Impaired Peripheral Oxygen Diffusion is the Primary Determinant of Exercise Intolerance in High-risk Older Breast Cancer Survivors

Background: Peak oxygen uptake (V̇O 2 peak) is a strong predictor of survival in breast cancer survivors (BCS), with values ≤1.09 L/min associated with increased mortality. The relative contributions of convective oxygen delivery (QO 2 ) and muscle oxygen diffusing capacity (D M O 2 ) to reduced V̇O 2 peak in BCS remain unclear. Materials and Methods: In 49 BCS, we measured V̇O 2 peak from cycle ergometry with gas-exchange analysis, and derived QO 2 and D M O 2 using Fick-based calculations and computational modeling. BCS were stratified by mortality risk: High-Risk (V̇O 2 peak ≤1.09 L/min; n=11) and Lower-Risk (n=38), and compared using t-tests, Mann-Whitney U tests and ANCOVA. Dominance analysis quantified the relative contributions of QO 2 and D M O 2 to V̇O 2 peak within each group. Results: 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 2 peak (1.0±0.1 vs. 1.4±0.2 L/min), QO 2 (1.8±0.3 vs. 2.5±0.5 L/min), and D M O 2 (28.2±4.8 vs. 41.5±9.0 mL/min/mmHg) (all p≤0.001). Dominance analysis revealed D M O 2 as the strongest contributor to V̇O 2 peak with 81.7% and 66.0% of explained variance in High-Risk and Lower-Risk groups while QO 2 accounted for 14.1% and 30.3%, respectively. Conclusions: In older, long-term BCS with reduced V̇O 2 peak (≤1.09 L/min), impairments in both QO 2 and D M O 2 contribute to reduced exercise tolerance. However, D m O 2 emerged as the strongest modeled contributor in the high-risk group. Interventions prioritizing skeletal muscle–vascular function, alongside complementary targeting of QO 2 , may have greater impact on V̇O 2 peak improvements and survival in this high-risk population.