Impaired peripheral oxygen diffusion is the primary determinant of exercise intolerance in high-risk older breast...

Peak oxygen uptake (V̇o_2peak) is a strong predictor of survival in breast cancer survivors (BCSs), with values ≤1.09 L/min associated with increased mortality. The relative contributions of convective oxygen delivery (QO₂) and muscle oxygen diffusing capacity (D_MO₂) to reduced V̇o_2peak in BCS remain unclear. In 49 BCS, we measured V̇o_2peak from cycle ergometry with gas-exchange analysis, and derived QO₂ and D_MO₂ using Fick-based calculations and computational modeling. BCS were stratified by mortality risk: high-risk (V̇o_2peak ≤1.09 L/min; n = 11) and lower-risk (n = 38), and compared using t tests, Mann-Whitney U tests, and analysis of covariance (ANCOVA). Dominance analysis quantified the relative contributions of QO₂ and D_MO₂ to V̇o_2peak within each group. The high-risk group was older (72 ± 6 vs. 69 ± 5 years), had longer time since treatment (17 ± 5 vs. 13 ± 6 years), and higher cumulative doxorubicin-equivalent doses (291 ± 134 vs. 163 ± 120 mg/m²; all P ≤ 0.05). After ANCOVA, the high-risk group had lower V̇o_2peak (1.0 ± 0.1 vs. 1.4 ± 0.2 L/min), QO₂ (1.8 ± 0.3 vs. 2.5 ± 0.5 L/min), and D_MO₂ (28.2 ± 4.8 vs. 41.5 ± 9.0 mL/min/mmHg; all P ≤ 0.001). Dominance analysis revealed D_MO₂ as the strongest contributor to V̇o_2peak with 81.7% and 66.0% of explained variance in high-risk and lower-risk groups, whereas QO₂ accounted for 14.1% and 30.3%, respectively. In older, long-term BCS with reduced V̇o_2peak (≤1.09 L/min), impairments in both QO₂ and D_MO₂ contribute to reduced exercise tolerance. However, D_MO₂ emerged as the strongest modeled contributor in the high-risk group. Interventions prioritizing skeletal muscle-vascular function, alongside complementary targeting of QO₂, may have a greater impact on V̇o_2peak improvements and survival in this high-risk population.NEW & NOTEWORTHY Exercise intolerance in older breast cancer survivors, particularly those with severely reduced peak oxygen uptake (i.e., ≤1.09 L/min), is predominantly associated with impaired peripheral muscle oxygen transport and utilization, and to a lesser extent by reductions in convective oxygen delivery. These findings support a comprehensive approach where therapeutic strategies primarily targeting skeletal muscle-vascular function, coupled with complementary attention to convective oxygen transport, may result in the greatest improvement in peak oxygen uptake, and potentially, long-term breast cancer survivorship.