Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer

Abstract

This cross-sectional study assesses whether treatment-induced cardiotoxicity is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2 -positive breast cancer. What are the long-term cardiopulmonary consequences of treatment-induced cardiotoxicity in patients who survive ERBB2 -positive breast cancer? In this cross-sectional case-control study of 42 patients who survived breast cancer, those with prior cardiotoxicity had significantly lower left ventricular ejection fraction, global longitudinal strain, and peak oxygen consumption. Global longitudinal strain was the only echocardiographic parameter associated with peak oxygen consumption. These findings suggest that cardiotoxicity due to breast cancer therapies appears to be associated with significant long-term impairment of cardiopulmonary function, and interventions to prevent and mitigate decline in peak oxygen consumption among breast cancer survivors are warranted. Trastuzumab improves outcomes in patients with ERBB2 -positive (formerly HER2 ) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer. To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2 -positive breast cancer. This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2 -positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019. Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO 2 ). A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, −17.8% [2.2%]; NOTOX group, −19.8% [2.2%]; HC group, −21.3% [1.8%]) ( P  < .001). Mean peak VO 2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P  = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P  < .001). In patients with breast cancer, GLS was significantly associated with peak VO 2 (β coefficient, −0.75; 95% CI, −1.32 to −0.18). Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2 -positive breast cancer.