Circulating Polyamines and Metabolic Changes Following a Mediterranean Diet with or Without Naltrexone/Bupropion in Breast Cancer Survivors: An Exploratory Secondary Analysis

Background/Objectives: The Mediterranean diet is widely recognized for its cardiovascular and metabolic benefits, including weight reduction; however, the metabolic mechanisms underlying these effects remain incompletely understood. This study investigated whether changes in circulating polyamines are associated with metabolic improvements following a Mediterranean diet intervention, particularly in breast cancer survivors. Methods: This exploratory secondary analysis used stored paired serum samples from a previously reported 8-week controlled intervention conducted in three groups: Group A (breast cancer survivors following a Mediterranean diet alone, n = 21), Group B (breast cancer survivors following a Mediterranean diet combined with naltrexone/bupropion, n = 23), and Group C (non-cancer participants receiving the combined intervention, n = 28). Paired polyamine data were available for 16, 9, and 16 participants, respectively. Breast cancer survivors were randomized to Groups A and B, whereas Group C was enrolled as a non-randomized active comparison group. Serum metabolic profiles were analyzed using liquid chromatography–mass spectrometry-based untargeted metabolomics, and nine polyamines were quantified using targeted analysis. An exploratory indirect-effect analysis examined associations between changes in serum polyamines and clinical outcomes, including body composition and lipid parameters. Results: Body weight, fat mass, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) decreased significantly within all three groups after the 8-week intervention (median changes: −1.9 to −2.8 kg, −1.9 to −2.8 kg, and −0.3 to −0.7, respectively). LDL cholesterol decreased significantly only within the two groups receiving naltrexone/bupropion (median changes: −20.6 and −10.1 mg/dL). However, between-group differences in these changes were not statistically significant. N-acetylspermine increased nominally in all groups (p < 0.01), whereas spermine increased only in the Mediterranean diet alone group (p = 0.015). Conclusions: Mediterranean diet-related metabolic improvements were accompanied by changes in circulating polyamines. Spermine and N-acetylspermine may represent candidate metabolic response markers associated with nutritional and pharmacological interventions in breast cancer survivorship.