Cardiotoxicity related to trastuzumab (Herceptin) appeared to persist over a median follow-up of 7 years, a small cross-sectional, case-control study indicated.
In 22 patients who developed cardiotoxicity in the form of long-term impairment in cardiorespiratory fitness (CRF) (TOX group) during trastuzumab treatment, the resting mean left ventricular ejection fraction (LVEF) was significantly lower, at 56.9% compared with 62.4% in the 20 patients who had no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group) and 65.3% among 15 healthy controls (P<0.001 for both endpoints), reported Anthony Yu, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and colleagues.
As shown in their study online in , global longitudinal strain (GLS) -- an additive method for evaluation of LVEF function -- was also lower in the TOX group compared with both the NOTOX and control groups, as was VO2, a measure of peak oxygen consumption.
Poor peak VO2 is associated with exercise intolerance, an increased risk of cardiovascular disease (CVD) and an increased risk of death after a cancer diagnosis.
"Systemic chemotherapy for breast cancer treatment causes impairment of cardiopulmonary function that cannot be detected by resting LVEF assessment," the researchers noted.
"These findings suggest that cardiotoxicity due to breast cancer therapies appears to be associated with significant long-term impairment of cardiopulmonary function ... and with continued improvements in breast cancer outcomes, a growing population of survivors previously treated with cardiotoxic cancer therapy will be at risk for long-term impairment in CRF, and by association, shortened survival," Yu and co-authors cautioned.
Ann Banke, MD, of Odense University Hospital in Denmark, who was not involved in the research, told 鶹ý by email that the study adds “valuable knowledge to the growing understanding that long-term myocardial dysfunction is prevalent after trastuzumab-related cardiotoxicity and sheds light on the clinical significance for the patients in terms of reduced exercise capacity.”
However, Banke cautioned that the authors themselves acknowledged the limitations of the cross-sectional design, which might induce selection bias.
Study Details
The study enrolled 42 women with a history of nonmetastatic ERBB2 (HER2)-positive breast cancer who were treated with trastuzumab at MSKCC.
Cardiac toxicity from trastuzumab was defined as an asymptomatic decrease in LVEF of 10% or more from baseline to less than 55%. Healthy controls had no history of cancer or cardiac disease and a normal LVEF of at least 55%. Participants underwent two-dimensional and Doppler echocardiography testing, while CRF was tested according to standard treadmill guidelines.
The patients' median age on study enrollment was 60.8 (Interquartile range [IQR] 52.7-65.7) and the median time since completion of trastuzumab therapy was 7 years (IQR 6.2-8.7 years). Prior to initiation of treatment, mean LVEF was similar between the TOX group at 64.5% and the NOTOX group at 65.4%. Overall, 90% of both groups received an anthracycline-based regimen.
The mean GLS was worse in the TOX group (-17.8%) compared with the NOTOX group (-19.8%; P=.005) and the healthy controls (-21.3%; P<.001), the researchers reported, adding that GLS was the only echocardiographic parameter independently associated with peak VO2 on multivariate analysis.
Other echocardiographic parameters, including mean global circumferential strain and global radial strain, were also reduced in the TOX group compared with the control group, although not the same measures in the NOTOX group, Yu and colleagues noted.
Mean peak VO2 in the TOX group was also 15% lower than in the NOTOX group (P=0.03) and 25% lower than in the healthy controls (P<0.001), the researchers noted. The TOX group also had a significantly lower mean post-exercise LVEF at 65.6% compared with 75.6% for healthy controls (P<0.01), while mean contractile reserve was also 25% lower in the TOX group compared with healthy controls (P=0.02).
"Exercise capacity among survivors of treatment-induced cardiotoxicity was severely impaired ... [while] resting GLS was significantly associated with peak VO2," Yu and colleagues observed. "These findings suggest that cardiac factors, specifically impairment of left ventricular systolic function, play an important role in limitation of exercise capacity among breast cancer survivors."
Aerobic exercise may help target any cardiac-specific limitations associated with trastuzumab-induced cardiotoxicity and improve peak VO2, the team explained.
Asked for his perspective, Cary Gross, MD, of Yale School of Medicine in New Haven, Connecticut, pointed out that while the study is based on a small sample size, it does raise important concerns about the persistent impact of therapy-induced cardiotoxicity among breast cancer survivors.
"Key questions include how cardiotoxicity affects functional status and other health outcomes and what can be done to prevent it," he told 鶹ý via email. "Are we restricting the use of cardiotoxic agents to those who truly need them, and treating patients who experience cardiotoxicity?"
In addition, Gross also noted that as cancer treatments improve -- and fortunately, more patients are now long-term survivors following their cancer treatment, he said -- "it's critical to make sure that we are minimizing the adverse outcomes of our treatments. Long-term studies like this, which focus on what happens after cancer treatment is completed, will play a major role in ensuring that the promise of new cancer therapies is actually delivering long-term health benefits."
Disclosures
Yu reported financial relationships with Glenmark Pharmaceuticals and Genentech.
Gross reported research funding from a National Comprehensive Cancer Network grant funded by Pfizer, as well as funding from Johnson & Johnson; he has also received reimbursement from Flatiron for travel and speaking fees.
Primary Source
JAMA Cardiology
Yu Anthony F, et al "Long-term cardiopulmonary consequences of treatment-induced cardiotoxicity in survivors of ERBB2-positive breast cancer" JAMA Cardiol 2020; doi:10.1001/jamacardio.2019.5586.