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Molecular Determinants of the Inflammatory Breast Cancer Phenotype

Molecular Determinants of the Inflammatory Breast Cancer Phenotype

Despite advances in multimodality treatment, inflammatory breast cancer (IBC) remains the most aggressive and lethal form of breast cancer. The use of primary human IBC cell lines and functional in vivo xenograft cancer models have revealed characteristics innate to IBC thought to confer a strong metastatic potential and aggressive phenotype. Classic descriptive markers in IBC (eg, estrogen and progesterone receptor status) often guide optimal therapy and aid in development of new diagnostic and prognostic technologies. Recent IBC research has examined two genes, RhoC GTPase and WISP3, which are concordantly altered in the majority of IBC tumors but not in non-IBC specimens. RhoC serves as a transforming oncogene by regulation of genes involved in the cell cycle, secretion of angiogenic factors, and activity of insulin-like growth factor (IGF). WISP3 functions as a tumor-suppressor gene by modulation of IGF activity and resultant inhibition of cell proliferation, growth, and angiogenesis. Continued research with molecular analysis technology is imperative in order to harness differential gene expression and fully discover a signature profile of IBC. The ultimate goal is to reveal the specific molecular determinants that underlie its aggressive phenotype so that we may accurately identify markers of disease, improve diagnostic tools and predictors of response to treatment, and even suggest targeted IBC-specific therapies that afford improved survival.

Since its early descriptions by Lee and Tannenbaum in 1924, inflammatory breast cancer (IBC) has been recognized as the most aggressive and lethal form of primary breast cancer. With distinct clinical, pathologic, biologic, and molecular features, IBC presents unique challenges and opportunities to breast oncologists and breast cancer researchers.

Definition and Epidemiology

IBC is rare in the United States and Western Europe, accounting for only 2.0% of all breast malignancies with an overall incidence of 2.5 per 100,000 woman-years.[1] IBC is characterized clinically by the rapid development of an enlarged breast that is edematous, reddened, warm, and often tender with thickened and brawny overlying skin that resembles an orange skin (“peau d’orange”). A mass is present in approximately one-third to one-half of cases on clinical or radiologic examination, and mammography is nearly always abnormal, with the most common findings being skin and trabecular thickening as well as axillary lymphadenopathy.

The pathologic hallmark of IBC on biopsy is invasion of the dermal lymphatic vessels by tumor emboli that impede the flow of lymph fluid, causing the clinical presentation to mimic classic inflammation. In fact, it is this embolic invasion, and not an inflammatory infiltrate, that leads to the erythema, edema, and induration seen in this syndrome and resulted in the misnomer “inflammatory” breast cancer. Other histologic features include extensive cellular pleomorphism, high histologic grade, a high intratumoral microvessel density, and highly atypical mitotic figures.[2-3]

Biologic Features
Three biologic features make IBC a unique form of locally advanced breast cancer (LABC). First, the tumor is rapidly progressive; in fact, the rate of progression is so rapid as to be easily misdiagnosed as acute infection. This symptom is often used to differentiate primary IBC from recurrent or untreated LABC with inflammatory signs. Second, the tumor is highly angiogenic and angioinvasive. And finally, the aggressive nature and angiogenicity are intrinsic to the tumor and are present from its inception rather than as late events during progression. This was elegantly demonstrated after immunocompromised mice were transplanted with a human IBC xenograft called MARY-X. Whereas implantation of noninflammatory human tumors into the mammary fat pads of nude mice led to the development of isolated subcutaneous nodules, implantation of MARY X resulted in exclusive growth of IBC within lymphatics and blood vessels with marked overlying skin erythema.[4]

These three traits seen in IBC are believed to confer an extremely high potential for metastasis. According to staging guidelines published by the American Joint Committee on Cancer, IBC is considered a T4d tumor. Thus, all patients with IBC are classified at diagnosis as being stage IIIb, IIIc, or IV, depending on nodal status and the presence of metastases.[5] The majority of patients have clinically overt axillary lymph node involvement, and up to 36% have distant metastases at the time of diagnosis.[6]

Despite recent advances in multimodality treatment (particularly the addition of anthracycline-based combined chemotherapy), the prognosis of IBC remains relatively poorer than for non-inflammatory breast cancer (non-IBC), with a median survival of 2.9 years compared to those with non-T4 breast cancer (> 10 years) and LABC (6.4 years).[1] The still discouraging survival associated with IBC is presumably related to its rapid progression and strong metastatic potential, as the prognosis was almost uniformly fatal prior to the advent and use of multimodality systemic chemotherapy.

Racial/Geographic Disparities
An intriguing aspect of IBC epidemiology is the disparity between black and white women with regard to age at diagnosis, incidence, and survival. Hance and colleagues examined these phenomena by evaluating Surveillance, Epidemiology, and End Results (SEER) program data between 1988 and 2000 with respect to IBC.[1] Black women were noted to have a higher age-adjusted incidence rate of IBC compared to white women (3.1 vs 2.2 cases per 100,000 woman-years), and if tumors were estrogen receptor (ER)-negative, a statistically significant younger age at diagnosis (Kolmogorov-Smirnov value [KS] = 0.15, P = .01).

Perhaps the most concerning epidemiologic issue is the stark contrast in survival between the races. Median survival in black women compared to white women was worse for both IBC (2.0 vs 3.0 years) and LABC (3.1 vs 7.5 years). African-American race has been shown to be an independent predictor of elevated risk for breast cancer mortality, advanced stage at diagnosis, and tumor aggressiveness.[7-11] This last quality is evidenced by a higher histologic grade in tumor specimens and higher rates of locoregional recurrence despite equivalent response rates to local and systemic therapy. These data suggest a biologic difference between IBC tumors in blacks and whites, and perhaps with further study, these differences can be elucidated and utilized for improved prognostic and therapeutic outcomes.

More recently, Lo and colleagues uncovered important differences in the molecular and histologic characteristics of IBC between Egyptian and US patients, indicating that the North African patients tended to have many more emboli and higher expression of the RhoC oncogene.[12] These features suggest a more aggressive form of the disease, which presents in a qualitatively identical manner throughout the populations studied so far. It would be of great interest and importance to uncover the risk factors and/or environmental variables that may foster this more aggressive subtype, even within a very aggressive cancer such as IBC. It is important to note that these tumors in North Africa are not neglected stage III indolent tumors. The latter may show tumor invasion into dermal lymphatics but they seldom show the profusion of dermal lymphatic emboli that characterizes the main tumor burden in IBC (see Figures 1 and 2).

In summary, IBC presents with a unique clinical syndrome brought about by well defined histologic features that are rare in other subtypes of breast cancer. As we will summarize below, the puzzle that is IBC has begun to be assembled from the perspective of its molecular determinants.

Molecular Genetics of IBC and Animal Models

In recent years, the primary endeavor of IBC research has been the elucidation of the molecular and genetic alterations (so-called genetic determinants) that underlie its aggressive phenotype and differentiate it from non-IBC. This has been accomplished through a body of work that was spearheaded by the development of two IBC cell lines, SUM149 and SUM190, derived from primary human IBC tumors.[13] With these cell lines, functional in vivo xenograft cancer models have been created. These are implanted into the mammary fat pads of immunocompromised mice.[4,14] The SUM149 xenografts form primary tumors that often metastasize to the lungs through lymph and blood vessels.

Molecular analysis technology—including comparative genomic hybridization, gene-expression profiling, cDNA and tissue microarrays, and differential display technology—has been harnessed to compare the genetic distinctions among different forms of breast cancer in order to define a signature profile of IBC. The ultimate goal of this research is to utilize an integrated profiling approach to gene-expression differences and thereby accurately identify markers of disease, improve diagnostic tools and predictors of response to treatment, and even suggest targeted IBC-specific therapies that afford improved survival.

Classic Descriptive Markers in IBC

Initial research on the molecular biology of IBC was done by evaluating biologic markers known or thought to have prognostic significance in non-IBC such as the status of hormone receptors, epidermal growth factor receptor (EGFR), and the p53 tumor-suppressor gene. While these molecular markers may serve as general prognostic tools, they are not specific to IBC and therefore cannot be employed for diagnostic purposes. It is useful, however, to briefly review their status in IBC.


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