Abstract 6804: High IL12family levels are associated with pathologic complete response amongst HER2- patients in the neoadjuvant I-SPY2 TRIAL
Authors: Chow Kingsley V. , Al Khafaji Silver , Wolf Denise , Yau Christina , Dubinsky Kailey , Tsopurashvili Elene , Ramalingam Kirthiga , van Nouhuijs Fluorentine , Xun Zheyun , van Montfort Anna , Heditsian Diane , Yee Douglas , Esserman Laura , Campbell Michael , van't Veer Laura , Sayaman Rosalyn W. 
Published: March 2024

Abstract
Background: Immune contexture of the tumor microenvironment (TME) is associated with response to therapy. We hypothesize that expression of interleukin (IL) family of cytokines which plays essential roles in the activation and differentiation of immune cells, shapes the landscape of therapeutic response in breast cancers. We leverage published gene expression, molecular and clinical data from the I-SPY2 Trial (PMID35623341) - a neoadjuvant trial for locally advanced breast cancers. We explored the contribution of expression-based signatures of IL signaling at pre-treatment in relation to pathological complete response (pCR).
Methods: We curated 32 IL gene sets from literature. Signatures scores characterizing IL signaling were calculated from gene expression profiles of pre-treatment tumor samples from 987 I-SPY2 patients in the first 10 treatment arms of the trial. Association of IL signatures with pCR in HR/HER2 receptor subtypes, and the five I-SPY response-predictive subtypes (RPS) were evaluated using non-parametric tests. Significance levels were defined at adj. p &lt; 0.05. Correlations of IL signatures with multiplex immunofluorescence staining of immune infiltrates in the PD1-inhibitor (PD1i) arm were also assessed.
Results: High expression of IL signatures in HER2- patients, regardless of HR status, was associated with pCR especially in the Trebananib, Veliparib/Carboplatin (VC) and PD1i arms. In the PD1i arm, expression of almost all IL signatures was highly correlated with density of T, CD8+ cytotoxic T, CD8- T, and B cells and their colocalization with tumor cells; IL-6 signatures correlated with density of proliferating tumor cells.Within RPS subtypes, enrichment of IL signatures in HER2-/Immune+ such as pro-inflammatory IL-1 and IL-12 signaling was associated with pCR in the VC, PD1i, Ganetespib, and control arms. Furthermore, we identified an IL-12 signature in the HER2-/Immune-/DRD- subtype associated with pCR, with responders characterized by high IL-12 family signaling (Fisher adj. p &lt; 0.05). IL-12 family signaling was positively associated with CD8+ cytotoxic T, Th1 and B cell enrichment, IFN-γ signaling, and inflammatory response overall and in HER2- breast cancers.
Conclusion: High pre-treatment expression of IL signatures was associated with HER2- receptor and RPS HER2-/Immune+ subtype-specific response to I-SPY2 agents, and the colocalization of immune and tumor cells in the tumor bed. In HER2- breast cancers, high levels of IL-12 family signaling were associated with response to therapy and enrichment of known IL-12-related pathways that stimulate effective anti-cancer response including CD8+ T cell expansion, Th1 cell differentiation, B cell activation, IFN-γ secretion, and inflammatory response. These findings suggest that IL signaling may serve as a valuable predictive biomarker in this patient population.
Citation Format: Kingsley V. Chow, Silver Al Khafaji, Denise Wolf, Christina Yau, Kailey Dubinsky, Elene Tsopurashvili, Kirthiga Ramalingam, Fluorentine van Nouhuijs, Zheyun Xun, Anna van Montfort, Diane Heditsian, Douglas Yee, Laura Esserman, Michael Campbell, Laura van't Veer, Rosalyn W. Sayaman. High IL12family levels are associated with pathologic complete response amongst HER2- patients in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6804.