Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling.

Flávia L C Faldoni,Silvia R Rogatto,Simon J Larsen,Jan Baumbach,Sarah S Cury,Fabio A Marchi,Cristiano P Souza,Mads M Aagaard,Cristovam Scapulatempo-Neto,Carlos E Fonseca-Alves,Rolando A R Villacis,Cynthia A B T Osório,Luisa M Canto

doi:10.3390/cancers12102816

Abstract

Simple SummaryInflammatory breast cancer (IBC) is an aggressive disease with high mortality rates. Nowadays, there is no targeted treatment for this tumor type. Based on this context, we investigated the molecular profile of this disease by using well-established methodologies (high-resolution microarray platform, targeted next-generation sequencing, and immunohistochemistry) that have proven potential to unveil cancer biomarkers. We found alterations related to IBC aggressiveness and metastasis (gains of MDM4, losses of CHL1, and high homologous recombination deficiency scores), and worse overall survival (variants in HR and mismatch repair genes). We also compared the mutational profiling of our cases with literature data, which includes both non-IBC and IBC cases, validating our findings. Overall, we describe genetic alterations with the potential to be used as prognostic or predictive biomarkers and ultimately improve IBC patients’ care.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.

Highlights

Inflammatory breast cancer (IBC) stands out as a rare and aggressive form of breast cancer (BC), accounting for only 2–4% of BC patients, but responsible for 7–10% of BC-related deaths [1,2,3].The IBC diagnosis is based on inflammatory clinical signs in more than 30% of the breast, with or without an underlying palpable mass [2,3,4,5]
Scores in IBC cases than in non-IBC patients. These findings suggest that aggressive IBC can have higher levels of homologous recombination deficiency (HRD), and the patients should benefit from platinum and/or PARP inhibitor therapies
We suggest that HRD-based genomic scars may be used in IBC to estimate deficiency in homologous recombination pathways, directing a better therapeutic strategy

Summary

Introduction

Inflammatory breast cancer (IBC) stands out as a rare and aggressive form of breast cancer (BC), accounting for only 2–4% of BC patients, but responsible for 7–10% of BC-related deaths [1,2,3]. The IBC diagnosis is based on inflammatory clinical signs (warmth, erythema, edema-peau d’orange, lasting no more than 6 months, with erythema occupying at least one-third of the breast) in more than 30% of the breast, with or without an underlying palpable mass [2,3,4,5]. Dermal lymphatic invasion is a non-obligatory histopathological feature supporting the diagnosis of IBC [2,3,4,5]. The median overall survival (OS) of patients with IBC stages III and IV is shorter compared to non-IBC cases (stage III: 4.75 versus 13.40 years and stage IV: 2.27 versus 3.40 years, respectively) [7,8]

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