Drs. Dawood and Cristofanilli provide a concise review of inflammatory breast cancer (IBC) and succinctly cover its most salient features, including its clinicopathologic characteristics, its key molecular features, and an overview of treatment outcomes. What is clear from the data presented by the authors is that we have a reasonably good understanding of which populations may be at increased risk for the development of IBC and how this disease behaves in affected persons. On the other hand, what is not clear is what exactly causes IBC to be different from non-inflammatory, locally advanced breast cancers (LABC) and which diagnostic criteria should be strictly upheld worldwide to ensure uniform diagnosis of primary IBC.
With regard to diagnostic criteria, the authors reiterate that IBC is diagnosed clinically, based on the classic hallmarks of erythema and edema of the breast (involving at least 1/3 of the breast), in the presence of supporting pathologic confirmation of an invasive breast cancer. Also included in the definition of IBC in the National Comprehensive Cancer Network (NCCN) guidelines [1] is the presence of a palpable border to the erythema, resulting from dermal lymphatic obstruction. However, while a skin biopsy revealing dermal tumor emboli is pathognomonic for IBC, it is neither required nor sufficient by itself to make a diagnosis of IBC.[2] What is perhaps less emphasized to clinicians is the additional need to document the clinical context in which the signs/symptoms of IBC appear. Unlike with the secondary inflammation associated with neglected LABC—or that which can occur after mastectomy as a result of chest wall recurrence—in primary IBC, the onset of breast enlargement and of inflammatory changes in the skin overlying the breast are typically rapid, occurring within weeks to a few months. While an attempt to strictly define the diagnostic criteria for primary IBC may seem academic, in actual fact, the lack of uniform and precisely upheld criteria for the diagnosis of IBC contributes to the difficulty in studying this relatively rare disease. To assist with the standardization of diagnosis and treatment, a joint consensus statement on IBC was issued by an international panel of experts (which included Drs. Dawood and Cristofanilli) after the meeting of the First International Conference on Inflammatory Breast Cancer.[3]
Potential challenges in the capture of precise data on IBC for research purposes can also arise because of recent changes in the coding requirements of tumor registries. As implemented in 2007 in all state cancer registries and Surveillance, Epidemiology, and End Results (SEER) registries, use of the International Classification of Oncology (ICD-O) histology code for IBC requires that a diagnosis of IBC be specified on pathology reports. However, because the diagnosis of IBC is primarily made on clinical grounds, it was demonstrated that this requirement would only enable the capture of a fraction of known cases of IBC; for example, of the known cases of IBC in a reference sample in the University of Texas M.D. Anderson Cancer Center tumor registry (which collects both clinical and pathologic diagnoses), only 30% would be identified as IBC using the ICD-O code. Thus, searching tumor registries by histology code may be misleading and may fail to accurately identify all cases of IBC unless Collaborative Staging Extension codes or the American Joint Committee on Cancer(AJCC)/TNM classification T4d (designated for IBC) is also incorporated.[4]
Until recently, most of what was known about differences between IBC and non-IBC stemmed from clinical observation. Dawood and Cristofanilli provide a synopsis of the clinical and epidemiologic factors that distinguish these two forms of breast cancer, including geographic and racial distributions, age at diagnosis, and prognosis. They also point out that from a clinical perspective, IBC is more likely than non-IBC to be hormone receptor–negative and to show amplification of HER2. However, due to the development of different molecular platforms for examining gene and protein expression, it has recently become possible to try to distinguish IBC from non-IBC on a molecular level. The authors provide an overview of various molecular profiling studies that have been done to better elucidate the underlying biology of IBC. These studies suggest that, similar to non-IBC, IBC is also a heterogeneous disease that can be divided into different molecular subtypes. Nevertheless, as the authors illustrate, there do appear to be molecular targets that may be more specific to IBC and that are attractive as rationale candidates for the development of more selective therapeutics. These targets include chemokine receptors and lymphangiogenic factors, which may interact to control invasion and metastasis.[5] Other signal-transduction pathways implicated in the characteristic growth patterns of IBC include those related to the Ras superfamily of small GTPases (RhoA and RhoC),[6], E-cadherin,[7] and nuclear transcription factors, such as NFκB.[8] Also intriguing is the report that IBC may be better distinguished from non-IBC on the basis of molecular signatures derived from tumor stroma—as opposed to signatures derived from tumor epithelial cells. This suggests that ultimately it may be the tumor microenvironment that underlies the characteristic phenotype of IBC and that regulates its growth potential.
Despite the observed molecular differences between IBC and non-inflammatory LABC, from a clinical standpoint, there are as yet few treatments specific to the care of patients with IBC, aside perhaps from local modalities. With regard to local therapies, as the authors indicate, mastectomy and axillary lymph node dissection are considered standard treatment for patients with non-metastatic IBC, since safety data for breast preservation and sentinel lymph node biopsy are lacking in this population. The authors also provide data to suggest a benefit from hyperfractionated radiation for a subpopulation of patients with IBC. With regard to systemic treatments, however, the development of new therapeutics selective for IBC has been slow, and up until now, systemic treatments for this disease have largely been based on advances made in the treatment of non-IBC. Certainly the use of preoperative chemotherapy with anthracyclines and taxanes has extended survival for patients with non-metastatic IBC.[9] In addition, the incorporation of HER2-targeted therapies has shown substantial benefit for those patients with HER2-positive IBC.[10] Since IBC is a relatively rare disease, future advancements in treatment outcomes will continue to rely on international efforts to more expeditiously bring preclinical science into clinical application.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
