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. 2025 Jul 15;31(14):3072-3083.
doi: 10.1158/1078-0432.CCR-24-2081.

Clinicogenomic Characterization of Inflammatory Breast Cancer

Nolan Priedigkeit #  1   2   3   4 , Beth Harrison #  2   4   5 , Robert Shue #  1   3 , Melissa E Hughes  1   4 , Yvonne Li  1   3 , Alinés Lebrón-Torres  3   4 , Gregory J Kirkner  1 , Liam F Spurr  1   3 , Marie Claire Remolano  1 , Sarah Strauss  1 , Janet Files  1 , Anne-Marie Feeney  1 , Libby Grant  1 , Ayesha Mohammed-Abreu  1 , Ana Garrido-Castro  1   2   4 , Romualdo Barroso-Sousa  1 , Brittany Bychkovsky  1   2   4   6 , Faina Nakhlis  2   4   7 , Jennifer R Bellon  2   4   8 , Tari A King  2   4   7 , Eric P Winer  1   2   4 , Neal Lindeman  2   4   5 , Bruce E Johnson  1   2 , Lynette Sholl  2   5 , Deborah Dillon  2   5 , Beth Overmoyer  1   2   4 , Sara M Tolaney  1   2   4 , Andrew D Cherniack  1   2   3 , Nancy U Lin  1   2   4 , Filipa Lynce  1   2   4
Affiliations

Clinicogenomic Characterization of Inflammatory Breast Cancer

Nolan Priedigkeit et al. Clin Cancer Res. .

Abstract

Purpose: 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 with non-IBC cases.

Experimental design: We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors.

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 of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC.

Conclusions: 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.

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Figures

Fig. 1.
Fig. 1.. Genomic landscape of inflammatory breast cancers.
Genes ordered by percentage of somatic alterations in overall cohort. Samples divided by breast cancer subtype and subdivided by primary or metastatic tissue tested. All variants represent oncogenic mutations or deep deletions/high amplifications. Tumor mutational burden (TMB) (mut/mb) is recorded on the top barplot of the OncoPrint. HER2+, human epidermal growth factor receptor 2-positive; HR+, hormone receptor-positive; TN-IBC, triple-negative inflammatory breast cancer
Fig. 2.
Fig. 2.. Frequency of most common SNVs (A, left) and CNVs (B, right) in IBC and non-IBC colored by subtype.
Shading represents the percentage of oncogenic events (defined by OncoKB for SNVs, defined by estimated high amplification or predicted double copy deletion for CNVs). For Fig. 2B, an annotation of “(A)” beside a gene represents an amplification and “(D)” represents a deletion. IBC, inflammatory breast cancer; SNVs, single nucleotide variants; CNVs, copy number variants; HER2+, human epidermal growth factor receptor 2-positive; HR+, hormone receptor-positive; TNBC, triple-negative breast cancer
Fig. 3.
Fig. 3.. Enrichment analysis of SNVs (A, left) and CNVs (B, right) in IBC.
Modeling performed using multivariate logistic regression accounting for HER2 and HR status. Only models that converged after 500 iterations are shown. Oncogenic mutations and high amplifications or deep deletions that appeared in over 1.5% of either all IBC or non-IBC samples were included in the analysis. IBC, inflammatory breast cancer; SNVs, single nucleotide variants; CNVs, copy number variants
Fig. 4.
Fig. 4.. Comparison of somatic alterations grouped by biological pathways and TMB between IBC and non-IBC cases.
(A) Proportion of samples with alterations within 6 biological pathways, segregated by breast cancer subtype; colored by IBC status (blue = IBC, red = non-IBC). Nominally significant enrichment (p < 0.05) highlighted with * above bar plots. (B) Tumor mutational burden (TMB, mutations / MB) between IBC and non-IBC cases; divided by subtype. Bottom right plot shows tumors segregated by primary vs. metastatic lesion assayed IBC, inflammatory breast cancer; HER2+, human epidermal growth factor receptor 2-positive; HR+, hormone receptor-positive; TNBC, triple-negative breast cancer
Fig. 5.
Fig. 5.. Comparative overall survival between IBC and non-IBC across subtypes and exploratory genomic outcome correlates in IBC.
(A) Kaplan-Meier curves comparing overall survival (OS) between IBC and non-IBC cases in hormone receptor- (HR)-positive (left), HER2-positive (center), and TNBC (right). Red curves represent patients with IBC, and blue curves represent patients with non-IBC. (B) Forest plots showing overall survival hazard ratios (HRs) for specific genomic alterations in patients with IBC across HR-positive (left), HER2-positive (center), and TN-IBC (right). Genomic alterations ranked top to bottom by p-value, p < 0.05 marked with red dot. (C) Kaplan-Meier curves for HR-positive IBC patients based on the presence or absence of CCND1 amplification (left) and TP53 alterations (right). Red lines indicate patients with alteration, blue without. IBC, inflammatory breast cancer; HR+, hormone receptor-positive; TNBC, triple-negative breast cancer; TN-IBC, triple-negative inflammatory breast cancer
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