Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data

Abstract

Purpose: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease.

Methods: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups.

Results: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics.

Conclusions: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Figure 1.. Odds of abnormal cardiopulmonary response.

Odds ratio of abnormal cardiopulmonary exercise response in the pooled breast cancer cohort relative to control. Abbreviations: HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; VO₂, oxygen uptake; VCO₂ carbon dioxide production; VE, ventilation; OUES, oxygen uptake efficiency slope.

Figure 2.. Exercise response patterns.

(A) VO₂ vs. time; (B) HR vs. VO₂ vs. O₂ pulse; (C) VE vs. VCO₂; (D) VE vs. VO₂; (E) VE/VO₂ & VE/VCO₂ vs. VO₂; (F) Vt vs. VO₂ vs. RR. Mean data for the pooled breast cancer (blue) and BC risk (black) cohorts. Individual patient data within each cohort averaged at 1-minute timepoints (truncated at the point reached by ≥85% of participants) and at peak. Abbreviations: VO₂, oxygen uptake; HR, heart rate; O₂, oxygen; VCO₂ carbon dioxide production; VE, ventilation; Vt, tidal volume; RR, respiration rate.

Figure 3.. Inter-individual oxygen uptake exercise response pattern by cohort.

Each gray line represents an individual study participant, blue lines represent mean data, and blue dots represent mean peak data. Abbreviations: VO₂, oxygen uptake.

Figure 4.. Cardiopulmonary response phenogrouping.

(A) Phenogroup heatmap. Columns represent individual study participants; rows represent phenotypes. Red indicates increased value and blue indicates decreased value of a phenotypic parameter relative to the mean; the intensity of the color represents the magnitude of increase or decrease. (B) VO₂ vs. time by phenogroup; (C) VE vs. VCO₂ by phenogroup; (D) O₂ pulse vs. VO₂ by phenogroup; (E) HR vs. VO₂ by phenogroup; (E). Abbreviations: VE, ventilation; VCO₂ carbon dioxide production; HR, heart rate; O₂, oxygen; VO₂, oxygen uptake.