Abstract

Simple Summary Current evidence supports a negative impact of obesity-associated metabolic dysfunction in several cancers. However, the evidence is still controversial regarding high-grade serous ovarian cancer (HGSOC). In this study, we demonstrated that body composition, particularly the presence of high visceral adiposity (with or without sarcopenia) estimated by aCT scan, is associated with worse survival in HGSOC. As a molecular proxy to CT-scan-based assessment of nutritional status and to identify putative biomarkers of metabolic disorders, we evaluated the expression levels of a set of 425 obesity- and lipid-metabolism-disorder-related genes across 273 tumor samples. We identified two obesity- and lipid-metabolism-related clusters with marked differences in survival and that were associated with molecular features predictive of immune checkpoint blocker response. Finally, we assessed the impact of nutritional/pharmacologic interventions affecting body composition/lipid metabolism on patient survival. We observed that the reduction of visceral adiposity, the increase of muscle mass, and the use of metformin/statins improve survival. Although obesity-associated metabolic disorders have a negative impact on various cancers, such evidence remains controversial for ovarian cancer. Here, we aimed to evaluate the impact of body composition (BC) and metabolism disorders on outcomes in high-grade serous ovarian cancer (HGSOC). Methods: We analyzed clinical/genomic data from two cohorts (PUC n = 123/TCGA-OV n = 415). BC was estimated using the measurement of adiposity/muscle mass by a CT scan. A list of 425 genes linked to obesity/lipid metabolism was used to cluster patients using non-negative matrix factorization. Differential expression, gene set enrichment analyses, and Ecotyper were performed. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival. High adiposity and sarcopenia were associated with worse outcomes. We also found that recovery of a normal BC and drug interventions to correct metabolism disorders had a positive impact on outcomes. Additionally, we showed that immune-cell-depleted microenvironments predominate in HGSOC, which was more evident among the BC types and the obesity/lipid metabolism cluster with worse prognosis. Conclusions: We have demonstrated the relevance of BC and metabolism disorders as determinants of outcomes in HGSOC. We have shone a spotlight on the relevance of incorporating corrective measures addressing these disorders to obtain better results.