Comprehensive Cardiovascular Magnetic Resonance Tissue Characterization and Cardiotoxicity in Women With Breast Cancer

Abstract

Importance: There is a growing interest in understanding whether cardiovascular magnetic resonance (CMR) myocardial tissue characterization helps identify risk of cancer therapy-related cardiac dysfunction (CTRCD).

Objective: To describe changes in CMR tissue biomarkers during breast cancer therapy and their association with CTRCD.

Design, setting, and participants: This was a prospective, multicenter, cohort study of women with ERBB2 (formerly HER2)-positive breast cancer (stages I-III) who were scheduled to receive anthracycline and trastuzumab therapy with/without adjuvant radiotherapy and surgery. From November 7, 2013, to January 16, 2019, participants were recruited from 3 University of Toronto-affiliated hospitals. Data were analyzed from July 2021 to June 2022.

Exposures: Sequential therapy with anthracyclines, trastuzumab, and radiation.

Main outcomes and measures: CMR, high-sensitivity cardiac troponin I (hs-cTnI), and B-type natriuretic peptide (BNP) measurements were performed before anthracycline treatment, after anthracycline and before trastuzumab treatment, and at 3-month intervals during trastuzumab therapy. CMR included left ventricular (LV) volumes, LV ejection fraction (EF), myocardial strain, early gadolinium enhancement imaging to assess hyperemia (inflammation marker), native/postcontrast T1 mapping (with extracellular volume fraction [ECV]) to assess edema and/or fibrosis, T2 mapping to assess edema, and late gadolinium enhancement (LGE) to assess replacement fibrosis. CTRCD was defined using the Cardiac Review and Evaluation Committee criteria. Fixed-effects models or generalized estimating equations were used in analyses.

Results: Of 136 women (mean [SD] age, 51.1 [9.2] years) recruited from 2013 to 2019, 37 (27%) developed CTRCD. Compared with baseline, tissue biomarkers of myocardial hyperemia and edema peaked after anthracycline therapy or 3 months after trastuzumab initiation as demonstrated by an increase in mean (SD) relative myocardial enhancement (baseline, 46.3% [16.8%] to peak, 56.2% [18.6%]), native T1 (1012 [26] milliseconds to 1035 [28] milliseconds), T2 (51.4 [2.2] milliseconds to 52.6 [2.2] milliseconds), and ECV (25.2% [2.4%] to 26.8% [2.7%]), with P <.001 for the entire follow-up. The observed values were mostly within the normal range, and the changes were small and recovered during follow-up. No new replacement fibrosis developed. Increase in T1, T2, and/or ECV was associated with increased ventricular volumes and BNP but not hs-cTnI level. None of the CMR tissue biomarkers were associated with changes in LVEF or myocardial strain. Change in ECV was associated with concurrent and subsequent CTRCD, but there was significant overlap between patients with and without CTRCD.

Conclusions and relevance: In women with ERBB2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, CMR tissue biomarkers suggest inflammation and edema peaking early during therapy and were associated with ventricular remodeling and BNP elevation. However, the increases in CMR biomarkers were transient, were not associated with LVEF or myocardial strain, and were not useful in identifying traditional CTRCD risk.

Figure 1.. Cardiovascular Magnetic Resonance (CMR) Tissue Biomarkers at Each Study Visit

Individual patient trajectories and overall trajectories (orange line) with corresponding 95% CI (orange shading) are shown for relative myocardial enhancement (A), relative skeletal enhancement (B), early gadolinium enhancement (C), global T1 (D), global T2 (E), and global extracellular volume fraction (ECV) (F). The P values assess if the estimated trajectory is different from a horizontal line (ie, no changes from baseline). Relative myocardial and skeletal muscle enhancement, T1, T2, and ECV all peaked after anthracycline (before trastuzumab) therapy or 3 months into trastuzumab therapy and returned to baseline by end of trastuzumab therapy (eFigures 10 and 11 and eTable 6 in Supplement 1 for grouping based on cancer therapy–related cardiac dysfunction status). Time points on the x-axis are as follows: 1, before anthracycline therapy; 2, after anthracycline but before trastuzumab therapy; 3, three months after trastuzumab initiation; 4, six months after trastuzumab initiation; and 6, after trastuzumab completion. No CMR data was collected at time point 5. Normal ranges for same CMR sequences and scanner from our prior publication is provided as dashed lines for T1, T2, and ECV.

Figure 2.. Left Ventricular (LV) Volumes, Mass, and Function at Each Visit

Individual patient trajectories and overall trajectories (orange line) with corresponding 95% CI (orange shading) are shown for LV end-diastolic volume (EDV) (A), LV end-systolic volume (ESV) (B), LV ejection fraction (C), LV mass indexed (D), global longitudinal strain (E), and global circumferential strain (F). On average, ventricular volumes and mass reached their largest, while LVEF and both strain measures reached their minimum first at 3 months into trastuzumab therapy with incomplete or no recovery by end of follow-up. The P values assess if the estimated trajectory is different from a horizontal line (ie, no changes from baseline). Figure 1 contains the definition of the time points. eFigures 8 and 9 in Supplement 1 display the same measures grouped based on cancer therapy–related cardiac dysfunction status.

Figure 3.. Regression-Adjusted Nonlinear Concurrent Associations Between Cardiovascular Magnetic Resonance (CMR) Tissue Biomarkers and Left Ventricular (LV) Volumes and Ejection Fraction

The graphs show the expected changes in outcome variables (y-axis) associated with changes in CMR tissue biomarkers (x-axis). For example, a change in T1 from 1000 to 1050 milliseconds was associated with an increase in LV end-diastolic volume (EDV) index of 3.12 (95% CI, 1.99-4.25) mL/m² and LV end-systolic volume (ESV) index of 1.07 (95% CI, 0.47-1.67) mL/m². The tick marks on the x-axis reflect individual observed measurements. The shaded region represents the 95% CI of the estimated association. P values <.05 suggest statistically significant associations. ECV indicates extracellular volume fraction.

Figure 4.. Regression-Adjusted Nonlinear Associations Between Cancer Therapy–Related Cardiac Dysfunction (CTRCD) at the Next Visit and Cardiovascular Magnetic Resonance (CMR) Tissue Biomarkers in Terms of Log Odds

The graphs show the log-odds of CTRCD (y-axis) associated with changes in the x-axis CMR tissue biomarkers: early gadolinium enhancement ratio (A), global T1 (B), global T2 (C), and global extracellular volume fraction (ECV) (D). For example, a change in ECV from 24% to 22% increased the log odds of CTRCD at the next visit by 1.232 (95% CI, 0.381-2.082), which translates to an odds ratio of 3.427 ( = 10^1.232). In other words, an absolute decrease from 24% to 22% in ECV was associated with a 242.7% increase in the likelihood of CTRCD at the next visit. The tick marks on the x-axis reflect individual observed measurements. The shaded region represents the 95% CI of the estimated association. P values <.05 suggest statistically significant associations.