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Background: Whether structured exercise therapy improves chemotherapy delivery, tolerability, and tumor response is unclear., Methods: This was a secondary analysis of a phase 2 trial investigating exercise therapy (n = 72) versus usual care (n = 72) in patients with primary breast cancer. Exercise therapy comprised individualized treadmill walking three times weekly for 20-50 minutes per session at 55%-100% of pretreatment exercise capacity. Chemotherapy delivery was assessed according to the relative dose intensity (RDI), tolerability was assessed according to patient-reported outcomes and blood laboratory values, and response was assessed based on the pathologic complete response rate in patients who received neoadjuvant chemotherapy., Results: In the exercise therapy group, 51 patients (71%) reached 100% RDI (median, 100%; interquartile range, 100%-100%) compared with 41 patients (57%) in the usual care group (median, 100%; interquartile range, 95%-100%; p = .08). Tolerability was similar in both groups; the rates of grade 3 or higher neutropenia and anemia were 22% versus 39% and 7% versus 10% in the exercise and usual care groups, respectively. In patients who received anthracyclines (n = 104), 41 (77%) had 100% chemotherapy RDI in the exercise therapy group versus 29 (57%) in the usual care group (p = .026). In the neoadjuvant chemotherapy subgroup (n = 51 tumors), the postneoadjuvant therapy (yp) pathologic complete response (ypT0ypN0) rate was 27% (95% confidence interval, 12%-50%) in the exercise therapy group compared with 28% (95% confidence interval, 13%-47%) in the usual care group (p > .9)., Conclusions: In patients with primary breast cancer, exercise therapy was associated with improved delivery of anthracycline-based chemotherapy. Although exercise therapy was not significantly associated with tumor response, effects varied by tumor subtype (trial registration: Clinicaltrials.gov identifier NCT01943695)., (© 2024 American Cancer Society.)