Examining the tumor microbiology and microenvironment of patients with triple-negative inflammatory breast cancer receiving KEYNOTE-522.

e12594 Background: Patients with Stage III triple negative (TN) inflammatory breast cancer (IBC) are treated based on standard-of-care practices inclusive of the Keynote 522 regimen (KN522). Outcomes, however, are inferior to what has been reported in the non-IBC setting. Patients achieving pathologic complete response (pCR) were compared to those not achieving pCR in a cohort of patients with IBC receiving KN522 to evaluate for predictors of response. Methods: RNA sequencing (RNA-seq) was performed on 26 samples from 23 patients with IBC undergoing KN522 in the neoadjuvant setting (N = 19 baseline pre-treatment, N = 7 surgical post treatment, N = 5 paired samples). BostonGene’s Breast Cancer Classifier (BCC) was utilized to determine intrinsic subtypes. Tumor microenvironment was determined by BostonGene’s Tumor Portrait assay. Results: Among patients achieving pCR in the studied cohort (N = 4), 75% (N = 3) and 25% (N = 1) patients had basal and luminal B subtype, respectively, while in the non-pCR group (N = 5), 30% (N = 3) were HER2-low. The pCR group demonstrated higher PD-L1 RNA-seq expression and a trend towards higher abundance of T cell subsets in the tumor cell microenvironment comparatively. Among non-pCR cases, deconvolution analysis revealed reduced tumor fractions following neoadjuvant systemic therapy. A shift in tumor portrait was observed in 3/5 samples, including increased fibrosis features in two cases and loss of immune component in one. These non-pCR cases showed increased angiogenesis and endothelial enrichment signatures, trending toward reduced matrix remodeling. No association was identified between immune-related adverse events (irAEs) and either pCR or BCC subtype. Conclusions: While the small sample size and molecular heterogeneity preclude our ability to draw definitive conclusions, our findings show that in TN IBC, response to neoadjuvant therapy correlated with high PD-L1 expression and T cell abundance, whereas non-responders demonstrated angiogenic and endothelial shifts. No association was observed between irAEs and pCR or BCC. These findings highlight potential biomarkers of response and progression in TN IBC; however, interpretation is limited by the small cohort size and molecular heterogeneity.