Abstract PD2-10: Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer
Authors: Hurvitz S , Martin M , Press M , Wijayawardana S , Brahmachary M , Ebert PJ , Young S , Jansen V , Slamon D 
Published: May 2019

Abstract
Background: Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- metastatic breast cancer (MBC) patients (pts) in combination with endocrine therapy or as monotherapy. Recent studies have demonstrated the potential for CDK4 & 6 inhibitors, including abemaciclib, to promote anti-tumor immunity. Schaer et al., (Cell Reports 2018) showed that abemaciclib monotherapy results in upregulation of antigen presentation on tumor cells and increases T-cell activation. These activities synergized with anti-PD-L1 therapy to further enhance immune activation leading to complete tumor rejection in murine tumor models (Schaer et al., Cell Reports 2018). In this exploratory analysis, we evaluated the early and late immune-modulating effects of abemaciclib in the neoadjuvant study neoMONARCH (NCT02441946).
Methods: NeoMONARCH is a Phase II trial in women with stage I-IIIB HR+, HER2- BC evaluating neoadjuvant treatment with 2 weeks of abemaciclib, alone or in combination with anastrozole (abemaciclib+ANZ), or ANZ alone. All patients received 14 weeks of abemaciclib +ANZ after the first 2 weeks of treatment. Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early - after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor biopsies at each time point and subjected to whole transcriptome RNA sequencing. The curated data were subjected to statistical analysis using ANOVA tests followed by pathway analysis using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA).
Results: Consistent with the known activity of abemaciclib to inhibit the cell cycle, we observed at the early and late time points a significant treatment induced downregulation of genes related to mitotic spindle organization, replication stress response, G2M checkpoint, and E2F targets. Abemaciclib treatment for 2 weeks, alone or in combination with ANZ, followed by 14 weeks of combination therapy was associated with upregulation of gene expression signatures related to T-cell immune response and antigen presentation. Importantly, this phenomenon was notobserved with 2 weeks of ANZ treatment alone followed by 14 weeks of combination therapy.
Conclusion: These data lend support that continuous inhibition of CDK4 & 6 signaling by abemaciclib treatment leads to prolonged cell cycle arrest resulting in tumor cell apoptosis & senescence, which then leads to an enhanced immune activation.
Citation Format: Hurvitz S, Martin M, Press M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer [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 PD2-10.