296P Identification of metabolism-related therapeutic targets to improve response to neoadjuvant chemotherapy in early breast cancers

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is known as a prognostic factor correlated with improved EFS and OS. Better prediction of pCR would allow better patient and treatment selection. We aim to reveal specific transcriptomic and metabolic signatures correlated with distinct responses to NAC based on patient diagnostic biopsies. We also compared metabolic profiles of in vitro models. We performed bulk-RNA sequencing on 95 samples from diagnostic biopsies from all subtypes of early BC treated with NAC (NCT03314870 study). Early triple-negative BC cell lines (HCC38, HCC1143, HCC1937) and patient-derived tumor organoids were cultured for drug testing, RT-qPCR and metabolomics studies using Seahorse bioenergetic analyzer. Transcriptomic analyses showed a down-regulation of genes related to tumor cell metabolism such as genes involved in the glycolysis (e.g. STC2, FDR = 0.05) in non-responding patients (n=39). Gene set enrichment analysis (hallmark and KEGG pathway databases) showed a down-regulation of the glycolysis and the oxidative phosphorylation pathways in non-responding patients (adjusted p-value <0.05). In 2D cell cultures, the HCC1937 cell line showed resistance to paclitaxel and a higher glycolysis profile than the HCC38 and HCC1143 cells. Exposure to epirubicin or paclitaxel decreased the glycolysis in HCC38 and HCC1937 cell lines, while a decrease in the oxidative phosphorylation was observed in all 3 cell lines. A triple-negative organoid model (BCO17), initiated from a treatment naive tumor, showed resistance to epirubicin and paclitaxel. In BCO17, exposure to epirubicin or paclitaxel did not change the glycolysis or oxidative phosphorylation profile. Targeting glycolysis with 2-deoxy-2-glucose (2DG) in monotherapy showed 50% of cell mortality in a 2D and organoid models, while combination of 2DG with epirubicin and paclitaxel did not increase the cell mortality. Glycolysis and oxidative phosphorylation are involved in non-response to NAC in early breast cancer. 2D and organoid models with distinct chemotherapy sensitivity showed different metabolic profiles that may be explored in drug development.