Abstract 4P
Background
Metabolic reprogramming exists within tumor cells and tumor microenvironment (TME) in breast cancer (BC), but little is known about how the immunometabolic interplay of BC evolves during treatment. Using temporal proteogenomic profiling, we studied in-depth BC immunometabolism and its potential therapeutic vulnerabilities.
Methods
BC tissue (pre/on/post neoadjuvant chemotherapy; NAC) was longitudinally collected from the PROMIX trial (NCT00957125) of NAC (n=150 patients) in HER2-negative BC and analyzed by: bulk RNA microarray (n=122), single nucleus RNA-seq (snRNA-seq) (n=8), whole-exome sequencing (WES) (n=20), and mass spectrometry-based proteomics (n=29), including bulk/single-cell immunometabolic phenotype/cluster deconvolution, protein correlation network and clonal evolution analyses.
Results
Baseline and dynamic change of immunometabolic phenotype based on bulk gene expression profiling suggested tumors with hot TME or downregulation of tricarboxylic acid (TCA) cycle, amino acid or nucleotide metabolism were associated with higher pathologic complete response in multivariable analysis. BC proteomes showed TCA cycle-related protein module was starkly elevated within cold tumors, and vice versa. Potential drug targets (FASN, LDHB, LDHA, IDH2, MDH2) in metabolic pathways regulating the TME were revealed through unbiased proteogenomic differential abundance analyses (cold vs hot). Fewer subclones were identified in hot (28.3%) tumors than cold (43.1%) tumors (P<.001), which were more likely to have accelerated growth relative to their parent if included known metabolic drivers (SDHA, CACNA1D, ACSL3, ATIC, MED12). Metabolic flexibility of breast epithelial cells was dissected by five snRNA-based metabolic clusters (C): C0 (normal and tumor cells, lowest global metabolic activity); C1 (OXPHOS and glycolysis, cold tumor exclusively); C2 (OXPHOS but mutually with glycolysis); C3 (glutathione); C4 (Notch signaling).
Conclusions
This longitudinal proteogenomic study shows that interaction of tumor intrinsic metabolic states and TME is associated with treatment outcome, shedding light on the importance to target tumor metabolism for immunoregulation.
Clinical trial identification
NCT00957125; September 8, 2016.
Legal entity responsible for the study
The authors.
Funding
Roche Sweden.
Disclosure
T. Foukakis: Financial Interests, Institutional, Other, contracted research: Pfizer, Roche; Financial Interests, Personal, Advisory Board: Affibody, Novartis, Pfizer, Roche, Exact Sciences, Veracyte; Financial Interests, Personal, Royalties: UpToDate; Non-Financial Interests, Personal, Speaker’s Bureau: Pfizer. All other authors have declared no conflicts of interest.