Abstract 2013: Serum immune markers are associated with pathological complete response and immune-related adverse events in immuno-oncology arms of the I-SPY2 breast cancer trial

Abstract Background: Predicting early response and immune-related adverse events (irAEs) is crucial for therapies with immune checkpoint inhibitors (ICI) in early-stage breast cancer (BC). This study evaluated serum immune markers at pre-treatment and early on-treatment, and changes between timepoints in women with BC treated with neoadjuvant chemotherapy plus ICI (anti-PD-1) or ICI plus SD-101 (an immunomodulatory toll-like receptor 9 agonist) in the I-SPY2 trial. Methods: Serum samples from women with HER2-negative BC (N=114) in the I-SPY2 trial were collected at baseline (T0) and three weeks post-treatment initiation (T1). Patients received paclitaxel with anti-PD-1 (N=49) or anti-PD-1 plus SD-101 (N=65), followed by anthracycline/cyclophosphamide. Serum was analyzed for 18 immune markers, including checkpoint molecules (sPD-L1, LAG-3), cytokines (IL-6, IL-8, IL-10, sCD25, G-CSF, IFNγ, TNFα), chemokines (CXCL9, CXCL10, CXCL11, CCL2, CXCL13), angiogenesis markers (VEGF-C), proteins and macrophages with inflammatory roles (CRP, CD163), and molecules that induce cell apoptosis (Granzyme B). Associations between serum markers and pathologic complete response (pCR) or irAEs were assessed using the Mann-Whitney test, and significance was defined at P<0.05. Associations were also assessed within hormone receptor (HR+/HER2- N=68, HR-/HER2- N=46) and I-SPY2 immune positive (ImPrint+, N=54) subtypes in both treatment arms. ImPrint is a 53-gene signature that was independently validated to predict the likelihood of a pCR with PD-1/PD-L1 ICIs with high sensitivity and specificity. Results: Among all HER2-negative patients, baseline CRP, CXCL10, and sCD25 levels were positively associated with pCR. In HR+/HER2- and HR-/HER2- patients, baseline CRP levels were also positively associated with pCR. In ImPrint+ patients, baseline G-CSF levels were positively associated with pCR, even after adjusting for HR status and treatment arm. T1 IFNγ levels were positively associated with pCR in HER2-negative patients, and within HR-/HER2- and ImPrint+ groups. Immune-related AEs were reported in 9 of 49 patients in the anti-PD-1 arm. VEGF-C increase between T0 and T1 was associated with irAEs in HR+/HER2- patients, while granzyme B increase was associated with irAEs in HR-/HER2- patients. Conclusions: Serum immune markers may influence tumor immune cell infiltration, potentially affecting the likelihood of achieving pCR and systemic immune activity linked to irAEs. Serum levels of CRP, CXCL10, sCD25, G-CSF, and IFNγ could be used to monitor and predict clinical benefit from anti-PD-1 and immunomodulatory agents. This study also suggests that VEGF-C and granzyme B can be possible candidate prognostic biomarkers for irAEs in patients receiving anti-PD-1 therapy. Validation in a larger sample size is crucial to confirm the observed trends. Citation Format: Silver Alkhafaji, Kingsley Chow, Denise Wolf, Rosalyn W. Sayaman, Amrita Basu, Lamorna Brown-Swigart, Rita Nanda, Jo Chien, Minetta Liu, Gillian Hirst, Laura J. Esserman, Laura van 't Veer, Michael J. Campbell. Serum immune markers are associated with pathological complete response and immune-related adverse events in immuno-oncology arms of the I-SPY2 breast cancer trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2013.