Abstract PD6-09: The immune microenvironment in hormone receptor-positive breast cancer patients and relationship to treatment outcome following preoperative chemotherapy plus bevacizumab
Authors: Waks AG , Stover DG , Barry W , Dillon D , Gjini E , Rodig SJ , Brock J , Baltay M , Savoie J , Winer EP , Krop I , Tolaney SM 
Published: February 2018

Abstract
Background: Hormone receptor-positive (HR+) tumors have fewer tumor-infiltrating lymphocytes (TILs) and lower response rates to immune checkpoint inhibitors (ICI), either as single agents or in combination with chemotherapy, than triple negative cancers. However, some HR+ cancers do respond to ICI and biomarkers that accurately reflect the immune microenvironment may help guide the use of ICI therapy. Prior evidence suggests that macrophage-related immune pathways may be relevant to the pathophysiology of HR+ BC.
Methods: HR+/HER2- patients were 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), and PD-L1 expression (by immunohistochemistry), TILs, and Nanostring PanCancer Immune Profiling Panel were evaluated on both pre-tx and post-tx specimens. Pre-tx whole transcriptome sequencing was performed. Pathologic response at surgery was centrally 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 and immune cell-specific signatures from MSigDB.
Results: 55 patients who received trial therapy and had at least 1 evaluable specimen were included for analysis. Pre-tx TILs and tumor PD-L1 (tPD-L1) scores are shown in the table. 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 macrophages as well as CD8 T-cell signatures (r&gt;0.65 and p&lt;0.001). Higher pre-tx TILs, tPD-L1, or immune score were each significantly associated with more favorable RCB and MP in unadjusted analyses (all Spearman p&lt;0.01 for pathologic markers; ANOVA p&lt;0.04 for immune score). After adjustment for age and tumor grade, higher pre-tx TILs and tPD-L1 were associated with favorable RCB (p&lt;0.01 for both), and higher pre-tx tPD-L1 correlated with favorable MP (p=0.03). 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, large changes (&gt;5%) in TILs or tPD-L1 from pre-tx to post-tx were rare: 2 pts each had large changes in TIL or tPD-L1 score (N=38/N=31 pairs, respectively).
Conclusions: High levels of tumor-lymphocyte interaction were seen in only a minority of untreated HR+ breast tumors, and did not typically change with chemo plus bev. An immune score derived from bulk RNAseq correlated with histological observations in these specimens. Nonetheless, TILs, tPD-L1, and signature-derived immune score were significantly associated with pathologic response to preop treatment in HR+ disease. Early data suggest that the role of M1 macrophages in HR+ tumors warrants further investigation.
ScoreTILs (N=50 evaluable)Tumor PD-L1 (N=51)0%0 pts (0%)28 pts (55%)&gt;0-5% (low)19 (38%)18 (35%)&gt;5-10% (intermediate)22 (44%)3 (6%)&gt;10% (high)9 (18%)2 (4%)
Citation Format: Waks AG, Stover DG, Barry W, Dillon D, Gjini E, Rodig SJ, Brock J, Baltay M, Savoie J, Winer EP, Krop I, Tolaney SM. The immune microenvironment in hormone receptor-positive breast cancer patients and relationship to treatment outcome following preoperative chemotherapy plus bevacizumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-09.