Further Perspectives on Inflammatory Breast Cancer
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.
Drs. Dawood and Cristofanilli present a concise and useful summary of the diagnosis and treatment of inflammatory breast cancer (IBC), as well as a few snippets of the relevant biology. IBC is the type of disease that inspired most of us to be physicians. It is severe, rapidly progressive, and lethal within weeks to months if left untreated-a great mystery among breast cancers and unusually aggressive, even if we consider all solid, nonhematologic tumors. The authors emphasize major pearls about diagnosis, treatment, and pathobiology of IBC. Below, I elaborate and comment on a few aspects of each of these issues that I think complement this excellent article.
The major point I would like to convey in this editorial is that, after making IBC a major focus of my research in the lab as well as the clinic for the past 13 years, I am convinced that the task of conquering IBC requires a unified multidisciplinary and muti-institutional effort: a true paradigm for team translational research.
Difficult Diagnosis
Rapid diagnosis of IBC is paramount in order to institute urgent neoadjuvant chemotherapy and try to avert progression and death. The problem, of course, is that as a very rare form of breast cancer in the United States and western Europe, IBC often goes undiagnosed by being confused with much more common infectious or noninfectious inflammatory conditions that give rise to a warm, red breast with occasional peau d'orange. I believe enhanced physician and public education and promotion of algorithms that specify antibiotic treatment for 7 to 10 days, with prompt follow-up for these kinds of breast symptoms and immediate core biopsy (not fine-needle aspiration) if symptoms persist, is critical.
In areas of high incidence, such as north Africa (notably Egypt and possibly Tunisia), educational interventions are in place at major centers, and more are being developed for more widespread use in populations with less access to health care and lower socioeconomic status. This is an area of great importance in IBC research and clinical care that would benefit from input by experts in health behavior and health communication.
Epidemiology-Biology Link
The epidemiology of IBC is tied to its biology and may hold important clues as to its etiology. The variability in incidence between the US and Egypt, for example, is striking. Understanding what factors predispose to IBC in Egypt and North Africa will tell us a lot about the biology of IBC and possibly about ways to control the environment or lifestyle to effect primary prevention. Several collaborative studies have been conducted in Egypt and Tunisia, and some are in the planning stages. So far, the studies continue to demonstrate higher incidence, but they are quite small in numbers of cases due to being woefully underfunded.
It is a major challenge for those of us designing these studies to figure out which funding mechanisms would be receptive to molecular genetic and epidemiologic studies comparing IBC in the United States to the disease in remote areas of the world, since it is not always perceived as relevant to public health in the US. Researchers, clinicians, and leaders of key institutions in North Africa and the Middle East have generally been very receptive and supportive of these collaborative efforts with researchers in the US and Europe. Given that we are dealing with an identical clinical disease in these two locations, it is extremely relevant to study IBC at international sites.
Because of the logistic barriers to such studies, if they are undertaken, sufficient funds should be harnessed to ensure that they are comprehensive and gather data on environmental chemical and biologic exposures, reproductive habits, diet, as well as tissues at diagnosis and following neoadjuvant chemotherapy.
Therapeutic Promise
The authors provide an excellent summary of the work on IBC, emphasizing especially the work at M.D. Anderson. The advent of new molecular therapies holds even greater promise than chemotherapy alone for improving survival. I am optimistic about this outlook in general, although I remain a bit more skeptical than the authors about the two major molecular therapies tested on IBC so far-trastuzumab (Herceptin) and lapatinib (Tykerb).
One must remember that the immediate response rate to multimodality cytotoxic therapy is excellent in IBC. The real test of efficacy in the clinic for new therapies should be in prolongation of time to recurrence and overall survival. In the meantime, we anticipate evaluating molecular markers that may be appropriate predictive markers. For example, understanding the role of early progenitors in the growth and repopulation of IBC lesions following good responses to primary therapy may help us design better trials.
Next Steps
Our next goal should be to use IBC as the ultimate paradigm for tailoring therapy in breast cancer, since in IBC more than in any other type of breast cancer, delivering the first-line therapy most likely to prevent a recurrence is crucial. Although no one can know this for sure yet, we all strongly suspect that patients with recurrent IBC are not the ones contributing to the increase in survival for breast cancer. Non-IBC patients with metastatic disease appear to be living longer and with higher quality of life, thanks to trastuzumab, newer hormonal therapies, higher-density chemotherapies, and rational combinations. With IBC, the gains are much more modest but the future looks bright.
The biology of IBC is dominated by cells that move very impressive distances in hours and invade in loosely assembled emboli that do not downregulate E-cadherin. When we disovered that RhoC GTPase appears to be a major driver for the IBC phenotype, we were indeed shocked to see that overactivation of RhoC alone was enough to transform immortalized mammary epithelial cells, without significantly affecting proliferation. RhoC is a transforming oncogene that can mediate the epithelial mesenchymal transition in breast cells, primarily through its effects on motility and invasion into the lymphatics it likely helps form. The development and testing of therapies against RhoC and related pathways may be the next major exciting step in our fight against IBC.
-Sofia D. Merajver, MD, PHD
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
