Abstract P6-18-03: Tumor profiling of inflammatory breast cancer: Advancing the tools needed for precision medicine
Authors: Hazra A , Warren L , Nakhlis F , Bellon JR , Hirshfield-Bartek J , Jacene H , Yeh ED , Dominici L , Schlosnagle E , Hirko K , Overmoyer B 
Published: May 2016

Introduction: Inflammatory breast cancer (IBC) is a rare and highly lethal form of breast cancer, accounting for approximately 10% of breast cancer mortality in the US. The clinical presentation of IBC includes rapid onset of symptoms, erythema &gt; 1/3 of the breast, and edema. The genomic changes underlying the clincopathologic manifestations of IBC are yet unknown. Identification of a unique molecular signature in de novo IBC may provide insight into the biology of this disease, allowing further investigation into the etiology and treatment of this aggressive disease. In previous studies, supervised analysis of gene expression data from surgical tissue specimens identified a molecular-subtype independent 79-gene signature associated with IBC compared to locally-advanced non-IBC. In this study, we propose to identify a gene expression signature associated with IBC using breast specimens collected from patients with non-metastatic IBC prior to initiating preoperative systemic treatment.

Methods: Formalin fixed paraffin embedded (FFPE) core biopsy specimens were collected from patients with inflammatory breast cancer prior to initiating systemic therapy. All specimens underwent centralized pathology review at Brigham and Women's Hospital, and the clinical diagnosis was confirmed through evaluation by the Dana Farber Cancer Institute Inflammatory Breast Cancer Program. Sufficient RNA and DNA were simultaneously extracted from 14 biopsy specimens using the Qiagen AllPrep Kit. The RNA was amplified using the Sensation kit and profiled using the Affymetrix Human Transcriptome Array (HTA) 2.0. DNA was profiled for druggable somatic mutations and genome-wide copy number variations using the Affymetrix OncoScan Array.

Results: Pearson correlation coefficients for overall gene expression for 4 technical replicates included in the HTA ranged from r=0.993 - 0.994 and suggest excellent reproducibility in archival biopsy tissue. In preliminary analyses, 765 mRNA transcripts and 335 non-coding transcripts were differentially expressed based on clinical presentation features. The strongest differential association for rapid onset of disease was observed for alternately spliced variants in the TSPAN1 gene. Somatic mutations in PIK3CA were detected in 3 of the IBC patients. Additional paired assays as well as single-gene and pathway analyses, and integrated analyses of the genome and transcriptome using the R/Bioconductor packages are ongoing.

Conclusion: An understanding of the genomic changes that contribute to the unique presentation and biologic features associated with IBC should lead to a significant impact on identifying etiologic risk factors and in optimizing treatment strategies. Our findings to date suggest a robust and reproducible method for genomic investigation using standard diagnostic breast core biopsies among IBC patients, and may inform profiling of biopsy specimens for other cancer types. The completion of this study will provide biological insights into the molecular mechanisms driving IBC and may identify clinically actionable targets for novel IBC therapies that warrant further exploration.

Citation Format: Hazra A, Warren L, Nakhlis F, Bellon JR, Hirshfield-Bartek J, Jacene H, Yeh ED, Dominici L, Schlosnagle E, Hirko K, Overmoyer B. Tumor profiling of inflammatory breast cancer: Advancing the tools needed for precision medicine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-03.