Background
Assessment of left ventricular systolic function is necessary during trastuzumab-based chemotherapy because of potential cardiotoxicity. Deformation indices have been proposed as an adjunct to clinical risk factors and ejection fraction (EF), but the optimal parameter and optimal cutoffs are undefined. The aim of this study was to determine the best means of early detection of subsequent reduction of EF in patients with breast cancer treated with trastuzumab.
Methods
Eighty-one consecutive women (mean age, 50 ± 11 years) receiving trastuzumab were prospectively studied, 37 of whom received concurrent anthracyclines. Conventional echocardiographic indices (mitral annular systolic [s′] and diastolic [e′] velocities) and myocardial deformation indices (global longitudinal peak systolic strain [GLS], global longitudinal peak systolic strain rate [GLSR-S], and global longitudinal early diastolic strain rate [GLSR-E]) were measured at baseline and at 6 and 12 months. Cardiotoxicity was defined as a >10% decline as a percentage of baseline EF in 12 months.
Results
In the 24 patients (30%) who later developed cardiotoxicity, myocardial deformation indices decreased at 6 months (GLS, P < .001; GLSR-S, P = .009; GLSR-E, P = .002 vs baseline), but e′ was unchanged. The strongest predictor of cardiotoxicity was ΔGLS (area under the curve, 0.84); an 11% reduction (95% confidence interval, 8.3%–14.6%) was the optimal cutoff, with sensitivity of 65% and specificity of 94%. In sequential models, the clinical model (χ 2 = 10.2) was improved by GLSR-S (χ 2 = 14.7, P = .03) and even more so by GLSR-E (χ 2 = 18.0, P = .005) or GLS (χ 2 = 21.3, P = .0008). Discrimination improvement by adding GLS was confirmed by an integrated discrimination improvement of 18.6% (95% confidence interval, 8.6%–28.6%; P = .0003). A net 29% of the patients without events were reclassified into lower risk categories, and a net 48% of the patients with events were reclassified into higher risk categories, resulting in a total continuous net reclassification improvement (>0) of 0.77 (95% confidence interval, 0.33–1.22; P = .036).
Conclusions
GLS is an independent early predictor of later reductions in EF, incremental to usual predictors in patients at risk for trastuzumab-induced cardiotoxicity.
Breast cancer is the most common malignancy in women all over the world and has been the most common malignancy in American women for more than three decades. The addition of adjuvant trastuzumab has substantially improved overall survival and reduced the risk for disease recurrence in women with human epidermal growth factor receptor type 2–positive breast cancers. Because of its potential cardiotoxicity, trastuzumab treatment requires careful monitoring of left ventricular (LV) function during treatment. Measurement of LV ejection fraction (EF) is the most common method of monitoring cardiac function during cancer treatment. Cardiotoxicity has been defined as a symptomatic EF reduction of 5% or an asymptomatic 10% reduction to an EF <55%. However, EF is an imperfect parameter for the detection of cardiotoxicity because of its inherent variability: the 95% confidence intervals (CIs) for EF measurement exceed 0.10. Moreover, EF fails to detect early subtle changes, and when reduced, it reflects a marker of advanced myocyte damage accompanied by a poor prognosis. Deformation parameters such as strain and strain rate have been useful to detect subclinical myocardial dysfunction, but the incremental value to traditional clinical variables and EF is unknown.
Thus, we sought (1) to elucidate the optimal parameter for early recognition of cardiotoxicity and (2) to ascertain whether deformation indices are incremental to clinical risk factors and baseline EF for detecting further reductions of systolic function in patients with breast cancer treated with trastuzumab.
Methods
Study Population
We enrolled 93 consecutive women receiving trastuzumab as part of their treatment for breast cancer at Cleveland Clinic (Cleveland, OH), and the University of Queensland (Brisbane, Australia). All patients underwent at least three echocardiographic studies (at baseline and at 6 and 12 months). Because β-blockers may have protective effect on chemotherapy-induced cardiomyopathy, 12 patients taking β-blockers were excluded from the analysis. The final population therefore comprised 81 patients (mean age, 50 ± 11 years).
The study was approved by the institutional review boards of both institutions, and written informed consent was gathered for studies obtained outside of usual medical care. The authors had full access to and take responsibility for the integrity of the data.
Standard Echocardiography
Patients underwent echocardiography at baseline (before the initiation of trastuzumab) and at 6 and 12 months of therapy. Echocardiography was performed using standard commercial echocardiographic systems (Vivid 7 and E9; GE Medical Systems, Milwaukee, WI). Sector size and depth were adjusted to achieve optimal visualization of all LV myocardium at the highest possible frame rate. Acquisition was obtained at end-expiration. Multiple consecutive cardiac cycles of the three standard apical views were acquired and stored digitally for subsequent analysis. EF was calculated using the biplane method of disks and traced at least twice by an experienced single observer. Cardiotoxicity was defined by an EF reduction of ≥10%.
Tissue Doppler–derived indices were measured using the apical four-chamber view. Peak systolic (s′) and early diastolic (e′) mitral annular velocities were calculated by averaging septal and lateral mitral annular velocities.
Measurement of Myocardial Strain and Strain Rate
Three apical views were used to obtain both global longitudinal peak systolic strain (GLS) and global longitudinal peak systolic strain rate (GLSR-S) and global longitudinal early diastolic strain rate (GLSR-E), using standard, commercially available software (EchoPAC PC version 11.0.0; GE Medical Systems). The adequacy of tracking was verified manually, and the region of interest was readjusted to achieve optimal tracking. Percentage change (Δ) was calculated between baseline and 6 months. In addition to longitudinal deformation parameters, global circumferential peak systolic strain and global radial peak systolic strain were measured from the parasternal short-axis view at the midpapillary muscle level and used for the evaluation of longitudinal, radial, and circumferential strain.
Reproducibility
Intraobserver and interobserver variability were evaluated in 10 random subjects using intraclass correlation coefficients with their 95% CIs and coefficients of variation with the root-mean-square method.
Statistical Analysis
Continuous data are presented as mean ± SD and categorical data as percentages. Student’s t tests and paired t tests were used to compare continuous variables as appropriate. Chi-square and Fisher’s exact tests were applied to compare categorical variables. Receiver operating characteristic curve analyses with 1,000 bootstraps were performed to compare the prediction of significant 12-month reduction in EF and to determine the optimal cutoff values. The best cutoff value was defined as the point with the highest sum of sensitivity and specificity. Logistic regression analysis was used to determine predictors of significant decrease in EF. Variables were put into the model on the basis of previously reported risk factors (age, hypertension, diabetes mellitus, dyslipidemia, smoking, and baseline EF). A series of nested models was constructed, starting with known clinical risk factors and followed successively by baseline EF, Δe′, Δs′, ΔGLS, and ΔGLSR-S. The incremental value was assessed using the likelihood ratio test using model χ 2 . Because five comparisons were performed, P values <.01 were considered to show a significant increment in the nested models. Reclassification was evaluated using the integrated discrimination improvement and net reclassification improvement (NRI) methods described by Pencina et al. The integrated discrimination improvement measured the change in the difference in the mean predicted probabilities of outcomes between subjects (with and without events) after adding GLS to the base model with known clinical risk factors and baseline EF. Because there is no established risk category for cardiotoxicity, category-free NRI (NRI > 0) is reported. Statistical analyses were performed using SPSS version 20.0.0 (SPSS, Inc., Chicago, IL) and MedCalc version 12.3.0.0 (MedCalc Software, Mariakerke, Belgium), and P values <.05 were considered statistically significant.
Results
Patient Characteristics
Clinical characteristics are summarized in Table 1 . Of the entire population, 37 patients (46%) received anthracycline sequentially with trastuzumab. Twenty-four women (30%) developed cardiotoxicity at 12 months. Baseline cardiac risk factors of both groups were similar. There were no differences in the staging of breast cancer, surgery, radiation, or the use of taxanes among the two groups. The maximal cumulative doses of anthracyclines (doxorubicin, 240 mg/m 2 ; epirubicin, 600 mg/m 2 ) were not exceeded in all patients and did not differ between the groups.
| Variable | Whole ( n = 81) | No cardiotoxicity ( n = 57) | Cardiotoxicity ( n = 24) | P |
|---|---|---|---|---|
| Age (y) | 50 ± 11 | 51 ± 12 | 50 ± 11 | .72 |
| Heart rate at baseline echocardiography (beats/min) | 75 ± 15 | 73 ± 14 | 80 ± 17 | .11 |
| Hypertension | 17 (21%) | 11 (20%) | 6 (25%) | .78 |
| Diabetes | 6 (7%) | 4 (7%) | 2 (8%) | .80 |
| Dyslipidemia | 13 (16%) | 11 (20%) | 2 (8%) | .37 |
| Smoking | 12 (15%) | 7 (11%) | 5 (25%) | .52 |
| Stage | .65 | |||
| Early | 37 (45%) | 24 (43%) | 13 (54%) | |
| Locally advanced | 32 (40%) | 24 (42%) | 8 (33%) | |
| Metastatic | 12 (15%) | 9 (16%) | 3 (13%) | |
| Surgery | 72 (89%) | 51 (89%) | 21 (88%) | .89 |
| Radiation | 50 (62%) | 37 (66%) | 13 (54%) | .51 |
| Anthracycline use | 37 (46%) | 26 (46%) | 11 (46%) | .82 |
| Doxorubicin | 25 (31%) | 16 (28%) | 9 (38%) | |
| Epirubicin | 12 (15%) | 10 (17%) | 2 (8%) | |
| Taxane use | 74 (91%) | 51 (89%) | 23 (96%) | .62 |
The intraobserver intraclass coefficients for GLS, GLSR-S, and GLSR-E, were 0.85 (95% CI, 0.54 to 0.96), 0.91 (95% CI, 0.70 to 0.98), and 0.90 (95% CI, 0.66 to 0.97), respectively. The corresponding interobserver intraclass coefficients were 0.71 (95% CI, 0.23 to 0.92), 0.85 (95% CI, 0.28 to 0.97), and 0.87 (95% CI, 0.56 to 0.97). Intraobserver and interobserver variability for EF were 0.74 (95% CI, 0.02 to 0.94) and 0.36 (95% CI, −1.42 to 0.84). Intraobserver and interobserver absolute (relative) differences of EF were 2 ± 2% (3 ± 4%) and 4 ± 4% (8 ± 5%).
Changes in Echocardiographic Parameters
A summary of serial echocardiographic parameters of both groups is shown in Table 2 . Although Δe′ was not significantly different between the groups at 6 months, s′ ( P = .04), ΔGLS ( P < .001), ΔGLSR-S ( P = .009), and ΔGLSR-E ( P = .002) were significantly reduced in patients developing cardiotoxicity ( Table 3 ).
| Variable | No cardiotoxicity | Cardiotoxicity | ||||
|---|---|---|---|---|---|---|
| Baseline | 6 mo | 12 mo | Baseline | 6 mo | 12 mo | |
| EF (%) | 62 ± 3.6 | 60 ± 3.7 | 60 ± 3.5 | 64 ± 4.6 | 58 ± 5.5 | 55 ± 5.3 |
| GLS (%) | −20.0 ± 2.0 | −19.7 ± 2.0 | −19.5 ± 2.4 | −20.7 ± 2.6 | −18.3 ± 2.1 | −18.3 ± 2.6 |
| GLSR-S (/sec) | −1.05 ± 0.16 | −1.05 ± 0.18 | −0.97 ± 0.16 | −1.17 ± 0.24 | −1.00 ± 0.15 | −0.97 ± 0.18 |
| GLSR-E (/sec) | 1.32 ± 0.31 | 1.35 ± 0.32 | 1.29 ± 0.33 | 1.36 ± 0.28 | 1.20 ± 0.27 | 1.13 ± 0.29 |
| s′ (cm/sec) | 8.0 ± 1.9 | 7.5 ± 2.0 | 6.8 ± 1.8 | 9.1 ± 2.1 | 7.2 ± 1.4 | 7.1 ± 1.6 |
| e′ (cm/sec) | 9.8 ± 3.5 | 9.6 ± 3.0 | 8.9 ± 3.3 | 10.0 ± 3.1 | 8.7 ± 2.6 | 8.9 ± 2.8 |
| GCS (%) | −17.0 ± 4.0 | −16.4 ± 3.0 | −15.7 ± 3.4 | −17.8 ± 3.9 | −15.9 ± 3.5 | −15.7 ± 4.3 |
| GRS (%) | 50.0 ± 17.1 | 47.2 ± 17.3 | 52.3 ± 17.7 | 50.9 ± 18.5 | 41.5 ± 14.9 | 45.7 ± 16.2 |
| No cardiotoxicity | Cardiotoxicity | P | |
|---|---|---|---|
| GLS | 0.2 ± 8.6 | 11.4 ± 9.8 | <.001 |
| GLSR-S | −0.2 ± 16.8 | 12.8 ± 19.4 | .009 |
| GLSR-E | 5.1 ± 21.2 | −11.9 ± 14.5 | .002 |
| s′ | −5.0 ± 18.9 | −17.0 ± 23.9 | .04 |
| e′ | 3.5 ± 37.1 | −10.0 ± 28.7 | .09 |
| GCS | −1.0 ± 29.7 | 9.3 ± 27.4 | .18 |
| GRS | 8.3 ± 48.5 | −10.0 ± 39.3 | .11 |
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