Abstract 4741: HER2 status correlated with interleukin-2 (IL-2) levels after systemic therapy in hormone receptor (HR)-positive metastatic breast cancer

Abstract Introduction: The immune response plays a crucial role in prognosis in metastatic breast cancer (MBC). Detecting plasma immune components, including cytokines and circulating tumor cells (CTCs), can help predict prognosis. We previously identified Interleukin-2 (IL-2) as a biomarker associated with disease progression in MBC. Similarly, HER2 is a critical tumor marker linked to therapeutic outcomes and poor prognosis in advanced breast cancer (2018-ASCO #1090, 2022-ASCO #1057). Here, we report a novel finding: HER2 status is correlated with plasma IL-2 levels following systemic therapy in MBC patients. Methods: Whole blood samples (7.5 mL each) were collected from 42 patients with MBC, including 25 ER+, 17 ER-, 12 HER2+, and 30 HER2- patients, both before systemic therapy (baseline, BL) and 3 months after therapy (follow-up) at Northwestern Memorial Hospital (IRB-NU16B06). CTC enumeration was performed using the FDA-approved CELLTRACKS System (Menarini). Plasma Interleukin-2 (IL-2) levels were analyzed using ELISA (Fisher). Estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 status were assessed in biopsy tissue (prior to surgery) by NU PathCore. Statistical analyses were conducted using Causal Inference with Ensemble Learning. Results: Based on pathological diagnoses, patients were categorized into 4 groups: 17 HR+/HER2- (Group 1), 8 HR+/HER2+ (Group 2), 4 HR-/HER2+ (Group 3), and 13 HR-/HER2- (Group 4). Ki67 expression was found in 9 patients in Group 1, 6 in Group 2, 1 in Group 3, and 6 in Group 4. There was no significant difference in baseline mean IL-2 levels among the groups, with values of 82.1 pg/mL, 78.6 pg/mL, 80.5 pg/mL, and 81.2 pg/mL for Groups 1, 2, 3, and 4, respectively (P > 0.05). After therapy, the mean IL-2 levels changed to 80.8 pg/mL, 69.3 pg/mL, 70.2 pg/mL, and 77.6 pg/mL at follow-up. A significant difference was observed between Groups 1 and 2 (P = 0.037), showing that IL-2 levels were notably higher in HR+/HER2- patients compared to HR+/HER2+ patients. There was no significant correlation between IL-2 and Ki67. Additionally, 20 patients (46%) had CTCs ≥5 at baseline, with 15 having HER2-negative CTCs (Group 5) and 5 having HER2-positive CTCs (Group 6). The mean IL-2 level was significantly higher in Group 5 (88.17 pg/mL) than Group 6 (66.81 pg/mL), indicating that patients with HER2-positive CTCs had significantly lower IL-2 levels (P = 0.02). Conclusion: The finding that HER2 status in CTCs correlates with lower plasma IL-2 levels, and that HER2 status in biopsy tumor tissue is associated with IL-2 levels after systemic treatment in HR-positive MBC patients, suggests that HER2 may contribute to immune suppression and weaken the immune response through its interaction with IL-2 during therapy. Exploring the HER2-IL-2 relationship could provide valuable insights into assessing therapeutic efficacy in hormone receptor-positive MBC. Citation Format: Justin W. Zhang, Qiang Zhang, Andrew A. Davis, Lorenzo Gerratana, Jianhua Jiao, Weijun Qin, Youbin Zhang, Paolo D’Amico, zheng Cai, Akhil Chawla, Lisa Flaum, Janice Lu, Leonidas C. Platanias, William J. Gradishar. HER2 status correlated with interleukin-2 (IL-2) levels after systemic therapy in hormone receptor (HR)-positive metastatic breast cancer [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 4741.