non-IBC Patients Research Articles

Abstract 5744: An exploratory study of inflammatory breast cancer in Tanzania

Abstract Objectives: Inflammatory Breast Cancer (IBC) is a rapidly developing and very lethal form of breast cancer. IBC is relatively rare in the US, accounting for only 1-2% of all breast cancer cases. It is associated with a much lower 3-year survival rate as well as a younger mean age of onset than non-IBC, with higher incidence and younger mean age in African American women than Whites. Though little research has been conducted on IBC internationally, a few studies have reported a higher frequency and a more aggressive form of the disease in Egypt, Tunisia, and Morocco. No information is available about breast cancer or IBC in native Sub-Saharan African populations. The purpose of this study was to describe the clinical and reproductive factors of breast cancer and to determine the proportion of IBC in Tanzania. The study also aimed at investigating pathological and molecular features of breast tumors, such as the presence of dermal lymphatics and overexpression of RhoC and E-Cadherin. Methods: Data was abstracted from the medical records of all breast cancer patients attending Ocean Road Cancer Institute (ORCI) in Dar Es Salaam, Tanzania for a 2-year period from July 2007 to June 2009. Tumor tissue samples were collected for those patients with symptoms suggestive of IBC as well as for non-IBC patients. Slides were cut from each paraffin block and one from each set was H & E stained. Results: Preliminary results of 223 breast cancer cases show that the average age at diagnosis is lower than that in the US at approximately 48 years (std. dev≈12) and that the average duration of symptoms is greater than 1 year. The majority of the clinical TNM diagnoses fall into the T4 category, with less than 3% diagnosed as T4d (IBC) clinically at some point in the record. Greater than 50% of cases are diagnosed as ductal carcinoma of the breast. The defining symptoms of IBC, erythema, edema, and peau d'orange, account for a minority of symptoms recorded and it is even rarer for a single patient to have all three symptoms present. 71 cases were analyzed for ER/PR status of which 53% were ER negative and 59% were PR negative. 88% of those that were ER positive were also PR positive. Conclusions: The proportion of IBC in Tanzania is not high and most cases are diagnosed at advanced disease stages. ER/PR results suggest that hormonal therapy would be valuable to approximately half of breast cancer cases. The descriptive and molecular analysis conducted could provide valuable insight into IBC both internationally and in the US as there are no standard histopathological diagnostic criteria to date. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5744.

Immune Profile of Inflammatory Breast Cancer Patients.

Abstract Background: Inflammatory breast cancer (IBC) is characterized by an acute inflammation of the skin of the affected breast due to blockage of the dermal lymphatics by tumor emboli. Cytokines and chemokines affect the migration of tumor cells and immune cell function that regulates the pathogenesis of IBC. Preliminary data suggest that sera of IBC patients contain several inflammatory cytokines and chemokines capable of regulating innate and adaptive cellular immune responses. Since there is a paucity of data on the characteristics and function of immune cells of IBC patients, we determined the immunophenotype and cytokine production by T cells and dendritic cells.Methods: From October 2008 through May 2009, peripheral blood (PB) from 34 IBC patients (18 non-metastatic and 16 metastatic), 18 non-IBC patients and 24 healthy donors (HD) were analyzed to determine the immunophenotype of T-cell subsets, activated and regulatory T-cells, B-cells, natural killer cell subsets (NKC), and dendritic cell (DC) subsets. Additionally, we assessed the ability of T-cells and DCs to synthesize cytokines following activation through the T-cell receptor (TCR) and toll-like receptors (TLR), respectively. The Kruskal-Wallis and Mann-Whitney U tests determined the differences between IBC patients, non-IBC patients, and HD.Results: IBC and non-IBC patients were well-matched in terms of ER, PR, Her2, high-grade tumor, tumor size, and menopause status. Both IBC and non-IBC patients had significantly fewer lymphocytes, total T-cells (CD3+), T-helper (CD4+), T-cytotoxic/suppressor (CD8+), and B (CD19+) than HD (all p < 0.01). Non-IBC patients had a significantly lower CD4/CD8 ratio than HD (p = 0.016) while IBC patients had significantly fewer T-regulatory (CD4+CD25hiCD127-) cells than HD (p = 0.02) and non-IBC patients (p < 0.05). With respect to innate immunity markers, IBC patients also had significantly lower percentages of ADCC/NK (CD16+CD56+, p = 0.034) and non-exhaustive NK (CD56+CD57+, p = 0.02) than HD and a significantly higher percentage of non-ADCC/NK cells than non-IBC patients (p = 0.03). Non-IBC patients and HD had similar innate immunity markers. Even though all groups had similar percentages of myeloid (mDC) and plasmacytoid (pDC) dendritic cells, mDC of IBC patients displayed a higher level of constitutive activation than non-IBC with increased expression of CD40 and CD80, and decreased CCR5 expression. IBC patients had more mDC that constitutively produced TNF-a (p 0.041) and IL-10 (p = 0.029) than HD, and more mDC than non-IBC patients that produced IL-10 (p = 0.028).Conclusion: The immune profile of patients with breast cancer suggests multiple abnormalities involving T-, B-, NK- and dendritic cells. Furthermore, IBC patients exhibited constitutive immune activation as measured by increased expression of co-stimulatory receptors (CD80, CD40) and constitutive production of TNF-a and IL-10 by mDC as well as fewer T-regulatory cells. Taken together, these preliminary data suggest that IBC patients are more likely than non-IBC patients to have a dysregulated immune function. Additional studies on T-cell activation and function are warranted to better understand factors associated with host defense mechanisms of IBC patients and possible therapeutic strategies to restore immune function. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4129.

Soluble Factors and Circulating Tumor Cells in Inflammatory Breast Cancer.

Abstract Background: Inflammatory breast cancer (IBC) is an insidious form of breast cancer. Cytokines and chemokines direct the metastatic potential of disease and serve as biomarkers for disease progression. Circulating tumor cells (CTC) are an independent prognostic factor in metastatic disease. Further, TGF-β is involved in the induction of the epithelial-mesenchymal transition (EMT) which regulates the metastatic ability of IBC. As prognostic factors of aggressive disease, we measured serum cytokines and leukocyte phenotypes, and correlated the values with known CTC results of IBC and non-IBC patients.Methods: Peripheral blood (PB) from 35 IBC patients (18 non-metastatic and 17 metastatic) and 19 non-IBC patients (7 LABC, 12 MBC) was collected prior to starting a new therapy to measure a panel of 33 cytokines, chemokines, and growth factors in serum by Luminex; CTC by CellSearch™; and PB leukocyte immunophenotype by FACS. The Kruskal-Wallis and Mann-Whitney U tests determined the differences in cytokine levels between IBC, non-IBC and healthy donors (HD) and presence of CTCs.Results: There were no differences in serum cytokine, chemokine or growth factor levels between IBC and non-IBC patients. EGF, IP-10, MIG, Eotaxin, MCP-1 and TNF-RI were significantly elevated in breast cancer patients compared to HD. TNF-RI, EGF, HGF, IP-10, MIG, Eotaxin, MCP-1 and interleukin (IL)-10 were higher in IBC patients than in HD. Compared to IBC patients, non-IBC patients had fewer dysregulated cytokines relative to HD including higher EGF, Eotaxin, MCP-1 and IL-8.Perhaps counter-intuitively, non-metastatic IBC patients had higher plasma levels of IL-2, -2R, -4, -5, -10, -12p70, -15, -17, FGF-b, IFN-γ, GM-CSF, and MIP1-α than metastatic IBC patients. Moreover, these differences were not observed between LABC and MBC patients. Furthermore, compared to HD, metastatic IBC had lower IL-4, -7, -17, -12p70, IFN-γ, RANTES, but higher levels of IP-10, Eotaxin, MCP-1, and TNF-RI. These data suggest that non-metastatic IBC patients are more immune competent than metastatic IBC patients. Finally, there were differences in the immunophenotype as well as cytokine levels between IBC patients with and without CTCs. IBC patients with CTC had a lower %T-cells (p=0.003) and higher %B-cells (p=0.008) and TNF-RI (p=0.01) than IBC patients without CTCs which may lead to a decrease in cellular immunity. Cell-mediated immunity may be further compromised by the elevated levels of serum TGF-β (p= 0.064) that can also promote EMT and metastatic progression.Conclusion: We report a comprehensive analysis of the serum cytokine and chemokine profiles in IBC patients. More importantly, this is the first report of potential interactions between soluble factors, CTC, and immune parameters in IBC patients. Non-metastatic IBC patients are more immune competent than metastatic IBC patients as evidenced by the high levels of pro- and anti-inflammatory factors; however, the presence of CTC in IBC tends to shift the immune response to a TH2 polarization with a decrease in T-cells, and a concomitant increase in B-cells and serum TGF-β and TNF-RI levels. Additional studies are needed to determine the role of soluble factors in the pathogenesis and progression of IBC and the impact on clinical outcome. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2135.

Clinical Outcomes in Two Different Cohorts of Patients with Inflammatory Breast Cancer (IBC) Treated at the MD Anderson Cancer Center: The Experience of the Morgan Welch IBC Research Program and Clinic.

Abstract BACKGROUND: Inflammatory Breast Cancer (IBC) is a rare but aggressive manifestation of primary breast cancer. Survival in patients with IBC is significantly lower than for non-IBC breast cancer patients. Appropriate diagnostic and treatment strategies provided by a specialized multidisciplinary team could impact the overall prognosis of the disease. We recently established an IBC research program and clinic including investigators from various disciplines solely dedicated to this disease. We sought to compare the characteristics and clinical outcomes of newly diagnosed IBC patients evaluated and treated using novel diagnostic and therapeutic approaches with an historical cohort of IBC patients treated at our institution.METHODS: We included 240 IBC patients treated at MD Anderson Cancer Center between January 1970 and August 2000. In this analysis we compared characteristics, 1 year progression free survival (PFS) and 1 year survival between the historic cohort and 47 patients diagnosed with IBC and seen at our IBC clinic between August 2007 and September 2008. The new patients are part of a prospective IBC registry. All of them had staging and monitoring with breast MRI and FDG-PET/CT. When indicated, they were treated with targeted therapies (e.g. trastuzumab and tipifarnib), that were not available for the patients in the old cohort. Descriptive statistics were used. Kaplan Meier product-limit method was used to calculate survival outcomes, groups were compare by log-rank test.RESULTS: Median age was similar in both cohorts (53 vs 51). In the new cohort 40% of the patients had evidence of distant metastasis at presentation. The most common sites were contralateral lymph nodes (26%), pleura (16%), bone (16%) and liver (11%). In the old cohort only 17% presented with stage IV. 38.7% of the new patients had Her2-neu amplified and 34%, triple receptor negative IBC. There was no difference in 1-year survival between the two groups (92.4% vs. 93.8%, p=0.637). For patients with stage III disease, the 1-year survival was 95% for both groups. The 1 year-PFS was 86.4% in the new cohort compared to 77.9% (p=0.43) in the old cohort. With a median follow up of 13 months, 51%of the patients in the new cohort are disease free and 87% are still alive.CONCLUSIONS: IBC is an aggressive but rare disease with poor prognosis. We have established a specialized IBC research program and clinic that introduces novel concepts and strategies in laboratory, imaging diagnostics and targeted therapies. This approach may accelerate our understanding of the biology, develop new therapeutic strategies and finally improve the outcome of IBC. Early results of this multidisciplinary approach show a modest, but not significant difference in outcome. We hope that with additional patients and longer follow-up a significant improvement in outcomes will become apparent. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5119.

Quantitative assessment of DNA hypermethylation in the inflammatory and non-inflammatory breast cancer phenotypes

In this study, a comparative quantitative methylation profiling of inflammatory breast cancer (IBC) and non-IBC was set up for the identification of tumor-specific methylation patterns. Methylation ratios of six genes measured in benign breast tissues (n=9) and in tumor samples from non-IBC (n=81) and IBC (n=19) patients using quantitative methylation-specific PCR. Median methylation ratios observed in breast cancer (n=100) were significantly higher than those observed in benign breast tissues for 5 of 6 genes (TWIST, HIN-1, RASSF1A, RARβ2 and APC). Only one of the individual genes studied, RARβ2, showed differential methylation ratios in IBC and non-IBC (P=0.016). Using the maximal methylation ratio observed in benign breast tissue as a threshold, the methylation frequency of two genes, RARβ2 and APC, was significantly increased in IBC (n=19) when compared to non-IBC (n=81): 53% vs. 23% for RARβ2 (P=0.012) and 84% vs. 54% for APC (P=0.017). Using hierarchical clustering, methylation patterns could not classify breast cancers according to their phenotype. The finding of differential frequencies of methylation in IBC and non-IBC for 2 out of 6 genes suggests that gene-specific patterns of methylation could provide a basis for molecular classification of IBC Testing for additional genes could help to define the IBC phenotype based on patterns of aberrant gene promoter methylation.

Increased Detection of Breast Cancer Virus Sequences in Inflammatory Breast Cancer

Earlier studies have suggested an association between breast cancer aggressiveness and the presence of viral sequences resembling mouse mammary tumor virus (MMTV). This study was to determine if inflammatory breast cancer (IBC) in the United States had a higher proportion of cases with these viral sequences than non-IBC patients and if specific risk factors for the sequences could be identified. Biospecimens from 67 patients in the North American IBC Registry were selected for sequencing of MMTV env- like sequences. The presence or absence of the viral sequences was compared to progression free survival (PFS), risk factors including exogenous hormones, and tumor markers. Of the 67 cases, 44 were positive for viral sequences (VSP), 17 were negative (VSN) and six were excluded from analysis because of insufficient DNA to perform replicates. The 72% of VSP cases was significantly more than the 40% in non-IBC U.S. breast cancer patients (p < 0.0001). Non-significant trends suggested that VSP patients were more likely to be HER-2 neu positive and ER negative, have a stronger exposure to exogenous hormones, and have a shorter PFS than VSN patients. MMTV-related sequences appear to be related to the aggressiveness of breast cancer with a higher incidence in North American IBC than in non-IBC breast cancer.

Circulating tumor cells in metastatic inflammatory breast cancer

BackgroundInflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Circulating tumor cells (CTCs) are an independent prognostic factor in metastatic breast cancer. The aim of this study was to assess the prognostic value of baseline CTCs in metastatic IBC patients. Patients and methodsThis retrospective study included 42 metastatic IBC and 107 metastatic non-IBC patients treated with first- or second-line chemotherapy from January 2004 to December 2007 at MD Anderson Cancer Center. CTCs were detected and enumerated before patients started chemotherapy using the CellSearch™ system. ResultsTen (23.8%) IBC patients versus 48 (44.9%) non-IBC patients had baseline CTCs ≥5 per 7.5 ml of peripheral blood. IBC patients had a lower mean±SEM CTCs than non-IBC patients (7.6±2.9 versus 34.2±9.1; P=0.02). The estimated median overall survival was 26.5 versus 18.3 months (P=0.68) in IBC patients and 37.4 versus 18.3 months (P=0.016) in non-IBC patients with CTCs <5 and CTCs ≥5, respectively. ConclusionsMetastatic IBC patients had a lower prevalence and fewer CTCs in comparison to metastatic non-IBC patients. Survival of metastatic IBC patients with <5 CTCs was not significantly better than that of patients with ≥5 CTCs. Further research is warranted with prospective assessment of CTCs in IBC patients and their biological characterization.

Analysis of RhoC expression and lymphovascular emboli in inflammatory vs non-inflammatory breast cancers in Egyptian patients

Understanding the molecular factors that distinguish inflammatory breast cancer (IBC) from non-IBC is important for IBC diagnosis. We reviewed the records of 48 IBC patients and 64 non-IBC patients from Egypt. We determined RhoC expression and tumor emboli and their relationship to demographic and reproductive characteristics. Compared with non-IBC patients, IBC patients had significantly lower parity ( P = 0.018) and fewer palpable tumors ( P < 0.0001). IBC tumors showed RhoC overexpression more frequently than non-IBC tumors (87% vs. 17%, respectively) ( P < 0.0001). Tumor emboli were significantly more frequent in IBC tumors than non-IBC tumors (Mean ± SD: 14.1 ± 14.0 vs. 7.0 ± 12.9, respectively) ( P < 0.0001). This study illustrates that RhoC overexpression and tumor emboli are more frequent in tumors of IBC relative to non-IBC from Egypt. Future studies should focus on relating epidemiologic factors to molecular features of IBC in this population.

Monocytes/macrophages and natural killer cells characterize the tumor microenvironment of inflammatory breast cancer in Egyptian patients.

Abstract Abstract #1054 Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. IBC incidence appears to be higher in Egypt as compared to USA. Although the role of leukocytes in regulating breast cancer dissemination has been studied extensively, their role in IBC progression is not well understood. Previously, we showed that human monocytes augment the invasiveness and proteolytic activity of IBC cell lines. Aim: To compare the immunophenotype of IBC and non-IBC and to identify IBC tumor-infiltrated immune cell that may be associated with poor prognosis of IBC.&amp;#x2028; Methods: We enrolled two groups of patients: IBC (n=13) and non-IBC (n=27) being treated at Ain Shams University hospitals. All patients underwent modified radical mastectomy. IBC patients had 7 or more metastatic axillary lymph nodes whereas non-IBC patients had 3 or less metastatic axillary lymph nodes. During surgery, blood draining from the breast tumor microenvironment, through branches of axillary vein, and peripheral blood was collected. Total mononuclear cells were isolated from collected blood and their phenotype was examined using flow cytometry. Monoclonal antibodies specific for cell surface markers for particular cells types were used: namely T-helper cells (CD3+CD4+), T-cytotoxic cells (CD3+CD4-), natural killer (NK) cells (CD56+) and monocytes/macrophages (CD14+). Results: Within each group we compared the leukocytic composition of blood collected from the tumor drainage to that of peripheral blood in IBC and non-IBC patients. 1) In IBC, we detected a significant increase in the mean percentage of NK cells and monocytes collected from the tumor site, but no significant difference in CD8+ and CD4+ cells. 2) In non-IBC, the percentage of CD4+ T cells collected from the tumor site was significantly higher than from peripheral blood. No significant differences were detected in CD8+, CD56+ and CD14+ cells.&amp;#x2028; We compared the leukocyte composition of blood collected from both IBC and non-IBC patients. 1) In peripheral blood of IBC patients, we detected a significant increase in CD4+ T cells, but no significant differences in CD8+, CD56+ and CD14+ cells when compared to non-IBC patients. 2) When we compared the leukocyte content of blood collected from the tumor site in IBC and non-IBC, we found a significant increase in CD56+, and CD14+ cells and a significant decrease in CD4+ T cells in IBC, but no significant difference in CD8+ T cells. Conclusion: Differences in the immunophenotype of IBC versus non-IBC suggests a role for these immune cells in the metastatic dissemination and progression of IBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1054.

Inflammatory versus grade III and IV breast cancer and effect of mammogram

1545 Background: Inflammatory breast cancer (IBC) is an aggressive manifestation of primary breast cancer. Demographic characteristics and survivality were compared between IBC and grade III and IV breast cancer using SEER data. Methods: SEER dataset were generated according to the manual. After excluding male gender, missing information, sarcomas, lymphoma and/or breast malignancy with different histologic origin, 1,430 IBC and 32,752 non-IBC grade III and IV breast cancer patients were used in the final analysis. In a subpopulation analysis IBC patients were dichotomized into patient who were diagnosed before and after year 2000. Results: There were no significant difference in mean age and white population between IBC and non-IBC patients. In IBC group 45% of patients were married whereas 56%of non-IBC patients were married (p value <0.001). Prevalence of estrogen and progesterone receptor status where very similar between the two groups. Prevalence of metastasis in IBC is much more higher (95.2%) than non-IBC (4.5%) patients. 5-year survivality was 29% for IBC and 74% for non-IBC patients. In a Cox regression model adjusted for age (continuous), race (white vs. non-white), marital status (married vs. not married), estrogen receptor status (positive vs. negative) and progesterone receptor status (positive vs. negative), IBC remained the only significant risk factor with hazard ratio of 4.12 (95% CI: 3.86, 4.41). There is no difference in the 5 year survivality among the IBC patients who were diagnosed before (N=884) and after (N=546) year 2000 (29% and 32% respectively and log-rank p value of 0.85). In a separate Cox regression model, for this sub-population, adjusted for same variables, risk of dying due to IBC was same (hazard ratio 1.00, 95% CI: 0.86, 1.16) between patients who were diagnosed before and after year 2000. Conclusions: IBC has significantly low 5-year survivality as compared to grade III and IV breast cancer patient. Mammogram in this population failed to increase survivality by early diagnosis. No significant financial relationships to disclose.

Molecular Heterogeneity of Inflammatory Breast Cancer: A Hyperproliferative Phenotype

Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays. For gene expression analysis, IBC (n=14) was clinically defined as rapid-onset cancer associated with erythema and skin changes, whereas non-IBC patients (n=20) had stage III breast cancers, and cDNA analysis was carried out using the Affymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from>2,000 non-IBC. Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93% versus 11%; P<0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P<0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P=0.002; progesterone receptor, 68% versus 42%; P=0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different. This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.

Are risk factors for breast cancer similar in women with inflammatory breast cancer and in those with non-inflammatory breast cancer?

The aim of the study was to compare reproductive factors in patients with inflammatory breast cancer (IBC), and with non-inflammatory breast cancer (non-IBC). The study was performed in two centers: one French including 49 IBC patients and 140 non-IBC and another Tunisian including 97 IBC and 139 non-IBC. Unconditional logistic regression was used for the analyses. The French IBC patients had a lower educational level, a higher body mass index and a longer cumulative duration of breast-feeding, and they included a greater proportion of non-European women, than the non-IBC patients. In the multivariate analysis, only breast-feeding duration remained associated with the IBC status (P=10(-3)). These results could not be verified in the Tunisian series, because the duration of breast-feeding was unavailable in this center. This study suggests that the etiology of IBC might be different of that of non-IBC.

RhoC-GTPase is a Novel Tissue Biomarker Associated with Biologically Aggressive Carcinomas of the Breast

There is a need for reliable predictors of breast cancer aggressiveness that will further refine the staging classification and help guide the implementation of novel therapies. We have identified RhoC as being nearly always overexpressed in the most aggressive form of breast cancer, inflammatory breast cancer (IBC); in subsequent work we identified RhoC to be a promising marker of aggressive behavior in breast cancers less than 1 cm in diameter. We hypothesized that RhoC expression would identify aggressive, non-IBC tumors breast cancer patients at any stage with worse outcomes defined as recurrence and/or metastasis. We constructed four high-density tissue microarrays (TMAs) using 801 tissue cores from 280 patients. These tissues represent a wide range of normal breast and breast disease, including intraductal hyperplasia, ductal carcinoma in situ (DCIS), invasive carcinomas, and distant metastases. The TMAs were immunostained using a polyclonal anti-RhoC antibody developed in our laboratory. Cytoplasmic RhoC expression was scored as negative, weak, moderate, or strong by a previously validated scoring schema. RhoC expression increases with breast cancer progression. All samples of normal breast epithelium had negative to weak staining, whereas staining intensity increased in hyperplasia, DCIS, invasive carcinoma, and metastases (Kruskal-Wallis p < 0.001). In patients with invasive carcinoma, high RhoC expression was associated with features of aggressive behavior including high histologic grade, positive lymph nodes, and negative hormonal receptor status. High RhoC expression was a predictor of overall survival in patients with breast cancer (log rank test, p = 0.002) and was associated with 100% increase in the risk of death as compared to patients with low RhoC expression. Importantly, high RhoC was an independent predictor of poor response to doxorubicin-based chemotherapy with a hazard ratio of 3.1 and a 95% CI of 1.2-7.7 (p = 0.02). RhoC expression increases with breast cancer progression and RhoC protein level in tumor tissue is strongly associated with biologically aggressive invasive carcinomas of the breast. RhoC expression, if validated, may identify patients who are less likely benefit from doxorubicin therapy and suggests RhoC overexpression as a new target for intervention.

Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Improved understanding of the mechanisms responsible for the differences between IBC and non-IBC might provide novel therapeutic targets. We studied 35 consecutive patients with IBC, biopsied prior to the initiation of chemotherapy. Angiogenesis was evaluated by Chalkley counting and by assessment of endothelial cell proliferation (ECP) and vessel maturity. The presence of fibrin, expression of the hypoxia marker carbonic anhydrase IX (CA IX) and epithelialcadherin (E-cadherin) expression were immunohistochemically detected. The same parameters were obtained in a group of 104 non-IBC patients. Vascular density, assessed by Chalkley counting (P<0.0001), and ECP (P=0.01) were significantly higher in IBC than in non-IBC. Abundant stromal fibrin deposition was observed in 26% of IBC and in only 8% of non-IBC (P=0.02). Expression of CA IX was significantly less frequent in IBC than in non-IBC with early metastasis (P=0.047). There was a significant positive correlation between the expression of CA IX and ECP in IBC (r=0.4, P=0.03), implying that the angiogenesis is partly hypoxia driven. However, the higher ECP in IBC and the less frequent expression of CA IX in IBC vs non-IBC points at a role for other factors than hypoxia in stimulating angiogenesis. Strong, homogeneous E-cadherin expression was found at cell–cell contacts in all but two IBC cases, both in lymphovascular tumour emboli and in infiltrating tumour cells, challenging our current understanding of the metastatic process. Both the intense angiogenesis and the strong E-cadherin expression may contribute to the highly metastatic phenotype of IBC.

Inflammatory breast cancer and body mass index.

No studies have investigated the etiology of inflammatory breast cancer (IBC), the most lethal form of breast cancer. Because high body mass index (BMI) is associated with decreased risk of premenopausal breast cancer but increased risk of postmenopausal breast cancer, we evaluated whether high BMI was a risk factor for IBC. In a case-comparison study, we matched by ethnicity and registration date 68 IBC patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1996 with 143 patients with non-IBC and 134 patients with cancer at sites other than the breast or reproductive tract (non-breast cancer). The non-breast cancer group was used in lieu of a population-based, healthy control group, which was not available. IBC patients were younger at menarche and the time of their first live birth than non-IBC and non-breast cancer patients. The proportion of premenopausal IBC patients was higher than the proportion of premenopausal women in the comparison groups, although differences were not significant. There were no differences in height, but IBC patients were heavier (77.6 kg) than non-IBC (70.0 kg) and non-breast cancer patients (68.0 kg). After adjusting for other factors, women in the highest BMI tertile (BMI > 26.65 kg/m2) relative to the lowest tertile (BMI < 22.27) had significantly increased IBC risk (IBC v non-IBC, odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.05 to 5.73; IBC v non-breast cancer, OR = 4.52, 95% CI = 1.85 to 11.04). This association was not significantly modified by menopausal status and was independent of age at menarche, family history of breast cancer, gravidity, smoking status, and alcohol use. Our investigation showed that high BMI was significantly associated with an increased risk of IBC. This association did not vary by menopausal status, although IBC patients were more likely to be premenopausal. Confirming our findings and identifying other IBC risk factors may provide directions for future research on the aggressive nature of IBC.

Inflammatory breast carcinoma incidence and survival

Little is known about the cause of inflammatory breast carcinoma (IBC), the most aggressive form of breast cancer. To the authors' knowledge, no studies have investigated whether IBC risk factors are different from those for breast carcinoma overall, and there has been only one report of IBC incidence and survival patterns. The authors used data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute for the period 1975-1992 to calculate age-adjusted incidence and survival rates for 913 white and 121 African American women with IBC involving dermal invasion of lymphatic ducts and 166,375 white and 13,674 African American women with other types of breast carcinoma (non-IBC). Between 1975-1977 and 1990-1992, IBC incidence doubled, increasing among whites from 0.3 to 0.7 cases per 100,000 person-years and among African Americans from 0.6 to 1.1 cases. However, rates for African Americans varied due to the small numbers of IBC cases. The twofold increase in IBC incidence was higher than that observed for non-IBC during the same period (27% for African Americans and 25% for whites). IBC patients were significantly younger at diagnosis than non-IBC patients; and among both IBC and non-IBC patients, African Americans were younger than whites. Overall survival was significantly worse for IBC patients than for non-IBC patients and for African Americans than for whites. Among whites, 3-year survival improved more for IBC patients than for non-IBC patients between 1975-1979 and 1988-1992, increasing from 32% to 42% for IBC patients (P=0.0001) and from 80% to 85% for non-IBC patients (P=0.0001). The disparities observed in incidence trends and age at diagnosis, particularly according to race, highlight the need for further investigation of the differences between IBC and non-IBC incidence.