Selected 2009 Inflammatory Breast Cancer published research.

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Morales , J. , & Alpaugh, ML. (2009). Gain in cellular organization of inflammatory breast cancer: a 3D in vitro model that mimics the in vivo metastasis. BMC Cancer, 23(9), 462. Abstract below, free full text may be found at link above.

BACKGROUND: The initial step of metastasis in carcinomas, often referred to as the epithelial-mesenchymal transition (EMT), occurs via the loss of adherens junctions (e.g. cadherins) by the tumor embolus. This leads to a subsequent loss of cell polarity and cellular differentiation and organization, enabling cells of the embolus to become motile and invasive. However highly malignant inflammatory breast cancer (IBC) over-expresses E-cadherin. The human xenograft model of IBC (MARY-X), like IBC, displays the signature phenotype of an exaggerated degree of lymphovascular invasion (LVI) in situ by tumor emboli. An intact E-cadherin/alpha, beta-catenin axis mediates the tight, compact clump of cells found both in vitro and in vivo as spheroids and tumor emboli, respectively. METHODS: Using electron microscopy and focused ion beam milling to acquire in situ sections, we performed ultrastructural analysis of both an IBC and non-IBC, E-cadherin positive cell line to determine if retention of this adhesion molecule contributed to cellular organization. RESULTS: Here we report through ultrastructural analysis that IBC exhibits a high degree of cellular organization with polar elements such as apical/lateral positioning of E-cadherin, apical surface microvilli, and tortuous lumen-like (canalis) structures. In contrast, agarose-induced spheroids of MCF-7, a weakly invasive E-cadherin positive breast carcinoma cell line, do not exhibit ultrastructural polar features. CONCLUSIONS: This study has determined that the highly metastatic IBC with an exaggerated malignant phenotype challenges conventional wisdom in that instead of displaying a loss of cellular organization, IBC acquires a highly structured architecture.These findings suggest that the metastatic efficiency might be linked to the formation and maintenance of these architectural features. The comparative architectural features of both the spheroid and embolus of MARY-X provide an in vitro model with tractable in vivo applications.

Damast, S., et al. (2009). Locoregional outcomes of inflammatory breast cancer patients treated with standard fractionation radiation and daily skin bolus in the taxane era. International Journal of Radiation Oncology, Biology, Physics, 77(4), 1105-12. Abstract below, free full text not available.

PURPOSE: To assess locoregional outcomes of inflammatory breast cancer (IBC) patients who received standard fractionation radiation with daily skin bolus and taxanes as part of combined-modality therapy (CMT). METHODS AND MATERIALS: We retrospectively reviewed the charts of 107 patients diagnosed with IBC between January 1995 and March 2006 who presented to our department for adjuvant radiation therapy (RT). RESULTS: All patients received chemotherapy (95% anthracycline and 95% taxane), modified radical mastectomy, and RT to the chest wall and regional lymphatics using standard fractionation to 50 Gy and daily skin bolus. The RT to the chest wall was delivered via electrons (55%) or photons (45%) in daily fractions of 180 cGy (73%) or 200 cGy (27%). Scar boost was performed in 11%. A majority (84%) of patients completed the prescribed treatment. Median follow-up was 47 months (range, 10-134 months). Locoregional control (LRC) at 3 years and 5 years was 90% and 87%, respectively. Distant metastases-free survival (DMFS) at 3 years and 5 years was 61% and 47%, respectively. CONCLUSIONS: Excellent locoregional control was observed in this population of IBC patients who received standard fractionation radiation with daily skin bolus and taxanes as part of combined-modality therapy. Distant metastases-free survival remains a significant therapeutic challenge.

Zhang, D., et al. (2009). Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clinical Cancer Research, 15(21), 6639-48. Abstract below, free full text may be found at link above.

PURPOSE: Inflammatory breast cancer (IBC) is a rare but aggressive type of advanced breast cancer. Epidermal growth factor receptor (EGFR) expression is an independent poor prognostic factor in IBC. The purpose of this study was to determine the effect on IBC tumorigenicity and metastasis of blocking the EGFR pathway. EXPERIMENTAL DESIGN: IBC cell lines, which express high level of EGFR, were treated with EGFR small interfering RNA and with the EGFR tyrosine kinase inhibitor erlotinib. The role of EGFR in IBC cell proliferation, motility, invasiveness, and change of the expression levels of epithelial-mesenchymal transition markers was examined. The role of extracellular signal-regulated kinase (ERK)-1/2 in erlotinib activity was also studied. The activity of erlotinib in tumor growth and metastasis was examined in an orthotopic xenograft model of IBC. RESULTS: Erlotinib inhibited proliferation and anchorage-independent growth of IBC cells, and this inhibition was ERK dependent. Erlotinib inhibited cell motility and invasiveness and reversed the mesenchymal phenotype of IBC cells to epithelial phenotype in three-dimensional culture. Erlotinib dramatically inhibited IBC tumor growth in a xenograft model. Interestingly, erlotinib inhibited spontaneous lung metastasis, even at a low dose that had no significant effect on primary tumor growth. These erlotinib-treated tumors were converted to epithelial phenotype from mesenchymal phenotype. CONCLUSIONS: The EGFR pathway is involved in tumor growth and metastasis of IBC. Targeting EGFR through the ERK pathway may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in EGFR-expressing IBC.

Rowan, K. (2009). Inflammatory breast cancer: new hopes and many hurdles. Journal of the National Cancer Institute, 101(19), 1302-4. No abstract available, free full text may be found at above link. From the full text article:

The field of inflammatory breast cancer (IBC) research is rife with enigmas and grim statistics. It is more aggressive and deadly than other breast cancers (see Stat Bite), and the mechanisms driving its rapid progression and metastasis remain unclear. Also perplexing is why the disease disproportionately strikes African American women and women of North African or Middle Eastern descent. Even its name needs deciphering; the typical redness and swelling of the breast seen in IBC that superficially resemble inflammation are actually due to lymph ducts that have been clogged with tumor cells.

Mego, M., et al. (2009). Circulating tumor cells in metastatic inflammatory breast cancer. Annals of Oncology, 20(11), 1824-8. Abstract below, free full text may be found at link above.

Inflammatory 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 METHODS: This 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. RESULTS: Ten (23.8%) IBC patients versus 48 (44.9%) non-IBC patients had baseline CTCs > or =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 > or =5, respectively. CONCLUSIONS: Metastatic 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 > or =5 CTCs. Further research is warranted with prospective assessment of CTCs in IBC patients and their biological characterization.

Yamauchi, H., et al. (2009). Molecular targets for treatment of inflammatory breast cancer. Nature Reviews. Clinical Oncology, 6(7), 387-94. Abstract below, free full text not available.

Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor. Therapies that target vasculolymphatic processes–angiogenesis, lymphangiogenesis, and vasculogenesis–have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in concert with other pathways. Therapies that target cell proliferation pathways are the most promising targeted therapies for IBC. In particular, therapies that target human epidermal growth factor receptor 2 (for example, trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patients with this disease. In this Review we discuss three pathways–vasculolymphatic, cell proliferation and metastatic–that could represent important targets in the treatment of IBC.

Kaufman, B., et al. (2009). Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study. The Lancet Oncology, 10(6), 581-8. Abstract below, free full text not available.

BACKGROUND: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. METHODS: From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. FINDINGS: Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. INTERPRETATION: Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer.

Man, YG., et al. . (2009). BP1, a putative signature marker for inflammatory breast cancer and tumor aggressiveness. Cancer Biomarkers, 5(1), 9-17. Abstract below, free full text not available.

Our previous studies revealed that beta protein 1 (BP1) was barely detectable in normal human breasts, but was seen in 21%, 46%, and 81% of hyperplastic, in situ, and invasive breast lesions, respectively. Our current study attempted to assess BP1 expression in inflammatory breast cancer (IBC), a very aggressive subtype of breast cancers characterized by extensive lympho-vascular invasion and involvement of dermal lymphatics. Paraffin-embedded tissue sections from 45 cases of IBC (nine with paired metastatic lymph nodes) and different controls were assayed immunohistochemically for BP1 expression. Positive BP1 immunoreactivities were present in all IBC cases. Strikingly, all cancer cells metastasized to lymph nodes and cells within lymphatic channels were uniformly and strongly immunoreactive to BP1. The percentage of BP1 positive cells and the intensity of BP1 immunostaining in IBC cases were significantly greater than those in non-IBC cases. Our findings suggest that BP1 may possess properties of onco-proteins that promote tumor progression, invasion, and metastasis, representing a putative signature marker for IBC and tumor aggressiveness.

Zell, JA., et al. (2009). Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 ibc patient cases from the California Cancer Registry. Breast Cancer Research, 11(1(R9)). Abstract below, free full text may be found at link above.

INTRODUCTION: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer associated with overexpression of Her2/Neu (human epidermal growth factor-like receptor 2 (HER2)) and poor survival. We investigated survival differences for IBC patient cases based on hormone receptor status and HER2 receptor status using data from the California Cancer Registry, as contrasted with locally advanced breast cancer (LABC), metastatic breast cancer (MBC) and non-T4 breast cancer. METHODS: A case-only analysis of 80,099 incident female breast cancer patient cases in the California Cancer Registry during 1999 to 2003 was performed, with follow-up through March 2007. Overall survival (OS) and breast cancer-specific survival (BC-SS) were analyzed using Kaplan-Meier methods and Cox proportional hazards ratios. RESULTS: A total of 2,014 IBC, 1,268 LABC, 3,059 MBC, and 73,758 non-T4 breast cancer patient cases were identified. HER2+ was associated with advanced tumor stage (P < 0.0001). IBC patient cases were more likely to be HER2+ (40%) and less likely to be hormone receptor-positive (HmR+) (59%) compared with LABC (35% and 69%, respectively), MBC (35% and 74%), and non-T4 patient cases (22% and 82%). HmR+ status was associated with improved OS and BC-SS for each breast cancer subtype after adjustment for clinically relevant factors. In multivariate analysis, HER2+ (versus HER2-) status was associated with poor BC-SS for non-T4 patient cases (hazards ratio = 1.16, 95% confidence interval 1.05 to 1.28) and had a borderline significant association with improved BC-SS for IBC (hazards ratio = 0.82, 95% confidence interval = 0.68 to 0.99). CONCLUSIONS: Despite an association with advanced tumor stage, HER2+ status is not an independent adverse prognostic factor for survival among IBC patient cases.

Houchens, NW., & Merajver, D. (2009). Molecular determinants of the inflammatory breast cancer phenotype. Oncology (Williston Park), 22(14), 1556-61. Abstract below, free full text not available.

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 vive xenograft cancer models have revealed characteristics innate to IBC thought to confer a strong metastatic potential and aggressive phenotype. Classic descriptive markers in IBC (e.g., 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.

Yang, R., et al. (2009). A comprehensive evaluation of outcomes for inflammatory breast cancer. Breast Cancer Research and Treatment, 117(3), 631-41. Abstract below, free full text not available.

OBJECTIVE: Inflammatory breast cancer (IBC) remains the breast malignancy with the worst prognosis. We sought to determine the effects of race, socioeconomic status and treatment on outcomes for women with IBC. Study design The Florida cancer registry, inpatient and ambulatory data were queried for patients diagnosed from 1998 to 2002. RESULTS: A total of 935 patients with IBC were identified (1.5% of all breast cancers). Overall, 83.1% were Caucasian, 13.9% African American (AA), and 15.7% Hispanic. The mean age of diagnosis was 57 years old. AA patients presented at a younger age, with higher tumor grade, and were less likely to undergo surgical therapy than their Caucasian counterparts. Median survival time (MST) for the entire cohort was 32 months, while MST for AA patients was 20 months. Patients who received chemotherapy before surgery, surgery without chemotherapy, and surgery before chemotherapy demonstrated an independent, significantly improved outcome in comparison to patients who underwent chemotherapy without surgical extirpation. The administration of radiation therapy did not demonstrate an improvement in survival. By multivariate analysis, AA race (HR = 2.19) and failure to provide surgery (HR = 2.3) were independent predictors of worse prognosis. No effect of poverty or ethnicity on outcome was observed. CONCLUSIONS: IBC carries a poor prognosis for all patients with significantly worse outcomes for AA women. Multimodality therapy provided the best survival rates.

Carkaci, S., et al. (2009). Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: preliminary data. Journal of Nuclear Medicine, 50(2), 231-8. Abstract below, free full text may be found at link above.

METHODS: The institutional review board waived informed consent and approved this study, which was compliant with the Health Insurance Portability and Accountability Act. The cases of 41 women with a mean age of 50 y (range, 25-71 y) and newly diagnosed IBC who underwent 18F-FDG PET/CT at diagnosis were retrospectively reviewed. All PET/CT images were analyzed visually and semiquantitatively by 2 physicians. The maximum standardized uptake value in the primary breast, regional nodes (axillary, subpectoral, supraclavicular, internal mammary), and extranodal regions was documented. The accuracy of PET/CT image interpretation was assessed by histopathologic analysis, if available; concurrent or subsequent imaging findings (contrast-enhanced CT, contrast-enhanced MRI, sonography, or PET/CT follow-up); or clinical follow-up. RESULTS: All patients presented with unilateral IBC. PET/CT showed hypermetabolic uptake in the skin in all patients, in the affected breast in 40 (98%), in the ipsilateral axillary nodes in 37 (90%), and in the ipsilateral subpectoral nodes in 18 (44%). Twenty patients (49%) were found to have distant metastases at staging, 7 (17%) of whom were not known to have metastases before undergoing PET/CT. Disease sites included bone, liver, contralateral axilla, lung, chest wall, pelvis, and the subpectoral, supraclavicular, internal mammary, mediastinal, and abdominal nodes. CONCLUSION: PET/CT should be considered in the initial staging of IBC, as the technique provided valuable information on locoregional and distant disease in this preliminary retrospective study.