Have We Made Progress in Inflammatory Breast Cancer? Not So Fast

Breast cancer has long been described as a very heterogeneous disease, and clinicians have struggled with identifying the appropriate treatment program for an individual patient on the basis of multiple variables, including histology, nuclear grade, tumor size, nodal status, hormone receptor status, and a variety of prognostic factors. One clinical subtype that has distinguished itself from all other types is inflammatory breast cancer (IBC). IBC is known to have an aggressive clinical course with poor survival rates. Despite the recognition that IBC is a distinct clinical entity, there remains significant debate regarding the appropriate treatment program for patients who present with this disease. In this issue of ONCOLOGY, Dawood and Cristofanilli review the advances in inflammatory breast cancer that have been made over the past few decades with respect to epidemiology, multidisciplinary treatment, and molecular underpinnings; the authors conclude by questioning whether we have made progress. As we review the developments, it seems that the most accurate response is that our approach to IBC is, in fact, a work in progress.

It is estimated that between 1% and 5% of all newly diagnosed breast cancers each year present as IBC; because of its rarity, it is listed with the Office of Rare Diseases at the National Institutes of Health.[1] While the number of cases of IBC is relatively small compared with the overall number of breast cancers, it is still a substantial number compared with many other rare tumor types. The clinical signs and symptoms associated with IBC may be subjective in nature, but an enlarged and edematous breast with diffuse erythema of the skin should bring up IBC in the differential diagnosis in every clinical situation in which these findings are seen. Other clinical features seen in women with IBC are younger age at diagnosis, African American race, and higher body mass index. Given that for the majority of patients with IBC the prognosis is poor with standard therapy, all patients with the disease should be encouraged to participate in a clinical trial. We cannot use the small number of cases as an excuse for the lack of clinical trials; rather, we should view it as a mandate for making novel treatment strategies available to all patients with this diagnosis.

If an accurate description of the clinical picture of IBC is difficult, the pathologic diagnosis is even more challenging. The classic description has been the presence of dermal lymphatic invasion on skin biopsy; however, this finding is not a requirement for the diagnosis and may be absent in cases with a classic clinical presentation. If a skin biopsy is negative for breast cancer cells within the dermal lymphatics, the clinician should pursue imaging studies such as MRI or ultrasonography that may reveal parenchymal abnormalities that could be the target for an image-guided biopsy that would establish the diagnosis. Much like with sporadic non-IBC tumors, the underlying cause of IBC remains elusive. Reports of a high incidence (71%) of retroviral sequences with homology to the mouse mammary tumor virus in IBC are intruiging; however, the same sequences have also been identified in up to 40% of non-IBC tumors.[2] Making the connection between cause and effect on the basis of animal models, or equating this finding with tumor aggressiveness, seems premature.

Investigations into molecular markers of IBC have revealed changes in many of the same genes altered in non-IBC tumors. Although they are not specific to IBC, some of the pathways that have been more consistently identified in molecular studies include the epidermal growth factor receptor family, angiogenesis, and inflammation and immunity. While molecular studies provide potential pathways that can be targeted in the treatment of IBC, it does not appear that there is any distinct pattern to the molecular characterization of IBC that can be identified on the basis of these studies. Taking a more global view, several groups have used gene expression profiling of IBC and compared the results directly with results in non-IBC tumors. These studies are characterized by very small sample sizes and differences with respect to timing of tumor sampling, with some samples having been obtained prechemotherapy and others after chemotherapy. Nonetheless, one consistent finding is that IBC can be classified into five molecular subtypes, similar to those seen in non-IBC tumors. This suggests that gene expression profiling could be an important prognostic tool in the management of patients with IBC. Further investigations into stromal and epithelial elements of IBC tumors may provide additional clues to the molecular and cellular differences in this type of breast cancer that result is such dramatic differences in clinical presentation and outcomes.

A clear and positive move forward in the field is the recognition that IBC requires multidisciplinary treatment and early initiation of systemic therapy. Standard breast imaging typically fails to show abnormalities beyond the edematous changes in the breast that are already evident to the clinician; however, ultrasound and MRI imaging can identify nodal metastases and parenchymal changes that help to define the extent of local-regional disease. IBC may be one of the best settings for the routine use of PET/CT imaging at diagnosis; one group found that up to 50% of patients had metastatic disease at initial presentation and that a substantial proportion of those metastases were not identified with other imaging studies.[3] The high rate of distant metastatic disease supports the concept that systemic therapy should be the initial treatment for patients with IBC. The routine use of anthracyclines and taxanes has resulted in improved survival in IBC as in non-IBC tumors, and pathologic complete response (pCR) to systemic therapy has the same prognostic significance. Although there may be dramatic clinical responses to preoperative chemotherapy, recurrent disease still develops in many patients, and there are currently no data to support a less aggressive approach with respect to surgical or radiation treatment strategies. Consensus guidelines have been developed to establish standards for the diagnosis and treatment of IBC;[4] however, as with non-IBC tumors, the optimal systemic therapy regimen depends on the expression of hormone receptors and HER2, and there is still limited information on the efficacy of strategies targeting angiogenesis and inflammation/immunity.

There have been major advances in the breast cancer field over the past few decades, and survival rates continue to improve. The outcomes of patients with IBC have also improved during this time. A large part of this success can be attributed to the remarkable developments in our understanding of the biology of breast cancer in general. There are many parallels between IBC and non-IBC tumors with respect to molecular subtypes and druggable targets. Advances in molecular diagnostics and prognostics in breast cancer should be utilized to the fullest in IBC to help determine which patients will benefit from a specific systemic therapy regimen. However, the reasons for the dramatic differences in clinical presentation and the propensity for early metastatic disease in IBC remain elusive. Herein lies the paradox. As the search for molecular-level differences between IBC and non-IBC tumors continues, we seem to find more similarities. There has been substantial progress but the work remains incomplete.

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.

References:

References:

1. Inflammatory breast cancer. Office of Rare Diseases Research. National Institutes of Health. Available at http://www.rarediseases.info.nih.gov.

2. Pogo B G-T, Holland JF, Levine PH. Human mammary tumor virus in inflammatory breast cancer. Cancer. 2010;116(11 suppl):2741-4.

3. Carkaci S, Macapinlac HA, et al. Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: preliminary data. J Nucl Med. 2009 Feb;50:231-8.

4. Dawood S, Merajver SD, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol. 2010 Aug 9. [Epub ahead of print]