Abstract P2-03-01: Akt inhibition associated with change in immunophenotype of tumor microenvironment (TME) in breast cancer (BC)

Abstract

Background: The PI3K/Akt/mTOR pathway is a known oncogenic pathway in BC. In addition, this pathway has demonstrated capacity to modulate host immune activity and may indirectly affect tumorigenesis. Clinicopathologic studies have demonstrated that lymphocyte density within the TME is predictive of chemosensitivity and improved prognosis in BC, while myeloid infiltration may play a deleterious role. To define the impact of Akt inhibition on the TME, we analyzed tumor tissue from patients (pts) with early-stage BC treated with single agent MK-2206, an Akt inhibitor, enrolled on a presurgical trial (NCT01319539). Methods: Quantitative immunofluorescence (qmIF) was performed for CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin on 4uM sections from biopsy and surgical specimens of MK-2206 (n=5) and control (n=5) pts. Images were analyzed using Vectra/inForm software (PerkinElmer), allowing for multiparameter phenotyping. Transcriptomic analysis was performed on surgical specimens to assess if differences exist in mRNA expression of tumor-associated and immune genes between pts treated with MK-2206 (n=5) and untreated matched controls (n=5) (nanoString). Statistical analysis was performed using t-Test, NetBID, and multiple comparison analysis by Benjamini-Hochberg. Gene set enrichment analysis (GSEA) was performed within R with gene sets from Molecular Signatures Database (Hallmark, Reactome, GO). Results: On qmIF analysis, MK-2206 treated pts exhibited a significant increase in median cytotoxic T-cell (CD3+CD8+, CTL) density between pretreatment biopsy and surgical excision specimens, as compared to the control pts (87% vs.0.2%, p in vivo activity of MK-2206 with lower expression levels of cell cycle, proliferation and anti-apoptotic genes (e.g. CTNNB1, CCND2, BAX) and greater expression of pro-apoptotic genes (e.g. BAD) associated with MK-2206 treatment (raw p-value Conclusion : mRNA and qmIF analysis suggest that Akt inhibition, may increase interferon signaling, CTL density, and decrease myeloid infiltration. Thus, Akt inhibition may promote a favorable TME. At present, there are both FDA approved and investigational agents that target the PI3K/mTOR pathway. Further investigation is warranted to understand the impact of Akt inhibition on the TME and potential therapeutic implications. Citation Format: Marks DK, Gartrell RD, Pan Q, El Asmar M, Hart TD, Esancy CL, Lu Y, Yu J, Hibshoosh H, Connolly E, Kalinsky K, Saenger YM. Akt inhibition associated with change in immunophenotype of tumor microenvironment (TME) in breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-01.