decline can safely continue anti-HER2 therapy with close monitoring and treatment with cardiac medications. (41), (42)
Global longitudinal strain (GLS) via speckle tracking echocardiography is a sensitive measure of LV systolic function and can detect early signs of cardiotoxicity. (43) A study by Negishi et al. demonstrated that an 11 percent change in GLS from baseline to six months was the strongest predictor of cardiotoxicity among patients treated with trastuzumab. (44) The American Society of Echocardiography guidelines state that a relative decrease in GLS of more than 15 percent is likely to reveal a clinically significant drop in LV function that may warrant intervention. (33) The SUCCOUR trial is an international prospective randomized trial comparing the effectiveness of GLS to ejection-fraction management strategies in 320 patients taking cardiotoxic chemotherapy. (45)
Since there is significant heterogeneity in tolerance to cardiotoxic cancer therapy, genetics may provide new insights. Changes in gene expression in response to therapy (46) and single nucleotide polymorphisms in genes involved with anthracycline metabolism and oxidative stress, such as ABCC2, CYBA, RAC2, ABCV1, and CBR3, have been proposed as biomarkers for identifying patients at high risk for cardiotoxicities associated with anthracyclines. (47), (48), (49) The HER2/neu Pro 1170 Ala polymorphism has been identified as a potential genetic marker for cardiotoxicity associated with trastuzumab. (44), (50), (51), (52)
Exercise and Fitness
The multiple hit of pre-existing cardiovascular disease risk factors, cardiotoxicities associated with treatment, and the weight gain, decreased physical activity, and impaired exercise capacity that commonly occur during treatment, can combine to result in cardiovascular disease. (53) Studies have shown that exercise during and after treatment is safe and may provide cardiovascular benefits. (54), (55), (56), (57) The OptiTrain trial showed that high-intensity interval training during treatment resulted in multiple benefits, including preventing cardiorespiratory fitness decline, reducing cancer-related fatigue, and improving muscle strength. (52) Several prospective studies are ongoing to evaluate the impact of exercise on cancer and cardiovascular outcomes. (58), (59)
Advancing Cardio-Oncologic Care
As advances in breast cancer treatment continue to improve survival outcomes, more patients are at risk for developing late adverse cardiovascular effects. Our cardio-oncology clinical research is focused on finding new ways to prevent, detect earlier, and better manage the cardiotoxic side effects of cancer treatment.
We are conducting a research study to investigate why some patients experience reduced heart function by creating cardiomyocytes derived from the blood of breast cancer patients treated with doxorubicin followed by trastuzumab therapy, or trastuzumab alone. The PREVENT-HF Trial is a Phase IIB study testing whether the drug carvedilol can reduce the risk of heart failure in survivors of childhood cancers who received anthracycline drugs. We are conducting an NCI-funded study to evaluate the cardiac safety of less frequent cardiac monitoring in low risk patients treated with non-anthracycline trastuzumab based regimens. MSK is also participating in the randomized RADCOMP consortium trial comparing 10-year cardiovascular outcomes of patients with non-metastatic breast cancer treated with proton versus photon radiotherapy.
Dr. Lee Chuy declares no conflict of interest. Dr. Yu has received compensation from Glenmark Pharmaceuticals, Takeda Oncology, Bristol-Myers Squibb, and Bayer for consulting services.