Clinicogenomic characterization of inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC to non-IBC cases. Patients and Methods: We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors, 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, 1,552 metastases). Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV), tumor mutational burden (TMB), and exploratory survival outcomes were compared between IBC and non-IBC. Results: The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment in TP53 SNVs in IBC, particularly in HER2+ and hormone receptor-positive (HR+) disease. TMB did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment in NOTCH pathway alterations. TP53, CCND1 and RB1 alterations were associated with poor outcomes in IBC. Conclusion: This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC; highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations—beyond bulk sequencing of the somatic genome—are required to better understand the biology driving this aggressive disease.