Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study

Abstract

Background: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO 2 peak), and prevent cardiac dysfunction. Methods: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO 2 peak and functional disability (VO 2 peak ≤18.0 mL·kg −1 ·min −1 ); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide]). Results: Among 104 participants randomized, greater study attrition was observed among UC participants ( P =0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11–0.94]; P =0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06–1.12]; P =0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P =0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg −1 ·min −1 improvement in VO 2 peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve ( P <0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P =0.002). There were no changes in BNP in either group. Conclusions: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO 2 peak and cardiac reserve. Registration: URL: https://www.anzctr.org.au/ ; Unique identifier: ACTRN12617001408370.