Abstract P2-04-03: Differential effect of chemotherapy on immune gene expression signatures based on molecular subtype of breast cancer
Authors: Hicks MJ , Estrada MV , Sanders ME , Salgado R , Cook RS , Arteaga CL , Balko JM 
Published: March 2017

Background: Neoadjuvant chemotherapy (NAC) is frequently used in triple negative breast cancers (TNBC), and patients who achieve pathological complete response (pCR) following NAC have improved outcomes over those with residual disease (non-pCR). Unfortunately only 30% of TNBC patients achieve pCR, with no good treatment options for other 70% with non-pCR. Tumor infiltrating lymphocytes (TILs) in TNBC are predictive of pCR to NAC, and TILs found in the residual disease further prognosticate patients with residual disease into an improved prognosis subset. These data suggest there is an immune component to TNBC that might be affected by chemotherapy. Given the advent of immunotherapy trials in breast cancer, specifically in combination with NAC, there is an unmet need to gain a better understanding of the immune microenvironment in TNBC.

Objective: We investigated the role of NAC on the immune microenvironment by examining breast cancer samples before (diagnostic biopsy) and after (residual disease) NAC, as these data are pertinent to the design and analysis of ongoing clinical trials in breast cancer combining immunotherapy with concurrent chemotherapy.

Methods: RNA was extracted from 51 paired (pre- and post-NAC) breast cancer specimens with extensive residual disease, and analyzed by nCounter analysis for expression of &gt;750 immune-related genes. Functional immune signature scores were generated, compared between matched pre- and post-NAC, and stratified by breast cancer molecular subtype (luminal (n=4), Her2-enriched (n=5), basal-like (n=17)). DNA extracted from a subset of these samples was utilized for T cell receptor sequencing to explore changes in T cell clonality following NAC in each subtype.

Results: Across all subtypes of breast cancer, immune scores decreased after NAC consistent with a broad decrease in TILs observed histologically. When samples were stratified by molecular subtype using the PAM50 analysis, luminal A/B and basal-like patients demonstrated a decrease in immune signatures after NAC, while Her2-enriched patients exhibited a global increase in immune scores. Importantly, basal-like patients had the greatest immune signature changes, including decreases in T cell functions and CD8+ T cell, T helper and T regulatory signatures (p&gt;0.05). Conversely, these signatures were increased after NAC in the Her2-enriched molecular subtype. Analyses of T-cell clonality are ongoing, but should yield insight into the effect of NAC on the landscape of effector T-cells in the micro-environment.

Conclusions: Our work suggests that NAC decreases immune infiltrate signatures,&lt;/del&gt; specifically related to effector T cells in patients who do not achieve pCR. However, we observed an increase after NAC in the same signatures in Her2-enriched patients, suggesting that these patients' tumors may respond differently to chemotherapy on the immune-molecular level. As clinical trials progress in TNBC with the combination of chemotherapy and immune therapy, more work is needed to understand who might benefit from these therapy regimens.

Citation Format: Hicks MJ, Estrada MV, Sanders ME, Salgado R, Cook RS, Arteaga CL, Balko JM. Differential effect of chemotherapy on immune gene expression signatures based on molecular subtype of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-03.