Abstract Background: Luminal BC represents around 70% of BC cases. Primary or secondary resistance to endocrine therapy (ET) is a treatment limiting factor. Little is known about the potential relationship between ET response and IIS. The main aim of this study is to characterize the IIS based on levels of circulating cytokines in luminal advanced BC. We previously reported first data about this relation, we do now explore its potential predictive and prognostic value and role in hormone resistance development. Methods: NIKOLE is a multicenter, prospective, observational, no post-authorization study in luminal advanced HER2-negative BC pts assigned to two different hormone-resistance cohorts (CohA, hormone-sensitive or CohB, hormone-resistant). Expression levels of cytokines and/or rNKG2D ligands: IL15, Granzyme, MICA, MICB, Perforin, IFNγ, IL6, IL8, IL10, TNFα, and VEGFA, were measured by the MILLIPLEX® immunoassays HCYTA-60K and HCKP2-11K in serum from serial peripheral blood collected at baseline (pts and healthy controls), after 6 weeks, at radiological re-evaluation (3 months after ET initiation) and progressive disease (PD). Log2 expression cytokine values were compared between groups and correlated with outcome including Clinical Benefit (CB) and Progression Free Survival (PFS). Continuous variables were compared using Student´s t-test, and contingency tables were analyzed with Fisher’s exact test. Differences in Kaplan-Meier (KM) plots were evaluated using log-rank test, Cox regression models were fitted and Bonferroni correction applied to adjust for multiple comparisons. Results: NIKOLE enrolled 6 healthy controls and 31 pts with advanced luminal BC treated with first or second ET. 25 (78%) first treatment pts were only considered, clinical characteristics are summarized in the table. No differences in baseline cytokines levels were found between pts vs controls nor CohA vs CohB. We observed significant increased levels between baseline and 3 months of IL15 (p=0.006), Granzyme (p=0.027), MICA (p=0.009) and MICB (p=0.018) and decreased VEGFA (p=0.005) and IFNγ levels (p=0.005), changes that were independent of pts hormone sensitivity status at the start of treatment. We also found better CB in pts with lower levels at 3 months of IFNγ (p=0.04) and VEGFA (p=0.04). Finally, MICA and granzyme baseline levels had prognostic value: pts with lower levels (median value as cutoff) showed longer PFS (26.55 vs 10.91 months) (p=0.035) and 26.55 vs 15.15 months (p=0.03), respectively. Conclusions: Here we highlight the importance of the IIS in advanced Luminal BC pts and the role of circulating cytokines as potential response predictive and prognostic biomarkers. Our results warrant additional research to investigate the specific role of the cytokines in the hormone-resistant BC and hopefully help in better pts’ selection to new immune therapies. Citation Format: E. García-Martínez, E. Navarro-Manzano, J. Cejalvo-Andújar, B. Álvarez-Abril, I. Garrido-Cano, E. García-Torralba, C. Tebar-Sánchez, P. De la Morena-Barrio, M. Martínez-Martínez, F. Ayala de la peña, C. Tapia-Céspedes, J. Herranz, I. Romero-Camarero, F. Rojo, B. Bermejo. Prognostic role of the innate immune system circulating cytokines in advanced luminal breast cancer (BC) patients (pts) of the GEICAM/2018-03 NIKOLE study 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 PS1-12-02.
García-Martínez et al. (Tue,) studied this question.