TREM-1 upregulation as a potential predictive immune biomarker of pathologic complete response (pCR) in patients (pts) with triple-negative breast cancer (TNBC) receiving neoadjuvant therapy (NAT).

Abstract

e12632 Background: There are no approved biomarkers to predict pCR after NAT based on the KEYNOTE-522 (KN-522) regimen for pts with TNBC. The tumor immune microenvironment likely plays a key role in the efficacy of NAT. We performed a prospective biomarker study in 28 women with newly diagnosed clinical stage II/III TNBC who were candidates for NAT. Methods: This is an IRB-approved study of pts with previously untreated stage II/III TNBC receiving NAT based on KN-522 followed by definitive surgery. Consented pts had blood samples collected at baseline (BL), cycle 3 day 1 (C3D1), and after surgery. The trial has met accrual goal, with 6 pts not yet assessable for pCR at data cutoff. Comprehensive proteomic assessment of peripheral blood samples was conducted using Olink Target96 Assay. The primary outcome was pCR. Expression of 276 biomarkers was analyzed (92 for immune response, 92 for inflammation, and 92 for metabolism). Expression of those with pCR vs. those without pCR at BL was summarized via averages in heatmaps, bar plots, and dot plots and compared via Kruskal-Wallis (with Benjamini-Hochberg procedure), while its correlation with pCR was analyzed via Pearson. The expression changes between BL and C3D1 and the association with pCR were analyzed using volcano plots, which represent the negative log[10]-transformed p-values (from t-tests) against the log2-fold change in expression. Results: Among 28 pts, median age was 46 yrs (range 29-78), 64% were stage III, 57% were white, 36% were black, and 61% (n = 17) had pCR. No differences in proteomic expressions between pCR and non-pCR were seen at BL. Upregulation (log2-fold change = 0.29) of Triggering receptor expressed on myeloid cells-1 (TREM-1) on C3D1 compared to BL was significantly associated with pCR ( p = 0.02). At BL, mean TREM-1 levels were 2.98 (SD 0.43) for pCR vs. 2.76 (SD 0.60) for no pCR, while at C3D1, TREM-1 levels were 2.54 (SD 0.54) for pCR vs. 2.04 (SD 0.68) for no pCR. TREM-1 upregulation was observed in 2 pts (2/2 pCR), while downregulation was observed in 26 pts (15/26 pCR vs. 11/26 no pCR). Conclusions: TREM-1, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, functions as a critical proinflammatory receptor to amplify innate immune responses and demonstrates selective expression patterns across various myeloid cell populations. Our findings suggest two potential therapeutic strategies: targeted depletion/inhibition of immunosuppressive myeloid cells or direct stimulation of TREM-1-mediated inflammatory signaling pathways. Both methods might reshape the tumor microenvironment from an immunosuppressive to an immunostimulatory state, enhancing anti-tumor immune responses. The identification of TREM-1 as a potential predictive biomarker for pCR provides both prognostic value and therapeutic targeting opportunities.