Abstract PS3-09-28: Clinical investigations into the metabolic pathways of early stage hormone receptor positive/HER2 negative breast cancer

Abstract Background: One of the recognized hallmarks of cancer cells is deregulated cellular metabolism, characterized by enhanced metabolic autonomy compared with non-transformed cells. Tumor cells display an overall increase in glucose metabolism, enhanced aerobic glycolysis and decreased oxidative phosphorylation, accompanied by a requirement for a high rate of protein, nucleotide, and fatty acid synthesis to provide the raw materials for cell division. Approximately 70-80% of all breast cancers (BC) are hormone receptor positive (HR+), and most HR+ breast cancers are HER2-negative (Her2-). The metabolic dependencies of HR+/Her2- BC and in particular, high-risk HR+ BC, are poorly understood. In depth analyses of in vivo metabolic processes by HR+ BC using carbon-13 labeled glucose (13C-glucose) infusions have never been done in humans. 13C-glucose is a stable isotope tracer that has been widely used in vitro, in vivo, and in patients in a variety of disease settings to study glucose, amino acid, and lipid metabolism. We hypothesize that HR+ breast cancers in vivo have altered use of metabolic pathways that can be determined by in vivo 13C isotope glucose labelling. The primary objective is to describe and discover new insights into the glucose, TCA cycle, amino acid, and lipid metabolic dependencies of HR+/Her2- BC, via liquid chromatography-mass spectrometry (LC-MS) and matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry analysis of in vivo U-13C-glucose-labeled biopsy of tumor and benign adjacent tissue. Methods: This is an ongoing pilot study that will enroll 16 patients with early stage I, II or III HR+/Her2- breast cancer who do not require neoadjuvant therapy and have planned curative primary resection. They will receive intraoperative 13C-glucose intravenous infusions followed by core biopsies of tumor and normal breast tissue and blood will be collected at time of resection. Tumor samples will be analyzed for metabolite labeling by LC-MS and spatial distribution of metabolite levels and labeling patterns by MALDI-MS. Genomic and proteomic analyses will be performed and related to observed metabolic fluxes. Demographic and clinicopathological information will be collected. ClinicalTrials.gov ID NCT05736367. Results: Preliminary results from LC-MS of tumors from the first four patients show avid glucose metabolism in HR+/Her2- BC. These tumors locally produce lactate from glucose, with higher 13C-lactate labeling observed in the tumor than in circulation. The contribution of glucose-derived lactate to the TCA cycle is approximately 30%, which is similar to what has previously been observed in hormone receptor-negative (HR-) BC. Interestingly, there was little to no labeling of the amino acid serine, demonstrating minimal activity of the de novo serine synthesis pathway in these tumors. This contrasts with previous results demonstrating extensive serine synthesis in HR-/Her2- BC and a common genomic amplification of the rate-limiting enzyme PHGDH in HR-/Her2- BC. This trial is ongoing, and further results will be presented at a future date. Conclusion: This study has the potential to discover new insights into the glucose, TCA cycle, amino acid, and lipid metabolic dependencies of HR+/Her2- breast cancer and will allow these critical pathways to be resolved spatially within the tumor, allowing analysis such as the effects of distance from blood vessels and of specific cell subpopulations. Grant Support: Ludwig Institute for Cancer Research, Ludwig Princeton Branch. Citation Format: C. Omene, S. Kumar, M. George, L. Potdevin, J. Smith, A. Shah, K. Matsuda, D. Toppmeyer, M. Gupta, K. Olszewski, E. White, J. Rabinowitz. Clinical investigations into the metabolic pathways of early stage hormone receptor positive/HER2 negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-09-28.