Author:
Priedigkeit Nolan,Harrison Beth,Shue Robert,Hughes Melissa,Li Yvonne,Kirkner Gregory J.,Spurr Liam F.,Remolano Marie Claire,Strauss Sarah,Files Janet,Feeney Anne-Marie,Grant Libby,Mohammed-Abreu Ayesha,Garrido-Castro Ana,Sousa Romualdo Barroso,Bychkovsky Brittany,Nakhlis Faina,Bellon Jennifer R.,King Tari A.,Winer Eric P.,Lindeman Neal,Johnson Bruce E.,Sholl Lynette,Dillon Deborah,Overmoyer Beth,Tolaney Sara M.,Cherniack Andrew,Lin Nancy U.,Lynce Filipa
Abstract
ABSTRACTBackgroundInflammatory 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 involvedTP53(72%),ERBB2(32%),PIK3CA(24%),CCND1(12%),MYC(9%),FGFR1(8%) andGATA3(8%). A multivariate logistic regression analysis revealed a significant enrichment inTP53SNVs 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 ofTP53mutations and a potential enrichment in NOTCH pathway activation—but overall; a lack of major genomic differences. These results both reinforce the importance ofTP53alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.
Publisher
Cold Spring Harbor Laboratory