Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer

Abstract

Purpose: Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC.

Methods: Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs).

Results: For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population.

Conclusion: Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

FIG 1.

(A) Restricted cubic splines from Cox proportional hazard regression models showing a nonlinear relationship (test for nonlinearity P = .0097) between exercise at diagnosis and risk of DRFI events in the overall cohort (N = 10,359 patients). (B) Kaplan-Meier estimates of DRFI in the overall IPTW cohort according to exercise at diagnosis, categorized in <5 MET-h/wk versus ≥5 MET-h/wk. DRFI, distant recurrence-free interval; IPTW, inverse probability treatment weighted; MET-h/wk, metabolic equivalent of task–hours per week.

FIG 2.

(A) Kaplan-Meier estimates of DRFI according to exercise at diagnosis, categorized into <5 MET-h/wk versus ≥5 MET-h/wk in the overall IPTW hormone receptor+/HER2– cohort. (B) Kaplan-Meier estimates of DRFI in <5 MET-h/wk versus ≥5 MET-h/wk in the overall IPTW hormone receptor–/HER2– cohort. DRFI, distant recurrence-free interval; HER2, human epidermal growth factor receptor 2; IPTW, inverse probability treatment weighted; MET-h/wk, metabolic equivalent of task–hours per week.

FIG 3.

Kaplan-Meier estimates of DRFI according to exercise at diagnosis, categorized into <5 MET-h/wk versus ≥5 MET-h/wk in the overall premenopausal IPTW cohort. DRFI, distant recurrence-free interval; IPTW, inverse probability treatment weighted; MET-h/wk, metabolic-equivalent task-hours per week.