Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling
Flávia Lima Costa Faldoni, Rolando André Rios Villacis, Luísa Matos do Canto, Carlos Eduardo Fonseca‐Alves, Sarah Santiloni Cury, Simon J. Larsen, Mads Malik Aagaard, Cristiano de Pádua Souza, Cristovam Scapulatempo‐Neto, Cynthia Aparecida Bueno de Toledo Osório, Jan Baumbach, Fábio Albuquerque Marchi, Sílvia Regina Rogatto
Abstract
Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related genes). The genes more frequently affected by gains were MYC (75%) and MDM4 (71%), while frequent losses encompassed TP53 (71%) and RB1 (58%). Increased MYC and MDM4 protein expression levels were detected in 18 cases. These genes have been related to IBC aggressiveness, and MDM4 is a potential therapeutic target in IBC. Functional enrichment analysis revealed genes associated with inflammatory regulation and immune response. High homologous recombination (HR) deficiency scores were detected in triple-negative and metastatic IBC cases. A high telomeric allelic imbalance score was found in patients having worse overall survival (OS). The mutational profiling was compared with non-IBC (TCGA, n = 250) and IBC (n = 118) from four datasets, validating our findings. Higher frequency of TP53 and BRCA2 variants were detected compared to non-IBC, while PIKC3A showed similar frequency. Variants in mismatch repair and HR genes were associated with worse OS. Our study provided a framework for improved diagnosis and therapeutic alternatives for this aggressive tumor type.