Background/Objectives: Breast cancer-related lymphedema (BCRL) is more prevalent and severe in women with overweight or obesity. This study evaluated the effect of a comprehensive lifestyle intervention—comprising supervised exercise, a hypocaloric Mediterranean diet, and optional meal replacement—on lymphedema outcomes in this population. Methods: In this pilot randomized controlled trial, 112 women with BCRL and BMI 25–40 kg/m² were assigned to an intervention group—receiving supervised resistance and aerobic training, dietary counseling, and optional high-protein meal replacement—or to a control group with standard advice. The primary outcome was change in affected limb volume at 3 and 6 months. Secondary outcomes included morphofunctional parameters, muscle strength, dietary intake, and serum levels of cytokines (IL-1β, IL-6, IL-10, and TNF-α). Analyses also explored outcomes according to whether participants achieved ≥ 5% weight loss. Results: Ninety-four participants completed the trial (intervention n = 43, control n = 51). At 6 months, women who achieved ≥5% weight loss had greater reductions in affected limb volume (−664.9 ± 362.1 mL vs. −395.6 ± 596.9 mL). The intervention group showed significantly greater improvements in BMI (−1.14 ± 1.22 kg/m²), waist circumference (−3.59 ± 4.6 cm), triceps skinfold (−4.61 ± 3.02 mm), fat mass (−2.38 ± 2.75 kg), extracellular water (−0.58 ± 0.85 L), and quadriceps strength (+7.1 ± 9.7 kg). No significant changes were observed in circulating cytokines. Conclusions: In this pilot randomized controlled trial, a structured dietary and exercise intervention improved morphofunctional outcomes in overweight women with BCRL. Weight loss of ≥5% emerged as a potentially relevant therapeutic target that may inform the design of future studies aimed at optimizing lymphedema management.

Breast cancer-related lymphedema (BCRL) is closely associated with obesity, yet the gut microbiota remains poorly characterized in this population. We longitudinally evaluated gut microbiota profiles in 48 women with overweight or obesity and BCRL who were randomized to either a multimodal lifestyle intervention combining an energy-restricted Mediterranean-style diet and exercise (n = 28) or control care (n = 20). Fecal samples collected at baseline, 3 months, and 6 months (144 samples) underwent 16S rRNA gene sequencing. The intervention resulted in greater reductions in body weight, body mass index, and fat mass over time (group × time p < 0.001, p = 0.001, and p = 0.002, respectively). No significant group × time interaction was observed for alpha diversity or overall microbial community composition based on Bray–Curtis dissimilarity (PERMANOVA R² = 0.006, F = 0.459, p = 0.324). Exploratory DESeq2 differential abundance analyses identified FDR-significant taxon-specific differences, including higher abundances of Barnesiellaceae and Desulfovibrionaceae in the intervention group and of Prevotella_7 and Lachnospiraceae_UCG_010 in controls (FDR-adjusted p < 0.05). These DESeq2 findings were not confirmed in mixed-effects sensitivity analyses after FDR correction. Prevotella_7 was more abundant in controls at baseline and at 6 months. Participant-blocked group × time models, which were given inferential priority, yielded FDR-significant baseline-to-3-month interaction tests for Izemoplasmatales and Frisingicoccus, although the corresponding shrunken effect estimates were close to zero. Secondary, hypothesis-generating analyses based on supplementation status, supplement adherence, and clinically relevant weight-loss response identified additional taxon-specific patterns associated with supplementation and adherence, including a tentative species-level association involving Bifidobacterium bifidum among supplemented participants, whereas no significant microbiota differences were observed by weight-loss response. Overall, these findings provide no evidence of broad restructuring of the gut microbial community but identify exploratory taxon-specific signals that warrant confirmation in larger longitudinal studies using strain-resolved and functional approaches.