Abstract 4564: The immune microenvironment in hormone receptor-positive breast cancer and treatment outcome following preoperative chemotherapy plus bevacizumab
Authors: Waks Adrienne G. , Stover Daniel G. , Barry William T. , Dillon Deborah A. , Gjini Evisa , Rodig Scott J. , Brock Jane E. , Baltay Michele , Savoie Jennifer , Winer Eric P. , Krop Ian E. , Tolaney Sara M. 
Published: August 2018

Abstract
Background: Hormone receptor-positive (HR+) breast cancers (BC) have fewer tumor-infiltrating lymphocytes (TILs) and lower response rates to immune checkpoint inhibitors in early phase studies than other breast cancer subtypes. Immune biomarkers that accurately reflect the immune microenvironment have important clinical implications in HR+ BC patients. Prior evidence suggests that macrophage-related immune pathways may be relevant to the pathophysiology of HR+ BC.
Methods: Patients identified from a prospective trial of preoperative bevacizumab (preop bev) followed by bev with adriamycin/cyclophosphamide/paclitaxel dose-dense chemotherapy (chemo). Tumor samples were collected at diagnosis and surgery (pre-tx and post-tx). TILs and immunohistochemical staining for PD-L1, CD8, and CD68 were scored. Whole transcriptome sequencing (RNAseq) and Nanostring PanCancer Immune Profiling Panel were performed. Pathologic response at surgery was assessed by Miller-Payne (MP) and residual cancer burden (RCB) scores. An immune score was calculated for each pre-tx specimen by integrating 10 published immune signatures. Immune cell subsets were inferred from bulk transcriptional data using CIBERSORT.
Results: 55 patients had at least 1 evaluable specimen and were included for analysis. 18% of pre-tx tumors had ‘high' (≥10%) TILs and ‘high' TILs were associated with significantly higher immune signature score (p=0.004). Immune score correlated highly with proportion of CIBERSORT anti-tumor M1 macrophage and CD8 T-cell signatures (r&gt;0.65 and p&lt;0.001) and was significantly associated with RCB. Higher pre-tx TILs, tPD-L1, sPD-L1, CD8, and CD68 were associated with favorable RCB significantly associated with more favorable RCB after adjustment for tumor size and grade. Pathologic complete response occurred in 4 pts; all 4 had high pre-tx TILs, pre-tx tPD-L1, or both. Among patients with residual disease, there were significantly fewer TILs and CD8 cells after chemotherapy (Wilcoxon signed rank p=0.037 and p=0.002, respectively), however tPD-L1 and CD68 were not significantly different. Nanostring analyses demonstrated that chemokines and complement pathway components were among most significantly enriched post-tx relative to pre-tx.
Conclusions: Most HR+/HER2- breast tumors demonstrate low levels of anti-tumor immune activity; however, those with higher levels have a more favorable response to chemo plus bev. Assessment of immune activity based on RNA signatures is consistent with histology and immune-related protein expression. T-cell- and checkpoint-related biomarkers tend to decrease following preoperative chemo plus bev in HR+/HER2- breast cancer. Following treatment with chemotherapy/bevacizumab, we observe increased expression of chemokines and complement pathway genes.
Citation Format: Adrienne G. Waks, Daniel G. Stover, William T. Barry, Deborah A. Dillon, Evisa Gjini, Scott J. Rodig, Jane E. Brock, Michele Baltay, Jennifer Savoie, Eric P. Winer, Ian E. Krop, Sara M. Tolaney. The immune microenvironment in hormone receptor-positive breast cancer and treatment outcome following preoperative chemotherapy plus bevacizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4564.