A Combined Echocardiography Approach for the Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Women With Early-Stage Breast Cancer

Abstract

Importance: Diagnosis of cancer therapy-related cardiac dysfunction (CTRCD) remains a challenge. Cardiovascular magnetic resonance (CMR) provides accurate measurement of left ventricular ejection fraction (LVEF), but access to repeated scans is limited.

Objective: To develop a diagnostic model for CTRCD using echocardiographic LVEF and strain and biomarkers, with CMR as the reference standard.

Design, setting, and participants: In this prospective cohort study, patients were recruited from University of Toronto-affiliated hospitals from November 2013 to January 2019 with all cardiac imaging performed at a single tertiary care center. Women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were included. The main exclusion criterion was contraindication to CMR. A total of 160 patients were recruited, 136 of whom completed the study.

Exposures: Sequential therapy with anthracyclines and trastuzumab.

Main outcomes and measures: Patients underwent echocardiography, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), and CMR studies preanthracycline and postanthracycline every 3 months during and after trastuzumab therapy. Echocardiographic measures included 2-dimensional (2-D) LVEF, 3-D LVEF, peak systolic global longitudinal strain (GLS), and global circumferential strain (GCS). LVEF CTRCD was defined using the Cardiac Review and Evaluation Committee Criteria, GLS or GCS CTRCD as a greater than 15% relative change, and abnormal hsTnI and BNP as greater than 26 pg/mL and ≥ 35 pg/mL, respectively, at any follow-up point. Combinations of echocardiographic measures and biomarkers were examined to diagnose CMR CTRCD using conditional inference tree models.

Results: Among 136 women (mean [SD] age, 51.1 [9.2] years), CMR-identified CTRCD occurred in 37 (27%), and among those with analyzable images, in 30 of 131 (23%) by 2-D LVEF, 27 of 124 (22%) by 3-D LVEF, 53 of 126 (42%) by GLS, 61 of 123 (50%) by GCS, 32 of 136 (24%) by BNP, and 14 of 136 (10%) by hsTnI. In isolation, 3-D LVEF had greater sensitivity and specificity than 2-D LVEF for CMR CTRCD while GLS had greater sensitivity than 2-D or 3-D LVEF. Regression tree analysis identified a sequential algorithm using 3-D LVEF, GLS, and GCS for the optimal diagnosis of CTRCD (area under the receiver operating characteristic curve, 89.3%). The probability of CTRCD when results for all 3 tests were negative was 1.0%. When 3-D LVEF was replaced by 2-D LVEF in the model, the algorithm still performed well; however, its primary value was to rule out CTRCD. Biomarkers did not improve the ability to diagnose CTRCD.

Conclusions and relevance: Using CMR CTRCD as the reference standard, these data suggest that a sequential approach combining echocardiographic 3-D LVEF with 2-D GLS and 2-D GCS may provide a timely diagnosis of CTRCD during routine CTRCD surveillance with greater accuracy than using these measures individually.

Trial registration: ClinicalTrials.gov Identifier: NCT02306538.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Esmaeilzadeh and Urzua Fresno, Ms Somerset, Drs Shalmon, Amir, and Fan, Ms Thampinathan, Ms Thevakumaran, Drs Koch, Abdel-Qadir, Woo, and Yip, Ms Chan, and Drs Wintersperger and Thavendiranathan are affiliated with University Health Network, which has a master research agreement with Siemens Healthineers. Dr Amir has received fees for expert testimony from Genentech/Roche and personal fees for consulting from Sandoz and Exact Sciences outside the submitted work. Dr Brezden-Masley has received grants from Canadian Institutes of Health Research and Hoffmann La Roche during the conduct of the study as well as research funds, honoraria, and consultancy fees from Hoffman La Roche, Amgen, Viatris (Mylan), Astra Zeneca, Novartis, Eli Lilly, Agendia, Gilead Sciences, Bristol Myers Squibb, Pfizer, Taiho, Myriad, and ApoBioligix outside the submitted work. Dr Yared has received speaking honoraria from Servier, Amgen, Bristol Myers Squibb, Pfizer, and Amgen. Dr Abdel-Qadir has received honoraria from Amgen. Dr Abdel-Qadir reported personal fees from Amgen Canada during the conduct of the study and payment from the Canadian Vigour Centre to serve on an end point adjudication committee for the THEMIS trial that was funded by Astra Zeneca. Dr Yip reported grants and personal fees from Abbott Diagnostics and personal fees from Roche Diagnostics and Nova Biomedical outside the submitted work. Dr Marwick reported grants from General Electric Healthcare Systems for the SUCCOUR trial outside the submitted work. Dr Wintersperger reported personal fees from Siemens Healthineers, research support from Siemens Healthineers, and personal fees from Bayer AG outside the submitted work. Dr Thavendiranathan has received speaker’s honoraria from Amgen, Boehringer Ingelheim, and Takeda. No other disclosures were reported.

Figures

Figure 1.. Timing of Cancer Therapy–Related Cardiac Dysfunction (CTRCD)

Timing of CTRCD defined by echocardiography-measured strain, 2-dimensional (2-D) and 3-D left ventricular ejection fraction (LVEF), and abnormal levels of high-sensitivity troponin I (>26 mg/mL) and B-type natriuretic peptide (BNP; ≥35 pg/mL) in comparison with cardiovascular magnetic resonance (CMR)–defined CTRCD. A, When using global longitudinal strain (GLS) or global circumferential strain (GCS), a greater proportion of patients developed a change of more than 15% than with CMR-defined CTRCD and at an earlier time point, highlighting the sensitivity of this method. B, Using LVEF, CMR-defined CTRCD occurred slightly earlier and in a greater proportion of patients. C, Abnormal troponin developed earlier in the treatment course, while abnormal BNP occurred both early and toward the end of the treatment course.

Figure 2.. Temporal Measurements of Left Ventricular Ejection Fraction (LVEF), Echocardiographic Strain, and Biomarkers

Measurements dichotomized based on patients with and without cardiovascular magnetic resonance (CMR)–defined cancer therapy–related cardiac dysfunction. There were clear and significant differences in the trajectories between the 2 cohorts for all measures except for high-sensitivity troponin I (HsTnI) and B-type natriuretic peptide (BNP). Each line represents 1 patient. 2-D indicates 2-dimensional; 3-D, 3-dimensional; GCS, global circumferential strain; GLS, global longitudinal strain.

Figure 3.. Fitted Regression Tree for the Diagnosis of Cardiovascular Magnetic Resonance (CMR) Cancer Therapy–Related Cardiac Dysfunction (CTRCD) Using Echocardiographic Methods

Patients who met 3 dimensional (3-D) CTRCD criteria had a 76.9% probability of having CTRCD (Figure 4A table insert). Those who did not meet 3-D echocardiographic (echo) criteria but had a more than 15% change in both global longitudinal strain (GLS) and global circumferential strain (GCS) compared with baseline have a 15.9% probability of CTRCD. Those who did not meet 3-D left ventricular ejection fraction (LVEF), GLS, or GCS criteria had a 1.0% probability of CTRCD. B, 3-D LVEF replaced with 2-dimensional (2-D) LVEF in the optimized regression tree model. Patients who met only 2-D LVEF criteria had a 60.6% probability of CMR CTRCD (Figure 4D table insert). However, with the use of the entire algorithm, the model’s discriminatory value remained similar. Those who did not meet 2-D LVEF, GLS, or GCS criteria had a 0.7% probability of CTRCD. The orange bars represent patients with CTRCD while the blue bars represent those without CTRCD; the y-axis of the boxes represents proportion. The numbers on the top of the boxes represent the number of echocardiography studies that met the proposed criteria within that branch.

Figure 4.. Receiver Operating Characteristic Curves for Models Estimating Risk of Cancer Therapy–Related Cardiac Dysfunction (CTRCD)

B, In this model, 27 patients met CTRCD criteria. C, In this model, 16 patients met CTRCD criteria. The table inserts provide the estimated probability of CTRCD at each node of the tree model in Figure 3. 2-D indicates 2-dimensional; 3-D, 3-dimensional; ASE, American Society of Echocardiography; AUC, area under the receiver operating characteristic curve; CREC, cardiac review and evaluation committee; EACVI, European Association of Cardiovascular Imaging; ESC, European Society of Cardiology; GCS, global circumferential strain; GLS, global longitudinal strain; prob, probability.