Cardiac dysfunction (CD) among breast cancer survivors (BCS): Role of cardiotoxic therapy and cardiovascular risk factors.
Authors: Bostany Geoffrey S. , Chen Yanjun , Francisco Liton , Dai Chen , Meng Qingrui , Sparks Jessica R , Sessions Min , Nabell Lisle , Stringer-Reasor Erica Michelle , Khoury Katia , Lenneman Carrie , Keene Kimberly Sue , Landier Wendy , Bhatia Smita 
Published: June 2023

12078

Background: CD is the leading cause of mortality in BCS. Limited information regarding the long-term risk of CD after exposure to cardiotoxic agents (anthracyclines, trastuzumab/pertuzumab and left breast/chest wall radiation) and additional factors that place BCS at highest risk has precluded development of surveillance guidelines for early detection of CD in BCS. Methods: Patients, who survived ≥1y after BC and received potentially cardiotoxic therapy, underwent q2y echocardiographic (echo) screening at a single center. All echos from BC diagnosis to CD or last follow-up were processed in Python via automated text analysis. New-onset CD was defined as left ventricular ejection fraction (LVEF) <50% or fractional shortening (FS) <28%. Treatment exposures, demographics and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia, obesity, smoking) were abstracted from medical records. Cumulative incidence of CD described the magnitude of risk in the entire cohort and among those who received anthracyclines (±radiation), trastuzumab/pertuzumab (±radiation), and radiation alone (without anthracyclines/trastuzumab/pertuzumab). Cox proportional hazards models estimated hazard ratios (HRs) and 95%CIs of associations between CD and treatment, adjusting for CVRFs (time varying) and demographics. Longitudinal echocardiographic analyses (adjusted for covariates) estimated trends in cardiac function prior to CD. Results: We evaluated 2,540 echos in 847 BCS exposed to potentially cardiotoxic therapy (median age at BC: 54.4y; median follow-up: 7.6y). Overall, 39% of BCS received anthracyclines, 17% received trastuzumab/pertuzumab, 5% received anthracyclines + trastuzumab/pertuzumab, and 39% received radiation alone. The cumulative incidence of CD in the entire cohort was 12.3% at 2y, increasing to 29.7% by 10y after BC. Multivariable analysis revealed the following to be independently associated with CD: treatment (anthracyclines: HR=2.72, 95%CI=1.9-3.9; trastuzumab/pertuzumab: HR=1.92, 95%CI=1.1-3.2; ref: radiation alone), presence of CVRFs before CD diagnosis (hypertension: HR=1.77, 95%CI=1.3-2.4; obesity: HR=1.82, 95%CI=1.4-2.4; and dyslipidemia: HR=1.63, 95%CI=1.3-2.1). Adjusted longitudinal echo analyses revealed a statistically significant decline in SF over 20y from BC diagnosis (but prior to CD onset) for the entire cohort (p=0.0007), trastuzumab/pertuzumab (p=0.006), anthracyclines (p=0.037), and radiation alone (p=0.01). Conclusions: In this large cohort of BCS followed longitudinally for an extended period, exposure to potentially cardiotoxic therapy results in a substantial burden of CD; the risk increases over time, and with CVRFs. These results provide evidence for close surveillance of BC survivors at increased risk of CD for extended periods, and aggressive management of CVRFs before, during and after BC.