Clinicogenomic characterization of inflammatory breast cancer

Priedigkeit, N.; Harrison, B.; Shue, R.; Hughes, M. E.; Li, Y.; Kirkner, G. J.; Spurr, L. F.; Remolano, M. C.; Strauss, S.; Files, J.; Feeney, A.-M.; Grant, L.; Mohammed-Abreu, A.; Garrido-Castro, A.; Sousa, R. B.; Bychkovsky, B.; Nakhlis, F.; Bellon, J. R.; King, T. A.; Winer, E. P.; Lindeman, N.; Johnson, B. E.; Sholl, L.; Dillon, D.; Overmoyer, B.; Tolaney, S. M.; Cherniack, A.; Lin, N. U.; Lynce, F.

doi:10.1101/2024.05.07.592972

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bioRxiv · 10.1101/2024.05.07.592972

Clinicogenomic characterization of inflammatory breast cancer

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Abstract

BackgroundInflammatory 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 MethodsA 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. ResultsClinicopathologic 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. ConclusionTaken 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.

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Priedigkeit, N., Harrison, B., Shue, R., Hughes, M. E., Li, Y., Kirkner, G. J., Spurr, L. F., Remolano, M. C., Strauss, S., Files, J., Feeney, A.-M., Grant, L., Mohammed-Abreu, A., Garrido-Castro, A., Sousa, R. B., Bychkovsky, B., Nakhlis, F., Bellon, J. R., King, T. A., Winer, E. P., Lindeman, N., Johnson, B. E., Sholl, L., Dillon, D., Overmoyer, B., Tolaney, S. M., Cherniack, A., Lin, N. U., Lynce, F.. 2024-05-10. Clinicogenomic characterization of inflammatory breast cancer. https://doi.org/10.1101/2024.05.07.592972

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