Inflammatory breast cancer (IBC) is a rare and aggressive form of the disease. It is diagnosed based on clinical signs of a rapidly enlarging, tender, erythematous, edematous breast that often presents without an underlying breast mass. IBC historically was considered a uniformly fatal disease. With the advent of multimodality treatments including primary systemic chemotherapy, surgery, and radiation therapy, approximately one-third of women diagnosed with IBC will become long-term survivors. This review examines the limitations of the current definition of IBC, explores our current understanding of the biology of IBC, and reviews the many exciting advances in locoregional and systemic treatment of IBC.
Inflammatory breast cancer (IBC), as described by Drs. Dawood and Cristofanilli, remains a very important but somewhat elusive clinical entity, despite its recognition as early as 1924. Although this excellent review of the subject encompasses most of the defined parameters of the disease, the clarity of our knowledge about its definition and treatment may be somewhat overstated.
For decades, IBC was felt to be a type of locally advanced breast cancer (LABC). This is largely because some of the components of the two clinical entities are similar, including their poor survival and the presence of dermal involvement. Only recently, however, have attempts been made to distinguish LABC and IBC, primarily by differences in survival. Survival differences and even differences in the age of presentation, while suggestive of different entities, are hardly a definitive basis for distinguishing two overlapping syndromes.
To add to the lack of clarity, while hyperemic skin changes are always present in IBC, the so-called patho-gnomonic finding of peau d'orange, which represents the development of skin edema, is not. Additionally, LABCs will often have peau d'orange as part of their presentation, and it remains unclear whether IBC and some LABCs with an aggressive phenotype may be variants of the same process. To further confuse the issue, breast cancer that presents en cuirasse-another entity caused by diffuse intradermal lymphatic invasion-does not often induce the skin edema so often associated with IBC. It is therefore unclear which of the main characteristics of IBC should define it as a unique clinical entity.
This confusion about IBC is evident in the varied criteria now considered acceptable for its classification. While the primary pathologic finding remains the demonstration of intradermal lymphatic tumor emboli, this is not necessary for diagnosis. IBC can be diagnosed strictly on a clinical basis, but making a diagnosis solely upon a single clinical finding can be problematic. First, no clinician need be reminded that a multitude of varied pathologic aberrations may underlie a single clinical sign, and skin edema may be no exception. Second, despite this wide latitude in how the diagnosis can be made, no study to date has ever determined why some flagrant cases of IBC with significant peau d'orange do not demonstrate dermal lymphatic invasion upon biopsy. In fact, it is not even clear what inflammatory components create this specific clinical finding, which has been recognized for over 80 years. It must therefore be admitted that the science behind even the two most fundamental findings in IBC remains a mystery.
These knowledge gaps in the scientific basis of IBC behavior are further underscored by the significant difficulties still encountered with local control-an issue that is not discussed in this review. Mastectomy alone offers poor local control, and results in a local recurrence rate of approximately 50%, despite a short mean survival time of usually less then 2 years.[2,3] Repeated demonstrations that surgery alone was inadequate treatment resulted in the use of radiotherapy as the primary treatment modality until the 1970s. Multimodality therapy has now improved both local control and survival, but outcomes remain disappointing.
In one series from M.D. Anderson Cancer Center, preoperative chemotherapy enabled 95% of patients to undergo surgery, but locoregional failure still occurred in 20% of patients. It is clear that multimodal therapy has enabled more frequent use of surgery for IBC over the past 2 decades. One analysis of 485 patients treated between 1980 and 2000 demonstrated an increase in the use of mastectomy after chemotherapy from 10.9% to 69% between the years of 1980-1985 and 1996-2000, while primary surgery dropped from 21.7% to 9.9%, and the proportion of patients having no surgery at all dropped from 67.4% to 21.8%. Poor local control after multimodality therapy is a hallmark of locally advanced and en cuirasse lesions as well, once again demonstrating that IBC clinical characteristics appear too broad to be useful.
The current standard of care for IBC, well described in this review, is preoperative chemotherapy followed by surgery and radiotherapy, moving the radiotherapy prior to surgery if complete resolution of the inflammatory skin changes does not occur with chemotherapy. This regimen works well for some, but a therapeutic roadblock is encountered if preoperative treatment is unsuccessful, as surgery in those cases does not assist in either local control or survival.
Although it sounds promising to state that "71% of all IBC patients [have] an objective response" to certain types of chemotherapy, 80% of all breast cancers combined demonstrate some response to chemotherapy; therefore, this is hardly a reason for optimism about current regimens, as IBC survival remains dismal. Drs. Dawood and Cristofanilli, however, very appropriately mention the ongoing attempts to clarify the genetic aberrations in IBC, and we would submit that it is only through these investigations that IBC can be better defined, in order to appropriately tailor treatment.
While this review does an excellent job of summarizing a conglomeration of data on this topic, it must be emphasized that IBC clearly represents an entity that remains poorly characterized by the oncology community. The current clinical classification method used to distinguish IBC from other syndromes such as LABC and breast cancer en cuirasse is clearly inadequate because of the phenotypic overlap between these entities. The limited progress in the past 80-plus years obtained using clinical criteria to conquer IBC indicate that a change in strategy is required. It cannot be overemphasized that genetic characterization appears to be the only likely means of achieving specificity in both how to define IBC, as well as how best to treat it.
-Richard J. Bleicher, MD
-Monica Morrow, MD
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.
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