Abstract P4-09-18: Characterization of circulating myeloid derived suppressor cells and cytokines in patients undergoing neo-adjuvant chemotherapy for breast cancer
Authors: Wesolowski R , Duggan M , Stiff A , Trikha P , Schoenfield L , Abdel-Rasoul M , Layman R , Ramaswamy B , Macrae E , Lustberg MB , Mrozek E , Carson WE 
Published: May 2016

Abstract
Myeloid derived suppressor cells (MDSC) are immature immune cells that expand in patients (pts) with cancer and suppress anti-tumor immunity. MDSC are also known to support angiogenesis. Higher circulating MDSC levels are seen in patients with greater tumor burden. Therefore, circulating MDSC levels could be affected by chemotherapy and could correlate with response. In this prospective pilot trial, peripheral blood (PB) levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured in pts with operable breast cancer (BC) treated with neo-adjuvant chemotherapy (NAC) to study their association with pathologic complete response. It was hypothesized that MDSC % would show an association with complete pathologic response (pCR). The association of 10 different cytokine levels (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNF-α) with pCR was also explored. Linear mixed models tested the associations between MDSC % or cytokines across time points with pCR. Levels of MDSC were measured by flow cytometry as a % of PB mononuclear cells prior to cycle (C) 1 and 2 of doxorubicin and cyclophosphamide (AC) and 1st and last administration of paclitaxel (T) or T and anti-HER2 therapy (in HER2+ pts). For other regimens, MDSC were measured prior to 1st, 2nd and last cycle. MDSC were defined as HLA-DR-, CD11b+, CD33+ cells with G-MDSC and M-MDSC cells expressing CD15 and CD14, respectively. Plasma cytokine levels were measured using a multiplex assay (Bio-Rad). Of 24 enrolled pts, 1, 20 and 3 had clinical stage I, II, IIIA, respectively. Median age was 48 (range 32-70). 11, 6 and 7 pts were triple negative (TN), HER2+ and hormone receptor (HR)+, respectively. PCR rate was 45.8% (46%, 50%, 43%, 20% for TN, HER2+, HR+ and &gt;10% HR+ pts). Rate of residual cancer burden (RCB) class 0-1 was 58.3% (63.6%, 50%, 57.1%, 40% in TN, HER2+, HR+ and &gt;10% HR+ pts). Mean M-MDSC % were &lt;1 at all time points. Mean G-MDSC % and 95% confidence intervals (CI) were 0.88 (0.23-1.54), 5.07 (2.45-7.69), 9.32(4.02-14.61) and 1.97 (0.53-3.41) at times 1-4. The increase in MDSC by C1 of T was significant (p&lt;0.0001) in all BC types. Baseline G-MDSC % did not differ in pts with or without pCR. G-MDSC levels at the last time point were also not statistically different but were numerically slightly lower in pts with pCR (1.15; 95%CI 0.14-2.16) versus pts with no pCR (2.71; 95%CI 0-5.47). Levels of all 10 cytokines were measurable in pts throughout NAC. The mean levels of IL-1β, IL-2, IL-4, IL-13 and IFN-γ peaked by C1 of T, while levels of IL-5, IL-6, IL-10, IL-12 and TNF-α were the highest at draw 1 and decreased during NAC. This pilot study confirmed feasibility of measuring circulating MDSC and cytokines in breast cancer pts receiving neo-adjuvant chemotherapy. The results showed that G-MDSC % increase during AC and then decrease during T and that a mixture of Th1 and Th2 cytokines peak during treatment. Levels of MDSC and cytokines did not significantly differ between pts with or without a pCR. However, a larger study with greater power to detect smaller differences and evaluate association between MDSC levels and pCR in different BC subtypes is needed.
Citation Format: Wesolowski R, Duggan M, Stiff A, Trikha P, Schoenfield L, Abdel-Rasoul M, Layman R, Ramaswamy B, Macrae E, Lustberg MB, Mrozek E, Carson WE. Characterization of circulating myeloid derived suppressor cells and cytokines in patients undergoing neo-adjuvant chemotherapy for breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-18.