Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer | Breast Cancer | JAMA Cardiology | JAMA Network
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Figure.  Cardiopulmonary Function as Assessed by Resting Left Ventricular Ejection Fraction (LVEF), Resting Global Longitudinal Strain (GLS), and Peak Oxygen Consumption (Peak VO2)
Cardiopulmonary Function as Assessed by Resting Left Ventricular Ejection Fraction (LVEF), Resting Global Longitudinal Strain (GLS), and Peak Oxygen Consumption (Peak VO2)

Box-plot analysis of resting LVEF, resting GLS, and peak VO2 among the patients who developed cardiotoxicity during trastuzumab treatment (TOX group), those with no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group), and age-matched healthy controls (HC group). The horizontal line within each box indicates the median, while the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box mark the 90th and 10th percentiles. The blue dot represents outliers.

Table 1.  Participant Characteristicsa
Participant Characteristicsa
Table 2.  Resting Echocardiographic Measuresa
Resting Echocardiographic Measuresa
Table 3.  Cardiopulmonary Exercise Performance
Cardiopulmonary Exercise Performance
Table 4.  Variables Associated With Peak VO2 in Survivors of ERBB2-Positive Breast Cancer
Variables Associated With Peak VO2 in Survivors of ERBB2-Positive Breast Cancer
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Original Investigation
January 15, 2020

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

Author Affiliations
  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Weill Cornell Medical College, New York, New York
  • 3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Duke Cancer Institute, Durham, North Carolina
JAMA Cardiol. 2020;5(3):309-317. doi:10.1001/jamacardio.2019.5586
Key Points

Question  What are the long-term cardiopulmonary consequences of treatment-induced cardiotoxicity in patients who survive ERBB2-positive breast cancer?

Findings  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.

Meaning  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.

Abstract

Importance  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.

Objective  To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 VO2).

Results  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 VO2 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 VO2 (β coefficient, −0.75; 95% CI, −1.32 to −0.18).

Conclusions and Relevance  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.

Introduction

Trastuzumab-containing regimens for ERBB2-positive (OMIM 164870) (formerly HER2) breast cancer are associated with cardiotoxicity. Risk of cardiotoxicity is highest when trastuzumab is administered sequentially after anthracyclines, with development of a significant decline in left ventricular ejection fraction (LVEF) in as many as 25% of patients or symptomatic heart failure in 0.8% to 4.0% of patients.1-4 Although the prevailing perception is that cardiotoxicity related to trastuzumab is reversible, full recovery of left ventricular systolic function is not always achieved, despite interruption of therapy, and may be attributable to the synergistic cardiac impairment caused by sequential treatment with anthracyclines and trastuzumab.5 Reports from clinical practice suggest that cardiotoxicity can result in long-term impairment of left ventricular systolic function with increased long-term risk of heart failure in patients who survived breast cancer (hereinafter referred to as breast cancer survivors).6,7

Evidence of the long-term cardiac safety of trastuzumab among breast cancer survivors is based on studies that use resting LVEF assessments to identify patients with left ventricular systolic dysfunction.8 However, LVEF as a measure of left ventricular systolic function is limited by load dependency, which can lead to changes in left ventricular volumes that do not directly reflect a change in myocardial contractility and reliance on geometric assumptions for calculation of left ventricular volumes that is subject to technical error.9 Systemic chemotherapy for breast cancer treatment causes impairment of cardiopulmonary function that cannot be detected by resting LVEF assessment.10,11 Cardiorespiratory fitness (CRF), as measured by peak oxygen consumption (peak VO2), is an integrative assessment of global cardiovascular function that declines as much as 26% after exposure to various systemic cancer treatment regimens and may not recover despite treatment cessation.10,12 Emerging evidence indicates that poor peak VO2 is associated with a higher symptom burden (eg, exercise intolerance or lower health-related quality of life), increased risk of cardiovascular disease, and increased risk of death after a cancer diagnosis.13-15 Despite the significant prognostic value of CRF, little is known to date on the late effects of trastuzumab on CRF in breast cancer survivors.

The primary objectives of this study were to compare cardiac structure, function, and CRF in ERBB2-positive breast cancer survivors with a history of treatment-induced cardiotoxicity (TOX group), relative to trastuzumab-treated control participants without cardiotoxicity (NOTOX group) and age-matched healthy controls (HC group). The secondary objective was to explore the association between echocardiographic parameters of left ventricular function (at rest and after exercise) and CRF among ERBB2-positive breast cancer survivors.

Methods
Participants and Study Design

This single-center cross-sectional case-control study enrolled 42 women with a history of nonmetastatic ERBB2-positive breast cancer who completed trastuzumab-based therapy at Memorial Sloan Kettering Cancer Center, New York, New York, at least 2 years before study entry (eFigure in the Supplement). The breast cancer survivors met 1 of the following criteria: (1) history of treatment-induced cardiotoxicity, defined as an absolute decrease of at least 10% from baseline LVEF to less than 55% during the trastuzumab treatment period without symptoms of heart failure (TOX group [n = 22]), or (2) normal left ventricular systolic function throughout the breast cancer treatment period as defined by a normal LVEF (≥55%) and a maximum decline in LVEF of 5% or less during at least 3 LVEF assessments (ie, at baseline and a minimum of 2 follow-ups during trastuzumab treatment) (NOTOX group [n = 20]). Inclusion in the NOTOX group was restricted to patients with no more than a 5% decline in LVEF during trastuzumab-based therapy to select for patients with stable left ventricular systolic function during breast cancer treatment. Exclusion criteria consisted of (1) symptomatic heart failure during trastuzumab treatment; (2) diagnosis of recurrent or metastatic breast cancer; (3) treatment with additional cardiotoxic cancer therapy since completion of targeted therapy for ERBB2-positive breast cancer; and (4) contraindication to cardiopulmonary exercise testing (CPET). Eligible patients were identified through an institutional database and were frequency matched by age strata at the time of enrollment (<55, 55-64, and ≥65 years) such that the proportion of enrolled patients in each age stratum was balanced between the TOX and NOTOX groups.16 Fifteen women with no history of cancer or known cardiac disease and normal LVEF (≥55%) and frequency matched by age strata to the TOX and NOTOX groups were recruited for the HC group. Data were collected from September 9, 2016, to August 10, 2018. Written informed consent was obtained from all participants. The study was approved by the institutional review board at Memorial Sloan Kettering Cancer Center and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

2-Dimensional, Doppler, and Strain Echocardiography

Resting 2-dimensional (2-D) and Doppler echocardiography were performed using an ultrasound scanner (Vivid E9; GE Medical Systems) in accordance with American Society of Echocardiography guidelines.17 Apical 2-, 3-, and 4-chamber views and short-axis views at the midpapillary level were acquired at a frame rate of 40 to 80 frames per second. Speckle-tracking strain analysis was performed offline (EchoPAC; GE Healthcare) to calculate peak systolic global longitudinal strain (GLS), global radial strain, and global circumferential strain as previously described.18 Interobserver and intraobserver variability for GLS, global radial strain, and global circumferential strain have previously been reported.19

Cardiopulmonary Function

Cardiopulmonary exercise testing was conducted using an electronic motorized treadmill with 12-lead electrocardiographic monitoring (Mac 5000; GE Healthcare) according to standard guidelines.20 Before initiating the CPET, a warm-up was performed wherein the starting treadmill speed was selected based on participant comfort (1.0-4.5 mph). Breath-by-breath (with a mean value calculated every 30 seconds) expired gases were analyzed continuously by a calibrated metabolic measurement system (TrueOne 2400; Parvo Medics). To stabilize gas measurement, 3 minutes of resting metabolic data were collected before exercise initiation. After stable resting metabolic values were achieved, participants began walking at a participant-specific designated speed at 0% grade for 2 minutes, and the speed and grade were increased every minute until exhaustion or a symptom-limited peak was achieved measured by peak VO2 measurement (in milliliters per kilogram per minute). All tests were completed within 8 to 12 minutes in line with CPET guidelines.20 During exercise, all participants were monitored continuously with 12-lead electrocardiography, oxyhemoglobin saturation was monitored continuously using a handheld pulse oximeter (BCI), and blood pressure was measured every 2 minutes. Rating of perceived exertion was evaluated at the end of each workload using the Borg scale. Acceptable test criteria for this assessment included any of the following: (1) a respiratory exchange ratio of at least 1.1, (2) attainment (±10 bpm) of age-predicted maximal heart rate, or (3) a rating of perceived exertion of at least 18 on the Borg scale. All VO2 data were calculated for the 30-second mean values, and the highest value achieved during the final 90 seconds of the test was considered peak. This protocol has previously been demonstrated to be safe and feasible in survivors of early-stage breast cancer.21

Immediately after exercise, participants were placed in the supine position and additional echocardiographic images were acquired in the apical 4-, 2-, and 3- chamber views. Cardiac index (at rest and after exercise) was calculated using 2-D pulsed-wave Doppler echocardiography as left ventricular stroke volume times heart rate (cardiac output), indexed to body surface area.22 Contractile reserve was calculated as the difference between the resting and postexercise cardiac index. Arterial-venous oxygen content difference (AVO2 difference), based on the Fick equation, was calculated as peak VO2 divided by cardiac output.

Statistical Analysis

Data were analyzed from November 20, 2018, to August 12, 2019. The sample size was calculated based on prior studies that have shown that GLS is a sensitive marker that can detect subclinical abnormalities in left ventricular systolic function23,24 and has significant prognostic value in populations with and without cancer.25,26 Assuming an SD of 2,21 enrollment of 20 participants in the TOX and NOTOX groups provided 88% power to detect a 2% absolute difference in GLS with a 2-sided type I error of 0.05.

Continuous data are summarized as mean and SD or median and interquartile range (IQR), as appropriate, and categorical measures as frequency and percentage. Differences in baseline characteristics were studied using Cochran-Mantel-Haenszel tests or linear models, both adjusted for the age strata used for matching. Differences in cardiopulmonary function between all groups were explored by analysis of variance. Linear regression was used to further investigate differences in resting (LVEF, GLS, global circumferential strain, and global radial strain) and postexercise (peak VO2, LVEF, contractile reserve, and AVO2 difference) parameters as the primary outcomes and study group (TOX vs NOTOX vs HC) as the primary variable associated with outcome, adjusting for covariates including age group, hypertension (yes or no), body mass index (calculated as weight in kilograms divided by the square of height in meter), and time since completion of targeted therapy for ERBB2-positive cancer as continuous variables. Univariate and multivariate linear regression were performed to identify covariates associated with peak VO2 using a stepwise approach with a threshold of 2-sided P < .05. All statistical analysis was performed in R, version 3.5.2 (R Foundation for Statistical Computing), and Stata, version 15.1 (StataCorp, LLC).

Results
Population

At the time of study enrollment, the median age among the 57 study participants was 60.8 (IQR, 52.7-65.7) years. Median time since completion of targeted therapy for ERBB2-positive cancer was 7.0 (IQR, 6.2-8.7) years. The prevalence of hypertension and hyperlipidemia was similar among the TOX, NOTOX, and HC groups. Median body mass index was higher in the TOX group (25.9 [IQR, 23.7-29.5]) compared with the NOTOX (24.6 [IQR, 22.1-29.3]) and HC groups (23.1 [IQR, 20.0-25.6]; P = .04). Baseline clinical characteristics of all participants are presented in Table 1.

At the time of initial breast cancer diagnosis (before beginning chemotherapy), mean LVEF was similar between the TOX (64.5% [4.6%]) and NOTOX (65.4% [6.4%]; P = .58) groups. Hypertension and hyperlipidemia before breast cancer treatment were present in 1 (5%) and 3 (14%) patients in the TOX group, respectively, and 4 (20%) and 4 (20%) patients in the NOTOX group, respectively. Median body mass index was 25.0 (IQR, 23.7-29.4) in the TOX group and 25.1 (IQR, 21.8-27.5) in the NOTOX group. Overall, 38 of 42 participants in both breast cancer survivor groups (90%) were treated with an anthracycline-based regimen (median doxorubicin-equivalent dose, 240 [IQR, 240-240] mg/m2). During the trastuzumab treatment period, the nadir mean LVEF was 48.2% (4.1%) in the TOX group compared with 65.5% (5.9%) in the NOTOX group.

After diagnosis of cardiotoxicity, 14 patients had treatment interrupted or discontinued and 6 patients who had a nadir LVEF of greater than 50% had no treatment interruption. Two patients had received the final dose of trastuzumab at the time of LVEF decline. Five patients received a β-blocker, 7 received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 13 received a cardiology consultation. The median cumulative trastuzumab dose received was 102 (IQR, 68-106) mg/kg in the TOX group and 106 (IQR, 100-108) mg/kg in the NOTOX group.

Left Ventricular Structure and Function

Resting echocardiographic measurements are shown in Table 2. Five patients in the TOX group but none in the NOTOX or HC groups had grade I diastolic dysfunction (P = .06). Echocardiographic parameters of left ventricular systolic function were lower in the breast cancer survivor groups (TOX and NOTOX) compared with the HC group in adjusted analyses. The mean LVEF was lower in the TOX group (56.9% [5.2%]) compared with the NOTOX group (62.4% [4.0%]; P < .001) and the HC group (65.3% [2.9%]; P < .001). Three participants in the TOX group but none in the NOTOX or HC groups had a LVEF of less than 53%. The mean GLS was worse in the TOX group (−17.8% [2.2%]) compared with the NOTOX group (−19.8% [2.2%]; P = .005) and the HC group (−21.3% [1.8%]; P < .001). Six participants in the TOX group but none in the NOTOX or HC groups had a GLS of less than −16%. Mean global circumferential strain and global radial strain were also reduced in the TOX group (−15.1% [3.9%] and 37.7% [16.9%], respectively) compared with the HC group (−19.6% [3.0%] and 57.3% [14.9%], respectively), but not the NOTOX group (−17.1% [2.2%] and 46.5% [21.1%], respectively).

CRF and Postexercise Cardiac Function

Cardiopulmonary exercise performance data are presented in Table 3. Before exercise, resting heart rate, systolic blood pressure, and diastolic blood pressure were highest in the TOX group compared with the NOTOX and HC groups. The mean (SD) peak heart rate was 166 (11) bpm in the TOX group, 163 (14) bpm in the NOTOX group, and 167 (10) bpm in the HC group. Three participants in the TOX group did not achieve a peak VO2 and were excluded from the analysis; 2 developed an exercise-induced arrhythmia (1 with rapid atrial fibrillation and 1 with ventricular bigeminy), and 1 was unable to comply with the CPET testing equipment, leading to early termination. The remaining 54 of 57 participants (95%) met the acceptable criteria for a peak VO2 during CPET testing. A peak test based on heart rate occurred in 50 participants (88%); based on respiratory exchange ratio, in 33 (58%); and based on rating of perceived exertion, in 35 (61%). Mean peak VO2 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) (Figure). In a sensitivity analysis, differences in peak VO2 between groups remained significant after exclusion of patients with a LVEF of less than 53% (TOX vs NOTOX groups, 22.8 [4.6] vs 27.0 [5.3] mL/kg/min [P = .006]; vs HC group, 30.5 [3.4] mL/kg/min [P < .001]).

The TOX group had a significantly lower mean postexercise LVEF compared with the HC group (65.6% [7.7%] vs 75.6% [5.1%]; P < .001). Similarly, the mean contractile reserve was 25% lower in the TOX group compared with the HC group (3.3 [0.9] vs 4.4 [1.2] L/min/m2; P = .02). There was no significant difference in AVO2 difference between the TOX group compared with the NOTOX or the HC group.

Echocardiographic Parameters and CRF

Among the breast cancer survivors, regression analysis was performed to identify factors associated with peak VO2. After multivariate analysis, age (β coefficient for 55-64 years, −3.85 [95% CI, −7.06 to −0.64; β coefficient for ≥65 years, −4.75 [95% CI, −8.19 to −1.31), BMI (β coefficient, −0.59 [95% CI, −0.85 to −0.32]), and resting GLS (β coefficient, −0.75 [95% CI, −1.32 to −0.18]) were associated with peak VO2 (Table 4). Because AVO2 difference was derived from peak VO2 rather than directly measured, it was not included in the regression analysis.

Discussion

Several novel and important findings emerge from this study, which characterized the long-term cardiopulmonary effects of treatment-induced cardiotoxicity. First, patients in the TOX group who had an asymptomatic decline of LVEF during trastuzumab treatment had a persistent reduction in left ventricular systolic function as measured by LVEF and GLS compared with the NOTOX and HC groups at a median follow-up of 7 years after completing trastuzumab therapy. We note that 90% of patients in the TOX and NOTOX groups received an anthracycline-based trastuzumab regimen. Second, exercise capacity among survivors of treatment-induced cardiotoxicity was severely impaired, with a peak VO2 that was 25% lower than that in the HC group and 15% lower than in the NOTOX group. Finally, resting GLS was significantly associated with peak VO2. 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. To date, there has been uncertainty regarding the clinical significance of an asymptomatic LVEF decline during trastuzumab therapy, which is the most common manifestation of cardiotoxicity during targeted therapy for ERBB2-positive breast cancer. Considering the adverse prognostic significance associated with low peak VO2, our findings suggest that treatment-induced cardiotoxicity may affect long-term cardiovascular outcomes and provide a strong rationale to develop effective strategies for prevention and management of treatment-induced cardiotoxicity.

Survivorship studies in several different cancer populations have shown that cardiotoxic cancer therapy is associated with reductions in CRF.10,11,21 The present study expands on these previous methods to demonstrate that treatment-induced cardiotoxicity plays an important role in the chronic reduction of CRF. We believe these findings are of particular clinical significance, given the association between low CRF and all-cause mortality, cardiovascular mortality, and cancer-related mortality.27 Low peak VO2 may also be linked to the high prevalence of fatigue and poor exercise tolerance that can negatively affect quality of life and are commonly reported by breast cancer survivors.28,29 In acknowledgment of the independent and additive prognostic information that is gained from a CRF assessment, the American Heart Association suggests that CRF be routinely measured in clinical practice among the general population.30 Among cancer survivors, CRF assessment may unmask the cardiotoxic effects of cancer therapy that cannot be detected with traditional cardiac imaging in this patient population such as 2-D echocardiography.

To further elucidate the underlying mechanism of impaired peak VO2 associated with treatment-induced cardiotoxicity, we evaluated for differences in resting and postexercise echocardiographic parameters. Based on the Fick equation, determinants of peak VO2 include cardiac output and AVO2 difference; therefore, reductions in either of these parameters will lead to a reduction in peak VO2.31 At rest, left ventricular dimensions and continuous diastolic function parameters were similar between all 3 groups, whereas resting LVEF and GLS were lower in the TOX group. Chronotropic incompetence during exercise was not a contributing factor to low peak VO2, with the TOX and NOTOX groups achieving a maximum heart rate that was similar to the HC group and 49 (86%) of participants achieving age-predicted maximal HR. Postexercise assessments of cardiac function, including LVEF and contractile reserve, were also lower in the TOX group compared with the HC group, whereas AVO2 difference was similar among all 3 groups. These findings point toward left ventricular systolic dysfunction as an important contributor to low peak VO2 in the TOX group.

In a multivariate analysis among the breast cancer survivor groups, GLS was the only echocardiographic parameter that was independently associated with peak VO2. These findings confirm and extend previous observations in patients with heart failure with preserved ejection fraction and breast cancer survivors. In heart failure with preserved ejection fraction, there is a strong association between GLS and peak VO2,32,33 suggesting that GLS assessment may help to identify patients with subclinical left ventricular systolic dysfunction and impaired exercise capacity. A study of breast cancer survivors21 previously reported an association between inotropic reserve and peak VO2, but not GLS, although that study evaluated patients with ERBB2-negative cancer who received anthracyclines without targeted ERBB2 agents.

Our findings suggest that 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. Preventive and/or therapeutic strategies are needed to counteract the cardiotoxic effects of cancer therapy and prevent reduction of peak VO2. Aerobic exercise training represents a potential intervention that can target the cardiac-specific limitation associated with cardiotoxicity and improve peak VO2.12,34-36 Data from Imboden et al37 suggest that every 1 metabolic equivalent increase in peak VO2 is associated with a 12% reduction in all-cause mortality and 16% reduction in cardiovascular mortality in asymptomatic men and women after approximately 18 years of follow-up.

Limitations

This study has several limitations. The cross-sectional design of this study introduces potential selection bias among the recruited participants. However, the cancer treatment exposures and cardiovascular comorbidities of the TOX group closely matched those of the NOTOX group. Temporality between cardiotoxicity and low peak VO2 cannot be inferred owing to the cross-sectional design but will be addressed in a future longitudinal study. Although the number of patients included in this study was modest, our study is the first, to our knowledge, to comprehensively evaluate the long-term sequelae of treatment-induced cardiotoxicity among ERBB2-positive breast cancer survivors and contributes to the growing knowledge base of the adverse effects of cancer treatment on CRF. Grade I diastolic dysfunction was more prevalent among the TOX group; however, assessment of an association between peak VO2 and categorical classifications of diastolic dysfunction was limited owing to the small number of patients meeting these criteria. Cardiopulmonary exercise testing was performed during upright exercise, whereas postpeak images were acquired in the supine position; thus, it is unknown whether the observed differences in contractile reserve extend to the upright position. Nevertheless, differences in contractile reserve likely persist given that peak heart rate was similar between groups.38 Finally, AVO2 difference was derived from peak VO2 rather than directly measured; therefore, the relative contribution of AVO2 difference on impaired CRF could not be assessed. However, the absence of any significant difference in AVO2 difference among the TOX, NOTOX, and HC groups in this study closely match findings by Jones et al39 in a similar population of breast cancer survivors.

Conclusions

In summary, ERBB2-positive breast cancer survivors with prior treatment-induced cardiotoxicity have a significant impairment of CRF many years after the completion of therapy. Impairment of cardiac function appears to play an important role in the mechanism of low peak VO2. Assessment of GLS may be helpful for identifying breast cancer survivors with impaired exercise capacity and poor prognosis. We think future interventional studies are needed to prevent and mitigate the decline in peak VO2 associated with treatment-induced cardiotoxicity, thereby reducing cardiovascular disease risk and all-cause mortality associated with low peak VO2. Aerobic exercise training represents a potential intervention to improve CRF among breast cancer survivors that warrants further investigation.

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Article Information

Accepted for Publication: November 21, 2019.

Corresponding Author: Anthony F. Yu, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (yua3@mskcc.org).

Published Online: January 15, 2020. doi:10.1001/jamacardio.2019.5586

Author Contributions: Dr Yu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yu, Moskowitz, Oeffinger, Liu, Jones, Steingart.

Acquisition, analysis, or interpretation of data: Yu, Flynn, Moskowitz, Scott, Oeffinger, Dang, Jones, Steingart.

Drafting of the manuscript: Yu, Moskowitz, Oeffinger, Jones, Steingart.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Yu, Flynn, Moskowitz, Dang.

Obtained funding: Yu, Steingart.

Administrative, technical, or material support: Yu, Scott, Liu, Steingart.

Supervision: Yu, Steingart.

Conflict of Interest Disclosures: Dr Yu reported receiving grants from American Heart Association and the National Institutes of Health (NIH) during the conduct of the study and consulting fees from Glenmark Pharmaceuticals and Genentech, Inc, outside the submitted work. Dr Scott reported receiving grants from AKTIV Against Cancer and the NIH during the conduct of the study. Dr Dang reported receiving grants from institutional research funding provided to Memorial Sloan Kettering Cancer Center (MSKCC) from Puma Biotechnology, Inc, and Roche Group/Genentech, Inc, and serving as a compensated advisory board member to Roche Group/Genentech, Inc, Eli Lilly and Company, Daiichi Sankyo Company, and Puma Biotechnology, Inc, during the conduct of the study. Dr Liu reported receiving consulting fees from Bay Labs outside the submitted work. Dr Jones reported owning stock in Pacylex Pharmaceuticals, Inc, outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grant 15MCPRP25710138 from the American Heart Association (Dr Yu), by grant K23 CA218897 from the NIH (Dr Yu), and in part by grant P30 CA008748 from the NIH.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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