New Therapeutic Targets in Inflammatory Breast Cancer

Inflammatory breast cancer (IBC) is the most lethal variant of locally advanced breast cancer. Although recognized as a distinct clinical entity, there have been few advances in the development of pre-clinical models of IBC, and a lack of IBC-specific therapeutic targets translated into clinical utility to increase overall survival, which is currently 40?% at three years. By use of newly developed pre-clinical models of IBC and patient tumor tissues, E-cadherin, anaplastic lymphoma kinase (ALK), and HSP90 have been identified as targets relevant to IBC that are matched by therapeutics that are either currently in clinical trials or will be tested in clinical trials within the next year. These exciting results illustrate the advances that have been made in recent years in defining the molecular basis of IBC as a distinct disease and the significant strides made in identifying more effective strategies for treatment of patients with IBC.     

Comparative aspects of canine and human inflammatory breast cancer

Inflammatory breast cancer (IBC) in humans is the most aggressive form of mammary gland cancer and shares clinical, pathologic, and molecular patterns of disease with canine inflammatory mammary carcinoma (CIMC). Despite the use of multimodal therapeutic approaches, including targeted therapies, the prognosis for IBC/CIMC remains poor. The aim of this review is to critically analyze IBC and CIMC in terms of biology and clinical features. While rodent cancer models have formed the basis of our understanding of cancer biology, the translation of this knowledge into improved outcomes has been limited. However, it is possible that a comparative “one health” approach to research, using a natural canine model of the disease, may help advance our knowledge on the biology of the disease. This will translate into better clinical outcomes for both species. We propose that CIMC has the potential to be a useful model for developing and testing novel therapies for IBC. Further, this strategy could significantly improve and accelerate the design and establishment of new clinical trials to identify novel and improved therapies for this devastating disease in a more predictable way.     

Pathologic aspects of inflammatory breast carcinoma: part 1. Histomorphology and differential diagnosis

Inflammatory breast carcinoma (IBC) is rare, but it is the most aggressive variant of breast cancer. Because a diagnosis of IBC is usually based on the presence of typical clinical symptoms that are not always associated with certain pathologic characteristics, the diagnosis often presents a great challenge even to the most experienced clinicians. Even more, IBC has not been associated with a specific histologic tumor type. With recent epidemiologic and molecular evidence now suggesting that IBC is a distinct disease entity rather than a subtype of locally advanced breast cancer, the accurate differentiation of this disease has never been more crucial to ensuring appropriate treatment. The focus of this chapter is on the histomorphologic characteristics of IBC and its broad differential diagnosis.     

Pathologic aspects of inflammatory breast cancer: part 2. Biologic insights into its aggressive phenotype

Inflammatory breast cancer (IBC) is the most aggressive and distinct form of primary breast cancer with a peculiar clinical presentation and dismal clinical outcome. This review addresses the pathologic aspects of this entity and discusses the molecular alterations involved in the highly malignant phenotype of IBC.     

The epidemiology of inflammatory breast cancer

The epidemiology of inflammatory breast cancer (IBC) has been of great interest to a number of investigators, but epidemiological research has been hampered by the lack of an agreed upon case definition and the relatively small number of patients available to any single investigator or institution. Several features of IBC have become apparent through population-based studies, which, although varying somewhat in case definition, generally agree on some key features of the disease. These include the incidence of the disease, apparently less than 3% of breast cancer cases in the United States, the younger age of onset compared to non-inflammatory breast cancer, the much higher incidence in Black women compared to White, the generally poor outcome of this disease compared to non-inflammatory breast cancer, and the continued increase in reported incidence, particularly as compared with non-inflammatory breast cancer in general and locally advanced breast cancer (LABC) in particular. There is an apparent striking geographic pattern, with a higher percentage of cases reported from North Africa, best documented in Tunisia. The risk factors for developing IBC are suggested by smaller studies with concordant conclusions, and some appear to be different than the risk factors for developing breast cancer in general. For example, obesity appears to be a risk factor for premenopausal IBC but is not for premenopausal non-inflammatory breast cancer. In addition, there is evidence that a young age at first birth predisposes to IBC but is protective against developing non-inflammatory breast cancer. In some malignancies, the use of molecular markers is helpful in defining subgroups that could assist in improving case definition as well as predicting prognosis. The increasing combination of improved epidemiologic and laboratory methods will hopefully accelerate our understanding of this challenging disease.     

Defining the molecular biology of inflammatory breast cancer

Inflammatory breast cancer (IBC) is a rare, but aggressive form of breast cancer. Despite the progress related to the introduction of primary combination chemotherapy (CT) to the multimodality treatment regimen, the prognosis of IBC remains poor with long-term survival inferior to 50%. Until recently, IBC remained understudied at the molecular level. In the past 10 years, advances have been made in the molecular characterization of the disease. Recently, the use of experimental models and new high-throughput molecular profiling technologies have led to the identification of genes or pathways potentially involved in disease development, which might represent new clinically relevant targets. The aim of this review is to present and discuss what is known about the biology of this particularly aggressive form of breast cancer and to discuss how this knowledge could improve its management.     

Two prognostic groups of inflammatory breast cancer have distinct genotypes.

PURPOSE: The prognosis of inflammatory breast cancer (IBC) remains poor despite the use of multimodality treatments, with a 10-year survival rate of not >30%. Clinicopathological and biological predictors of outcome are inadequate in this setting. Analysis of loss of heterozygosity (LOH) can provide a molecular portrait of the genetic alterations underlying stepwise cancer progression. We tested the value of LOH patterns as diagnostic and prognostic markers in IBC. EXPERIMENTAL DESIGN: In a previous study of 64 patients with IBC who were treated homogeneously between 1988 and 1999, we determined LOH frequencies at 71 loci located in 20 chromosomal regions associated with primary breast cancer. Six of these regions bore alterations that were less frequent in non-IBC. In the present study, we sought correlations between these molecular data and the clinicopathological features and clinical outcome of the same 64 patients. RESULTS: With the exception of stage IV disease, extensive breast inflammation at first clinical examination was the main factor associated with poor outcome (P = 0.00065 versus localized inflammation). The overall frequency of LOH was also higher in this group (P = 0.000073). LOH patterns differed between patients with localized and extensive breast inflammation. CONCLUSION: Patients with IBC can be separated into two major prognostic groups on the basis of initial clinical signs, which appear to be subtended by different molecular alterations.     

Biology and management of inflammatory breast cancer

Inflammatory breast cancer is an aggressive subtype of a locally advanced breast cancer that is thought to account for approximately 1–5% of all newly diagnosed breast cancers diagnosed in the USA. Historically, IBC was considered to be a uniformly fatal disease with less than 5% of patients surviving past 5 years. With the advent of a multidisciplinary approach to management, survival outcomes have improved with 5-year survival rates of over 40% being reported. Research efforts are now focused on trying to better understand the epidemiological and molecular characteristics of this disease to further improve survival. Two genes, Rhoc GTPase and WISP3, have been identified that have been found to be concordantly altered in the majority of inflammatory breast cancer tumors and may serve as potential targets for future therapeutic agents. The purpose of this review is to summarize the latest epidemiological and molecular characteristics of IBC, describe the difficulties encountered in trying to clinically diagnose this entity, highlight the importance of a multidisciplinary approach and present some of the latest data on the management of this disease.     

Inflammatory Breast Cancer: Novel Preoperative Therapies

The treatment of inflammatory breast cancer (IBC) has been hampered by the diagnostic rarity of the disease and its consequent inclusion in clinical trials of preoperative treatment for the more indolent locally advanced breast cancer (LABC). Patients with IBC have a 2-fold greater probability of dying of their disease compared with patients diagnosed with LABC. The aggressive clinical portrait of IBC supports the recent investigative focus on determining molecular changes specific to IBC and developing novel systemic therapies that will favorably affect its poor disease prognosis. A significant amount of laboratory research has been involved in defining a specific "inflammatory signature" for IBC, denoting molecular changes consistently found in IBC. This work has involved human IBC tissue and cell lines and has demonstrated overexpression of several molecules governing metastatic dissemination, such as overexpression of E-cadherin concurrent with a dysfunctional mucin 1. An increased prevalence of mutant TP53, overexpression of RhoC, and vascular endothelial growth factor-A has been found to contribute to the dominant influence of angiogenesis in this disease. A greater understanding of the molecular mechanisms governing the pathophysiology of IBC has led to the development and clinical application of novel targeting agents for preoperative therapy. This study reviews the advances in molecular understanding of IBC and focuses on the efficacy of therapies that target the epidermal growth factor pathway and angiogenesis as well as early investigational therapies involving RhoC and TP53.     

Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC‐specific targeted therapies exist. In this study, we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC vs non‐IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non‐IBC cell lines. High expression was associated with poor‐prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2‐silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC.     

Circulating Cell-free miRNA Expression and its Association with Clinicopathologic Features in Inflammatory and Non- Inflammatory Breast Cancer

Recent discovery showing the presence of microRNAs (miRNAs) in the circulation sparked interest in their use as potential biomarkers. Our previous studies showed the diagnostic potential of miR-451 as a serological marker for inflammatory breast cancer (IBC), miR-337- 5p and miR-30b for non-inflammatory breast cancer (non-IBC). The aim of this study is to investigate the prognostic values of circulating miRNAs by comparing the amounts of 12 circulating miRNAs in the serum of IBC and non-IBC from Tunisian breast cancer patients, and by determinating whether correlated pairs of miRNAs could provide useful information in the diagnosis of IBC and non-IBC patients. TaqMan qPCR was performed to detect circulating expression of miRNAs in serum of 20 IBC, 20 non-IBC and 20 healthy controls. Nonparametric rank Spearman rho correlation coefficient was used to examine the prognostic value of miRNAs and to assess the correlation profile between miRNAs expression. Further, a large number of miRNAs were highly correlated (rho>0.5) in both patients groups and controls. Also, the correlations profiles were different between IBC, non-IBC and healthy controls indicating important changes in molecular pathways in cancer cells. Our results showed that miR-335 was significantly overexpressed in premenopausal non-IBC patients; miR-24 was significantly overexpressed in non-IBC postmenopausal patients. Patients with previous parity had higher serum of miR-342-5p levels than those without. Furthermore, patients with HER2 IBC present lower serum levels of miR-15a than patients with HER2- disease. Together, these results underline the potential of miRNAs to function as diagnostic and prognostic markers for IBC and non-IBC, with links to the menopausal state, Her2 status and parity.     

Gene expression profiling identifies molecular subtypes of inflammatory breast cancer

Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of approximately 8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form.     

Update on inflammatory breast cancer

Inflammatory breast cancer (IBC) is both the least frequent and the most severe form of epithelial breast cancer. The diagnosis is based on clinical inflammatory signs and is reinforced by pathological findings. Significant progress has been made in the management of IBC in the past 20 years. Yet survival among IBC patients is still only one-half that among patients with non-IBC. Identification of the molecular determinants of IBC would probably lead to more specific treatments and to improved survival. In the present article we review recent advances in the molecular pathogenesis of IBC. A more comprehensive view will probably be obtained by pan-genomic analysis of human IBC samples, and by functional in vitro and in vivo assays. These approaches may offer better patient outcome in the near future.     

Update on inflammatory breast cancer

Inflammatory breast cancer (IBC) is both the least frequent and the most severe form of epithelial breast cancer. The diagnosis is based on clinical inflammatory signs and is reinforced by pathological findings. Significant progress has been made in the management of IBC in the past 20 years. Yet survival among IBC patients is still only one-half that among patients with non-IBC. Identification of the molecular determinants of IBC would probably lead to more specific treatments and to improved survival. In the present article we review recent advances in the molecular pathogenesis of IBC. A more comprehensive view will probably be obtained by pan-genomic analysis of human IBC samples, and by functional in vitro and in vivo assays. These approaches may offer better patient outcome in the near future.     

Inflammatory and non-inflammatory breast cancer survival by socioeconomic position in the Surveillance, Epidemiology, and End Results database, 1990–2008

Although it has been previously reported that patients with inflammatory breast cancer (IBC) experience worse survival than patients with other breast cancer (BC) types, the socioeconomic and ethnic factors leading to this survival difference are not fully understood. The association between county-level percent of persons below the poverty level and BC-specific (BCS) survival for cases diagnosed from 1990 to 2008 in the Surveillance, Epidemiology, and End Results (SEER) database linked to census derived county attributes was examined. A sub-analysis of cases from 2000 to 2008 also examined BCS survival by an index combining percent below poverty and less than high school graduates as well as metropolitan versus non-metropolitan county of residence. The Kaplan-Meier estimator was used to construct survival curves by stage, inflammatory status, and county-level socioeconomic position (SEP). Stage and inflammatory status stratified proportional hazards models, adjusted for age, race/ethnicity, tumor and treatment characteristics were used to determine the hazard of BCS death by county-level SEP. Kaplan-Meier survival curves indicated IBC has worse survival than stage matched non-IBC, (stage III IBC median survival = 4.75 years vs. non-IBC = 13.4 years, p < 0.0001). Residing in a lower SEP, non-metro county significantly worsens BCS survival for non-IBC in multivariate proportional hazards models. African American cases appear to have worse survival than non-Hispanic Whites regardless of inflammatory status, stage, county-level SEP, tumor, or treatment characteristics. This is the first study to examine IBC survival by SEP in a nation-wide population-based tumor registry. As this analysis found generally poorer survival for IBC, regardless of SEP or race/ethnicity, it is important that interventions that help educate women on IBC symptoms target women in various SEP and race/ethnicity groups.     

An update on inflammatory breast cancer

Inflammatory breast cancer is one of the most aggressive forms of breast cancer. Once considered to be a uniformly fatal disease, treatment of this entity has evolved significantly over the last two decades. In this article, we review the epidemiology, pathology, biologic underpinnings, radiologic advances, and treatment modalities for inflammatory breast cancer. Updates in surgical therapy, medical oncologic therapy and radiation therapy are reviewed. Emphasis is on cutting edge information regarding inflammatory breast cancer. The management of inflammatory breast cancer is best served by a multidisciplinary team. Continued research into molecular pathways and potential targets is imperative. Future clinical trials should include evaluation of conventional therapy with targeted therapies.     

Inflammatory breast cancer: A decade of experience

Inflammatory breast cancer (IBC) is an aggressive and rare form of breast cancer. At present, there are no established diagnostic, radiological, pathological or molecular diagnostic criteria for this entity. The aim of this study was to examine the patterns of presentation, treatment and outcomes of IBC in this institution over the course of a decade. This is a retrospective observational study using data from the Royal Perth Hospital from January 2001 to December 2010. Our results identified 57 women with IBC, representing 1.9% of all new breast cancer presentations. Human Epidermal Growth Factor Receptor 2 (HER2)‐positive and triple negative tumors were overrepresented (41% and 18%, respectively). Forty‐four (77%) patients had early disease at diagnosis, of whom 35 underwent surgery and 16 are relapse‐free. All six patients achieving complete pathological response were relapse‐free in contrast to 11 (38%) with lesser responses at a median follow‐up of 59 months. Median survival in 13 patients with metastatic disease at diagnosis was 21.7 months, with two patients still in remission. Clearly, this small but important group continues to offer management challenges and warrants ongoing study, including better molecular and pathological profiling of tumors to allow improved diagnostic clarity and more effective targeted therapy.     

miRNA expression profiling of inflammatory breast cancer identifies a 5‐miRNA signature predictive of breast tumor aggressiveness

IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT‐PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non‐stage‐matched non‐IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non‐IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non‐IBC. Among these, a 5‐miRNA signature comprising miR‐421, miR‐486, miR‐503, miR‐720 and miR‐1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis‐Free Survival in non‐IBC patients.     

WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer

Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s), the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.