Breast cancer responds heterogeneously to treatment. This study evaluated the efficacy of image registration-based lesion tracking for assessing lesion-wise response in metastatic breast cancer (MBC). [18F]FDG PET/CT images from 15 patients with MBC from the multi-center IMPACT-MBC study were analyzed. Manual segmentation identified 644 lesions in baseline scans and 804 lesions in 2-week post-treatment scans. A deformable image registration method, validated for whole-body PET/CT scans of patients with cancer, was applied. Lesion tracking was performed using spatial overlap resulting from within-subject image registration, yielding a precision of 0.93 ± 0.07, a sensitivity of 0.87 ± 0.17, and an F1 score of 0.89 ± 0.10. Performance was consistent across lesion sites and lesion count-based disease burden. Sensitivity decreased for lesions under 1 mL. Image registration direction did not affect results. Between-subject registration enabled quantitative visualization and analysis of metabolic response patterns in bone lesions across the cohort. Results demonstrate the potential for automated, accurate lesion-wise response assessment, which may improve treatment monitoring in MBC.