Background Anthracycline chemotherapy may be associated with decreased cardiac function and functional capacity measured as the peak oxygen uptake during exercise ([Formula: see text] peak). We sought to determine (a) whether a structured exercise training program would attenuate reductions in [Formula: see text] peak and (b) whether exercise cardiac imaging is a more sensitive marker of cardiac injury than the current standard of care resting left ventricular ejection fraction (LVEF). Methods Twenty-eight patients with early stage breast cancer undergoing anthracycline chemotherapy were able to choose between exercise training (mean ± SD age 47 ± 9 years, n = 14) or usual care (mean ± SD age 53 ± 9 years, n = 14). Measurements performed before and after anthracycline chemotherapy included cardiopulmonary exercise testing to determine [Formula: see text] peak and functional disability ([Formula: see text] peak < 18 ml/min/kg), resting echocardiography (LVEF and global longitudinal strain), cardiac biomarkers (troponin and B-type natriuretic peptide) and exercise cardiac magnetic resonance imaging to determine stroke volume and peak cardiac output. The exercise training group completed 2 × 60 minute supervised exercise sessions per week. Results Decreases in [Formula: see text] peak during chemotherapy were attenuated with exercise training (15 vs. 4% reduction, P = 0.010) and fewer participants in the exercise training group met the functional disability criteria after anthracycline chemotherapy compared with those in the usual care group (7 vs. 50%, P = 0.01). Compared with the baseline, the peak exercise heart rate was higher and the stroke volume was lower after chemotherapy ( P = 0.003 and P = 0.06, respectively). There was a reduction in resting LVEF (from 63 ± 5 to 60 ± 5%, P = 0.002) and an increase in troponin (from 2.9 ± 1.3 to 28.5 ± 22.4 ng/mL, P < 0.0001), but no difference was observed between the usual care and exercise training group. The baseline peak cardiac output was the strongest predictor of functional capacity after anthracycline chemotherapy in a model containing age and resting cardiac function (LVEF and global longitudinal strain). Conclusions The peak exercise cardiac output can identify patients at risk of chemotherapy-induced functional disability, whereas current clinical standards are unhelpful. Functional disability can be prevented with exercise training.

Background: Breast cancer (BC) 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 early-stage BC patients scheduled for AC to determine if 12-months of exercise training (ExT) could attenuate functional disability (primary endpoint), improve cardiorespiratory fitness (VO 2 peak) and prevent cardiac dysfunction. Methods: Women aged 40-75 years with stage I-III BC scheduled for AC were randomized to 3-4 days/wk of aerobic and resistance ExT for 12-months (n = 52) or usual care ([ UC ], n = 52). Functional measures were performed at baseline, 4-weeks following AC (4-months) and at 12-months comprising: 1) cardiopulmonary exercise testing to quantify VO 2 peak and functional disability (VO 2 peak ≤18.0mL/kg/min), 2) cardiac reserve (response from rest to peak exercise) quantified using exercise cardiac magnetic resonance measures to determine changes in left- and right-ventricular ejection fraction [ LVEF, RVEF ], cardiac output [ CO ], and stroke volume [ SV ]), 3) standard-of-care echocardiography-derived resting LVEF and global longitudinal strain [ GLS ], and 4) biochemistry (troponin and B-type natriuretic peptide [ BNP ]). 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 at 12-months (ExT: n=49, UC: n=38). ExT attenuated functional disability at 4-months (OR: 0.32 [95% CI 0.11, 0.94], P=0.03), but not at 12-months (OR: 0.27, [95% CI 0.06, 1.12], P=0.07). In a per-protocol analysis, functional disability was entirely prevented at 12-months among participants adherent to ExT (ExT: 0% vs. UC: 20%, P=0.005). As compared with UC at 12-months, ExT was associated with a net +3.5 mL/kg/min improvement in VO 2 peak that coincided with greater CO, SV, LVEF and RVEF reserve (P<0.001 for all). There was no effect of ExT on resting measures of LV function. Post-chemotherapy troponin increased less in ExT than UC (8-fold vs. 16-fold increase, P=0.002). There were no changes in BNP in either group. Conclusions: In women with early-stage BC undergoing AC, 12-months of ExT did not attenuate functional disability but provided large and clinically meaningful benefits on VO2peak and cardiac reserve. Clinical Trial Registration: URL: https://www.anzctr.org.au/ Unique Identifier: ACTRN12617001408370