Genomic and expression analysis of microdissected inflammatory breast cancer

Abstract

Purpose Inflammatory breast cancer (IBC) is a unique clinical entity characterized by rapid onset of erythema and swelling of the breast often without an obvious breast mass. Many studies have examined and compared gene expression between IBC and non-IBC (nIBC), repeatedly finding clusters associated with receptor subtype, but no consistent gene signature associated with IBC has been validated. Here we compared microdissected IBC tumor cells to microdissected nIBC tumor cells matched based on estrogen and HER-2/neu receptor status. Methods Gene expression analysis and comparative genomic hybridization were performed. An IBC gene set and genomic set were identified using a training set and validated on the remaining data. The IBC gene set was further tested using data from IBC consortium samples and publically available data. Results Receptor driven clusters were identified in IBC; however no IBC-specific gene signature was identified. Fifteen genes were correlated between increased genomic copy number and gene overexpression data. An expression-guided gene set upregulated in the IBC training set clustered the validation set into two clusters independent of receptor subtype but segregated only 75% of samples in each group into IBC or nIBC. In a larger consortium cohort and in published data the gene set failed to optimally enrich for IBC samples. However, this gene set had a high negative predictive value for excluding the diagnosis of IBC in publically available data (100%). An IBC enriched genomic data set accurately identified 10/16 cases in the validation data set. Conclusions Even with microdissection, no IBC-specific gene signature distinguishes IBC from nIBC. Using microdissected data, a validated gene set was identified that is associated with IBC tumor cells. IBC comparative genomic hybridization data are presented, but a validated genomic data set that identifies IBC is not demonstrated.

Analysis of hierarchical organization in gene expression networks reveals underlying principles of collective tumor cell dissemination and metastatic aggressiveness of inflammatory breast cancer

“…Further, bootstrap distributions for the normalized CCC values for the two are groups were statistically distinct with p-value < 10 −5 for the Kolmogorov-Smirnov test). However, we did not observe a significant trend for the breast cancer samples characterized by Boersma et al [41] and for the samples characterized by Woodward et al [21], fig. 2 (B) and (C).…”

“…4 (A). A similar trend in the CCC values for IBC and non-IBC patient groups was observed for breast cancer patients in the two other independent breast cancer datasets, Woodward et al [21] and Boersma et al [41], fig. 4 (B) and (C).…”

“…We constructed such networks for the epithelial and mesenchymal cell lines in the Grosse-Wilde et al [36] dataset and for the epithelial, mesenchymal, and epithelial / mesenchymal hybrid cell lines in the NCI60 dataset. Such networks were also constructed for IBC and non-IBC patients in the three breast cancer datasets, Iwamoto et al [40], Woodward et al [21], and Boersma et al [41], using each of the two gene sets described previously, genes associated with collective dissemination of tumor cell clusters and genes associated with the IBC phenotype.…”

“…Inflammatory Breast Cancer (IBC) is a highly aggressive breast cancer subtype that has been reported to predominantly metastasize via CTC clusters [19]. Characterized by breast erythema, edema, and peau d'orange presenting with or without a noticeable tumoral mass [20,21], IBC involves tumoral infiltrate in the dermal lymphatics, and about 30% of IBC patients have distant metastases at the time of diagnosis as compared to only 5% of non-IBC type breast cancer patients [22]. Though only 2-4% of breast cancer cases each year in the United States are of the IBC type, IBC patients account for 10% of the annual breast cancer related mortalities.…”

Pathological Response and Circulating Tumor Cell Count Identifies Treated HER2+ Inflammatory Breast Cancer Patients with Excellent Prognosis: BEVERLY-2 Survival Data

“…Biologically, IBC remains poorly characterized. No consistent gene signature associated with IBC has been validated (4). Recently, it has been showed that IBC is transcriptionally heterogeneous and that all molecular subtypes described in non-IBC are detectable in IBC, albeit with a different frequency (5).…”