Impact of Body Composition Changes on Treatment-Related Toxicities and Clinical Outcomes in HER2-Positive Metastatic Breast Cancer Patients Receiving Trastuzumab Deruxtecan

Background/Objectives: Breast cancer remains a significant global health concern, with HER2-positive metastatic breast cancer continuing to present persistent challenges despite advancements in targeted therapies, including trastuzumab deruxtecan (T-DXd). This study aimed to verify the impact of body composition changes on treatment-related toxicities, dose modifications, and clinical outcomes in patients receiving T-DXd. Methods: A retrospective analysis on 35 patients with HER2-positive metastatic breast cancer was conducted, analyzing body composition parameters such as subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle area (SMA), and skeletal muscle index (SMI)—assessed using CT scans at baseline (T0) and after a median follow-up of 4 months (T1)—and calculating ΔT0–T1% of each parameter. Results: Significant reductions over time were observed in SAT (mean ΔSAT% = −5.7%, p = 0.023) and SMA (mean ΔSMA% = −4.9%, p = 0.001). Treatment-related adverse events (AEs) were common, with 31% of patients experiencing severe (Grade 3–4) toxicities. Patients with higher ΔSAT% (above the median value) experienced Grade 3–4 toxicities more frequently compared to those with lower ΔSAT% (below the median) (p < 0.05). Among patients without toxicities, a significant decrease in SAT was observed between T0 and T1 (p = 0.003), while no significant change was detected in patients with Grade 3–4 toxicities (p = 0.929). Greater reductions in SMA were associated with increased rates of treatment discontinuation (75% vs. 29%, p = 0.009). Kaplan–Meier analysis confirmed that greater reductions in SMA significantly increased the risk of mortality (HR 5.1, 95% CI: 1.05–24.79; p = 0.025) and showed a trend toward higher risk of disease progression (HR 2.58, 95% CI: 0.89–7.49; p = 0.063). Conclusions: Changes in body composition, particularly reductions in SMA, were associated with increased treatment discontinuation and mortality in HER2-positive metastatic breast cancer receiving T-DXd. Increase in SAT was associated with higher rates of severe toxicities, highlighting its potential role in predicting treatment-related complications, and the clinical relevance of nutritional changes on outcomes in this setting.