Abstract 1395: Genomic and transcriptomic analyses identify distinct features of triple-negative inflammatory breast cancer
Authors: Wang Xiaoping , Zhao Li , Semba Takashi , Song Xingzhi , Knafl Mark , Krishnamurthy Savitri , Shao Shan , Coffer Larry W. , Alexander Angela , Wood Anita , Bopparaju Swetha , Woodward Wendy A. , Chu Randy , Zhang Jianhua , Woodman Scott , Futreal Andrew , Yam Clinton , Tripathy Debu , Ueno Naoto T. 
Published: April 2023

Abstract
Background: Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive breast cancer. It is important to identify its unique genetic and molecular features. In this study we performed comprehensive genomic and transcriptomic analyses of TN-IBC patient samples and identified TN-IBC unique features.
Methods: We collected matched pretreatment blood and tumor samples from 19 patients with primary TN-IBC enrolled in a phase II clinical trial (NCT01036087). Patients were treated with neoadjuvant chemotherapy (NAC) or the anti-EGFR antibody panitumumab (PmAb) plus NAC (PmAb/NAC). Whole-exome sequencing, RNA sequencing, and multiplexed immunofluorescent staining were used to compare genetic and molecular profiles of these TN-IBC samples with 60 similarly analyzed stage III TN-non-IBC patient samples. We also compared the genetic and molecular characteristics of TN-IBC in patients who had a pathologic complete response (pCR) to NAC or PmAb/NAC treatment, a suitable surrogate end point for IBC, with those who did not have pCR (non-pCR).
Results: Most TN-IBC patients (90%) had somatic gene alterations, most frequently in TP53 (42%), GATA3 (37%), and PI3KCA (26%). TN-IBC had distinct molecular and cellular differences from TN-non-IBC: a higher frequency of alteration of GATA3 (adj-p=0.001), KEAP1 (adj-p=0.05), CDKN1B (adj-p=0.05), amplification of ARNT, DDR2, BCL9, LMNA, and NDRG1, lower mutation load, and fewer copy number variations (p&lt;0.0001). TN-IBC had significantly higher expression of BRCA1, BRCA2, PIK3CA, PALB2, and RB1 (log2FC≥1, adj-p&lt;0.0001), enriched mitotic spindle and protein secretion hallmark gene sets, fewer CD8 T cells (p=0.01), and more γδ T cells (p=0.004) and M1 macrophages (p=0.01) than TN-non-IBC. TN-IBC patients in the NAC arm who had pCR had significantly higher somatic mutation load (p=0.04), upregulated expression of KRT36, KRT43P, and OR6K3 (log2FC≥1, adj-p&lt;0.0001), enriched MTORC1 signaling and E2F targets, and a significantly higher percentage of M2 macrophages (p=0.04) than those without pCR. Patients with pCR to PmAb/NAC had upregulated expression of SERPINA9, OR52N5, and CLEC3A (log2FC≥1, adj-p&lt;0.01), enriched interferon-α and -γ responses, and significantly lower percentages of monocytes (p=0.03) and M0 macrophages (p=0.05) compared to non-pCR patients.
Conclusion: Our study demonstrated distinct genetic abnormalities, immune responses, and molecular characteristics associated with TN-IBC as well as differences related to patients’ responses to NAC and PmAb/NAC. This first comprehensive genomic, transcriptomic, and immune profiling of the largest TN-IBC patient cohort improves our understanding of the molecular landscape of the most aggressive subtype of breast cancer. Our analysis could lead to the discovery of novel prognostic biomarkers and druggable targets for TN-IBC.
Citation Format: Xiaoping Wang, Li Zhao, Takashi Semba, Xingzhi Song, Mark Knafl, Savitri Krishnamurthy, Shan Shao, Larry W. Coffer II, Angela Alexander, Anita Wood, Swetha Bopparaju, Wendy A. Woodward, Randy Chu, Jianhua Zhang, Scott Woodman, Andrew Futreal, Clinton Yam, Debu Tripathy, Naoto T. Ueno. Genomic and transcriptomic analyses identify distinct features of triple-negative inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1395.