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[Preprint]. 2024 May 10:2024.05.07.592972.
doi: 10.1101/2024.05.07.592972.

Clinicogenomic characterization of inflammatory breast cancer

Nolan Priedigkeit  1   2   3 , Beth Harrison  2   4   5 , Robert Shue  1   3 , Melissa Hughes  1   4 , Yvonne Li  1   3 , 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 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. bioRxiv. .

Update in

  • Clinicogenomic Characterization of Inflammatory Breast Cancer.
    Priedigkeit N, Harrison B, Shue R, Hughes ME, Li Y, Lebrón-Torres A, Kirkner GJ, Spurr LF, Remolano MC, Strauss S, Files J, Feeney AM, Grant L, Mohammed-Abreu A, Garrido-Castro A, Barroso-Sousa R, Bychkovsky B, Nakhlis F, Bellon JR, King TA, Winer EP, Lindeman N, Johnson BE, Sholl L, Dillon D, Overmoyer B, Tolaney SM, Cherniack AD, Lin NU, Lynce F. Priedigkeit N, et al. Clin Cancer Res. 2025 Jul 15;31(14):3072-3083. doi: 10.1158/1078-0432.CCR-24-2081. Clin Cancer Res. 2025. PMID: 40378057 Free PMC article.

Abstract

Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts.

Patients and methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases.

Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease.

Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

Keywords: Breast cancer; TP53; cancer genomics; inflammatory breast cancer; metastasis; tumor profiling.

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Conflict of interest statement

DISCLOSURES: TAK reports compensated service on advisory board and speakers honoraria from Exact Sciences, and compensated service as faculty for PrecisCa cancer information service. SMT reports consulting or advisory roles for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corporation, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, and Arvinas; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep; and travel support from Eli Lilly, Sanofi, Gilead, and Jazz Pharmaceuticals. NUL reports institutional research support from Genentech (and Zion Pharmaceutical as part of GNE), Pfizer, Merck, Seattle Genetics (now Pfizer), Olema Pharmaceuticals, and AstraZeneca; consulting honoraria from Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., and Eisai; royalties from UpToDate (book); and travel support from Olema Pharmaceuticals. FL reports consulting/advisory roles for AstraZeneca, Pfizer, Merck and Daiichi Sankyo; and institutional research funding from Eisai, AstraZeneca, CytomX and Gilead Sciences. ADC receives research funding from Bayer. The remaining authors declare no conflicts of interest.

Figures

Figure 1.
Figure 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; TNBC, triple-negative breast cancer
Figure 2.
Figure 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 Figure 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
Figure 3.
Figure 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
Figure 4.
Figure 4.. Comparison of somatic alterations grouped by biological pathways between IBC and non-IBC cases.
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. HER2+, human epidermal growth factor receptor 2-positive; HR+, hormone receptor-positive; TNBC, triple-negative breast cancer
Figure 5.
Figure 5.. Comparison of TMB between IBC and non-IBC cases.
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
Figure 6.
Figure 6.. Landscape of TP53 alterations in IBC and association with worse outcomes in HR+ IBC.
(A) Lollipop plot of TP53 mutations identified in IBC cases (top) and non-IBC cases (bottom). (B) Overall survival after OncoPanel testing in advanced IBC cases segregated by presence or absence of TP53 mutation. Median overall survival (date of OncoPanel testing to date of last follow-up) 495 days in TP53 mutated cases versus 993 days in cases without a TP53 mutation detected. Logrank p-value shown on plot.
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