Abstract PD7-03: Circulating Immune Correlates of Pathological Response to Neoadjuvant Pembrolizumab plus Chemotherapy in High-Risk, Early-Stage Triple-Negative Breast Cancer

Abstract Background: The incorporation of immune checkpoint inhibitors, specifically pembrolizumab (anti-PD-1), into neoadjuvant therapy, has improved outcomes for patients with stage II-III triple-negative breast cancer (TNBC). However, due to the risk of of immune-related adverse events, there remains a critical need to identify patients most likely to benefit, in order to optimize the risk-benefit ratio in this curative setting. Here, we report circulating immune biomarkers associated with pathological response in patients treated with neoadjuvant pembrolizumab plus chemotherapy (KEYNOTE-522 regimen). Methods: Patients with stage II-III TNBC planned to receive the KEYNOTE-522 regimen were enrolled on the prospective ARTEMIS trial (NCT02276443). Pre-operative peripheral blood mononuclear cells were collected at three timepoints: baseline (TPBL), after completion of paclitaxel, carboplatin, and pembrolizumab (PC/PB) but prior to initiating doxorubicin, cyclophosphamide, and pembrolizumab (AC/PB) (TPMID), and after completing AC/PB (TPPOST). Immune profiling of 148 samples (TPBL=64, TPMID=52, TPPOST=32) from 79 unique patients was performed using multi-parameter flow cytometry to quantify immune cell populations and BostonGene (BG) Immunotype Signature Scores (G1 Naive, G2 Primed, G3 Progressive, G4 Chronic, G5 Suppressive). Pathological response was assessed using the residual cancer burden (RCB) index. Response (R) and non-response (NR) were defined as pCR/RCB-I and RCB-II/RCB-III, respectively. Results: Seventy-nine patients had at least one blood sample drawn for immune profiling and were included in this analysis. The overall pCR/RCB-I rate was 75% (pCR=49; RCB-I=10; RCB-II=13; RCB-III=2; inevaluable=5). Baseline clinicopathological characteristics did not significantly differ between patients with R and NR, indicating that traditional features lack discriminative power in this cohort. At TPBL, R exhibited significantly higher levels of activated CD4 memory T cells, activated CD8 memory T cells, regulatory T cells (Tregs), and B cells, along with lower levels of natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, naïve CD4 Tregs, and γδ T cells compared to NR. Patients with R also had significantly higher percentages of CD39+ CD8 T cells at TPBL (ROC AUC 0.76, p=0.003). However, there were no significant differences in BG Immunotype Signature Scores at TPBL between R and NR groups. In both R and NR cohorts, monocyte concentrations decreased significantly by TPMID (p=5.03e-09 TPMID vs TPBL) and subsequently increased at TPPOST (p=2.86e-06 TPPOST vs TPMID). B cell concentrations declined progressively during treatment (TPMID vs TPBL, p=3.49e-06; TPPOST vs TPMID, p=1.81e-0.5), as did CD4 T cell concentrations (TPMID vs TPBL, p=4.52e-04; TPPOST vs TPMID, p=0.0421). Notably, increases in G2 Primed Immunotype Scores (reflecting central/transitional memory T cells) were significant greater in R compared to NR (p=0.0105). Conclusions: Baseline peripheral immune signatures, notably higher CD39+ CD8 T cells and adaptive immune cell levels, and dynamic evolution towards a G2 Primed Immunotype post-treatment, are significantly associated with improved pathological response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage TNBC. These findings suggest that, if validated in larger studies, peripheral immune profiling could be strategically employed as a minimally invasive biomarker to optimize neoadjuvant therapy in patients with TNBC. Citation Format: C. Yam, A. Radko, L. Huo, S. Akshara, E. Ohanjanyan, A. Yudina, V. Kushnarev, H. Hill, S. Abouharb, B. Adrada, B. Arun, C. Barcenas, A. Bisen, A. Brewster, A. Buzdar, M. Chavez Mac Gregor, S. Damodaran, H. Garber, M. Guirguis, A. Hassan, N. Ibrahim, M. Karuturi, E. Kong, R. Layman, G. Moscol, J. Mouabbi, R. Murthy, A. Nasrazadani, B. Nelson, A. Nwosu Iheme, O. Oke, M. Patel, P. Pohlmann, D. Ramirez, S. Saleem, J. Sukumar, J. Sun, P. Thomas, R. Walters, P. Wei, M. Williams, M. Wright, W. Woodward, K. Hunt, J. Litton, V. Valero, D. Tripathy, G. Rauch, M. Goldberg, A. Korkut. Circulating Immune Correlates of Pathological Response to Neoadjuvant Pembrolizumab plus Chemotherapy in High-Risk, Early-Stage Triple-Negative Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD7-03.