Selected 2011 Inflammatory Breast Cancer published research.

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Le-Petross, H. T., et al. (2011). MRI features of inflammatory breast cancer. American Journal of Roentgenology, 197(4), 769-76. Abstract below, free full text available at link in article title.

OBJECTIVE:
The aim of this study was to evaluate the features of inflammatory breast carcinoma (IBC) on MRI compared with mammography and ultrasound and to better define the role of MRI in patients with this aggressive disease.
MATERIALS AND METHODS:
A retrospective analysis was performed of patients with newly diagnosed IBC evaluated at a single institution between 2003 and 2008. Baseline MRI examinations were performed on a 1.5- or 3-T scanner using contrast-enhanced 3D T1-weighted gradient-echo sequences with parallel imaging. MRI findings were rated in accordance with the BI-RADS MRI lexicon established by the American College of Radiology. All patients underwent concomitant mammography and ultrasound examinations.
RESULTS:
Eighty women with a clinical diagnosis of IBC were included in the study (median age, 52 years; age range, 25-78 years). MRI detected a primary breast lesion in 78 of 80 symptomatic breasts (98%) compared with 53 of 78 (68%) with mammography (p < 0.0001) and 75 of 80 (94%) with ultrasound. Of the 78 breasts with a primary lesion, the most common MRI finding was a mass or multiple masses (57/78, 73%). Masses were frequently multiple, small, and confluent (47/57, 82%); mass margins, irregular (43/57, 75%); and internal enhancement pattern, heterogeneous (47/57, 82%). Kinetic analysis revealed a delayed washout pattern in 66 of 78 tumors (85%). MRI showed skin thickening in 74 of 80 breasts (93%), whereas mammography showed skin thickening in 56 of 78 breasts (72%).
CONCLUSION:
Multiple small, confluent, heterogeneously enhancing masses and global skin thickening are key MRI features of IBC that contribute to improved detection of a primary breast cancer and delineation of disease extent compared with mammography.

Bekhouche, I., et al. (2011). High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes. PLoS One, 6(2), Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037286/. Abstract below, free full text available at link in article title.

BACKGROUND:
Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples.
METHODOLOGY/FINDINGS:
Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent “complex” patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. The percentage of genes whose mRNA expression correlated with CNAs was similar in both types for the gained genes, but ?7-fold lower in IBCs for the lost genes. Integrated analysis identified 24 potential candidate IBC-specific genes. Their combined expression accurately distinguished IBCs and nIBCS in an independent validation set, and retained an independent prognostic value in a series of 1,781 nIBCs, reinforcing the hypothesis for a link with IBC aggressiveness. Consistent with the hyperproliferative and invasive phenotype of IBC these genes are notably involved in protein translation, cell cycle, RNA processing and transcription, metabolism, and cell migration.
CONCLUSIONS:
Our results suggest a higher genomic instability of IBC. We established the first repertory of DNA copy number alterations in this tumor, and provided a list of genes that may contribute to its aggressiveness and represent novel therapeutic targets.

Iwamoto, T., et al. (2011). Different gene expressions are associated with the different molecular subtypes of inflammatory breast cancer. Breast Cancer Research and Treatment, 125(3), 785-95. Abstract below, free full text not available.

The goal of this study was to determine whether gene expression differences exist between inflammatory breast cancers (IBC) and T stage-matched non-IBC patients stratified by hormone receptor and HER2 status. We used Affymetrix GeneChips to analyze 82 tumor samples (25 T4d patients, and 57 T4a-c patients) of newly diagnosed breast cancers. Genes that were differentially expressed between the IBC and non-IBC specimens were identified using the t test, and differential expression of gene sets was assessed using gene set analysis. Three distinct clinical subtypes of IBC and non-IBC were compared: ER-positive/HER2-normal, HER2-amplified, and ER-negative/HER2-normal. When we compared expression data from all IBC with all non-IBC, we found no significant differences after adjusting for multiple testing. When IBC and non-IBC tumors were compared by clinical subtype, however, significant differences emerged. Complement and immune system-related pathways were overexpressed in ER-positive/HER2-normal IBC. Protein translation and mTOR signaling were overexpressed in HER2-amplified IBC. Apoptosis-, neural-, and lipid metabolism-related pathways were overexpressed in ER-negative/HER2-normal IBC compared with non-IBC of the same receptor phenotype. In this T stage-matched case-control study, the survival curves of patients with IBC and non-IBC were similar for all three clinical subtypes. IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC.

Goldfarb, J. M., & Pippen, J. E. (2011). Inflammatory breast cancer: the experience of Baylor University Medical Center at Dallas. Baylor University Medical Center Proceedings, 24(2), 86-0. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069510/. No abstract, free full text at link in article title.

Li, J., et al. (2011). Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer. Oncologist, 16(12), 1675-83. Free full text not available, abstract below.

BACKGROUND:
Numerous studies have demonstrated that expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2 is important for predicting overall survival (OS), distant relapse (DR), and locoregional relapse (LRR) in early and advanced breast cancer patients. However, these findings have not been confirmed for inflammatory breast cancer (IBC), which has different biological features than non-IBC.
METHODS:
We retrospectively analyzed the records of 316 women who presented to MD Anderson Cancer Center in 1989-2008 with newly diagnosed IBC without distant
metastases. Most patients received neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Patients were grouped according to receptor status: ER(+) (ER(+)/PR(+) and HER-2-; n = 105), ER(+)HER-2(+) (ER(+)/PR(+) and HER-2(+); n = 37), HER-2(+) (ER(-)/PR(-) and HER-2(+); n = 83), or triple-negative (TN) (ER(-)PR(-)HER-2(-); n = 91). Kaplan-Meier and Cox proportional hazards methods were used to assess LRR, DR, and OS rates and their associations with prognostic factors.
RESULTS:
The median age was 50 years (range, 24-83 years). The median follow-up time and median OS time for all patients were both 33 months. The 5-year actuarial OS rates were 58.7% for the entire cohort, 69.7% for ER(+) patients, 73.5% for ER(+)HER-2(+) patients, 54.0% for HER=2(+) patients, and 42.7% for TN patients (p < .0001); 5-year LRR rates were 20.3%, 8.0%, 12.6%, 22.6%, and 38.6%, respectively, for the four subgroups (p < .0001); and 5-year DR rates were 45.5%, 28.8%, 50.1%, 52.1%, and 56.7%, respectively (p < .001). OS and LRR rates were worse for TN patients than for any other subgroup (p < .0001-.03).
CONCLUSIONS:
TN disease is associated with worse OS, DR, and LRR outcomes in IBC patients, indicating the need for developing new locoregional and systemic treatment
strategies for patients with this aggressive subtype.

Dawood, S., et al. (2011). Differences in survival among women with stage III inflammatory and noninflammatory locally advanced breast cancer appear early: a large population-based study. Cancer, 117(9), 1819-26. Abstract below, free full text not available.

BACKGROUND: Significant improvements in the survival of women with breast cancer have been observed and are attributed to a multidisciplinary approach and the introduction of polychemotherapy and endocrine regimens. The objective of this population-based study was to determine whether women with inflammatory breast cancer (IBC) who received treatment in a modern era had a poorer survival compared those with non-IBC locally advanced breast cancer (LABC). METHODS: The Surveillance, Epidemiology, and End Results program registry was searched to identify women with stage IIIB/C breast cancer diagnosed between 2004 and 2007 who had undergone surgery and radiotherapy. Patients were categorized as either having IBC or non-IBC LABC according the sixth edition of the American Joint Committee on Cancer (AJCC) criteria. Breast cancer-specific survival (BCS) was estimated using the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. Cox models were then fitted to compare the association between breast cancer type and BCS after adjusting for patient and tumor characteristics. RESULTS: A total of 828 (19.2%) women and 3476 (80.8%) women had stage IIIB/C IBC and non-IBC LABC, respectively. The median follow-up was 19 months. The 2-year BCS rate was 90% (95% confidence interval [95% CI], 88%-91%) for the entire cohort and 84% (95%CI, 80%-87%) and 91% (95%CI, 90%-91%) among women with IBC and non-IBC LABC, respectively. In the multivariable model, patients with IBC were found to have a 43% increased risk of death from breast cancer compared with patients with non-IBC LABC (hazard ratio, 1.43; 95%CI, 1.10-1.86 [P = .008]). CONCLUSIONS: In the era of multidisciplinary management and anthracycline-based and taxane-based polychemotherapy regimens, women with IBC continue to have worse survival outcomes compared with those with non-IBC LABC.

Schairer, C., Brown, LM., & Mai, PL. (2011). Inflammatory breast cancer: high risk of contralateral breast cancer compared to comparably staged non-inflammatory breast cancer. Breast Cancer Research and Treatment, [Epub ahead of print]. Abstract below, free full text not available.

Inflammatory breast cancer (IBC), the most lethal form of breast cancer, has characteristics linked to higher risk of contralateral breast cancer. However, no large studies have examined risk of contralateral breast cancer following IBC. We calculated absolute risk of invasive contralateral breast cancer among 5,631 IBC and 174,634 comparably staged non-IBC first breast cancer cases who survived at least 2 months following diagnosis and were reported to 13 Surveillance, Epidemiology, and End Results (SEER) registries between January 1, 1973 and December 31, 2006. We considered that contralateral cancers occurring within 2-23 months of first cancer diagnosis may more likely be metastatic/recurrent disease and those occurring 2 or more years after diagnosis independent primaries. Absolute risk of contralateral breast cancer was generally greater following IBC than regional/distant non-IBC, regardless of age and hormone receptor status of first cancer diagnosis. Much of the increase in absolute risk following IBC occurred within 2-23 months of first cancer diagnosis, while the risk for non-IBC occurred more gradually over time since diagnosis. For instance, among women first diagnosed before age 50, absolute risks following IBC and non-IBC were 4.9 vs. 1.1% at 2 years, 6.0 vs. 2.2% at 5 years, and 7.7 vs. 6.1% at 20 years after diagnosis. However, patterns of higher risk following IBC than non-IBC were also evident for at least 10-15 years in the subcohort of women who survived at least 24 months without a contralateral cancer. In conclusion, our results suggest that IBC has higher risk of cancer in the contralateral breast than comparably staged non-IBC, possibly due to both metastatic/recurrent disease and independent primaries.

Thomas, ZI., et al. (2011). Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. British Journal of Cancer, [Epub ahead of print]. Abstract below, free full text not available.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. METHODS: The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. RESULTS: Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. CONCLUSION: Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.

Bekhouche, I., et al. (2011). High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes. PLoS One, 6(2). Abstract below, free full text may be found at link above.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples. METHODOLOGY/FINDINGS: Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent “complex” patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. The percentage of genes whose mRNA expression correlated with CNAs was similar in both types for the gained genes, but ?7-fold lower in IBCs for the lost genes. Integrated analysis identified 24 potential candidate IBC-specific genes. Their combined expression accurately distinguished IBCs and nIBCS in an independent validation set, and retained an independent prognostic value in a series of 1,781 nIBCs, reinforcing the hypothesis for a link with IBC aggressiveness. Consistent with the hyperproliferative and invasive phenotype of IBC these genes are notably involved in protein translation, cell cycle, RNA processing and transcription, metabolism, and cell migration. CONCLUSIONS: Our results suggest a higher genomic instability of IBC. We established the first repertory of DNA copy number alterations in this tumor, and provided a list of genes that may contribute to its aggressiveness and represent novel therapeutic targets.

Sezgin, C., et al. (2011). p53 protein accumulation and presence of visceral metastasis are independent prognostic factors for survival in patients with metastatic inflammatory breast carcinoma. Medical Principles and Practice, 20(2), 159-64. Abstract below, free full text not available.

OBJECTIVE: The aim of this study was to determine the markers of prognosis in metastatic inflammatory breast cancer (IBC). SUBJECTS AND METHODS: The prognostic value of patients’ clinical characteristics and expression of c-erbB-2, p53, Ki-67, ER and PgR were assessed in the 45 patients with IBC who had developed distant metastasis. Immunohistochemical methods were used to detect the expression of c-erbB-2, p53, Ki-67, ER and PgR in surgical resection specimens of the patients’ primary tumor. RESULTS: The median overall survival (OS) measured from the diagnosis of metastatic disease was 23 months. In the univariate analysis, p53 protein accumulation and the presence of visceral metastasis were predictive of poor survival (p = 0.01 and 0.003, respectively). In the multivariate analysis, accumulation of p53 protein and the presence of visceral metastasis correlated with OS (p = 0.02 and 0.008, respectively). CONCLUSION: In metastatic IBC, accumulation of p53 protein and presence of visceral metastasis are independent prognostic factors for OS. Established prognostic factors in non-IBC patients such as patient age, histologic grade, hormone receptor status and c-erbB-2 status did not have independent significance in IBC in this study.

Nouh, MA., et al. (2011). Cathepsin B: a potential prognostic marker for inflammatory breast cancer. Journal of Translational Medicine, 9(1). Abstract below, free full text may be found at link above.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. In non-IBC, the cysteine protease cathepsin B (CTSB) is known to be involved in cancer progression and invasion; however, very little is known about its role in IBC. METHODS: In this study, we enrolled 23 IBC and 27 non-IBC patients. All patient tissues used for analysis were from untreated patients. Using immunohistochemistry and immunoblotting, we assessed the levels of expression of CTSB in IBC versus non-IBC patient tissues. Previously, we found that CTSB is localized to caveolar membrane microdomains in cancer cell lines including IBC, and therefore, we also examined the expression of caveolin-1 (cav-1), a structural protein of caveolae in IBC versus non-IBC tissues. In addition, we tested the correlation between the expression of CTSB and cav-1 and the number of positive metastatic lymph nodes in both patient groups. RESULTS: Our results revealed that CTSB and cav-1 were overexpressed in IBC as compared to non-IBC tissues. Moreover, there was a significant positive correlation between the expression of CTSB and the number of positive metastatic lymph nodes in IBC. CONCLUSIONS: CTSB may initiate proteolytic pathways crucial for IBC invasion. Thus, our data demonstrate that CTSB may be a potential prognostic marker for lymph node metastasis in IBC.

Iwamoto, T., et al. (2011). Different gene expressions are associated with the different molecular subtypes of inflammatory breast cancer. Breast Cancer Research and Treatment, 125(3), 785-95. Abstract below, free full text not available.

The goal of this study was to determine whether gene expression differences exist between inflammatory breast cancers (IBC) and T stage-matched non-IBC patients stratified by hormone receptor and HER2 status. We used Affymetrix GeneChips to analyze 82 tumor samples (25 T4d patients, and 57 T4a-c patients) of newly diagnosed breast cancers. Genes that were differentially expressed between the IBC and non-IBC specimens were identified using the t test, and differential expression of gene sets was assessed using gene set analysis. Three distinct clinical subtypes of IBC and non-IBC were compared: ER-positive/HER2-normal, HER2-amplified, and ER-negative/HER2-normal. When we compared expression data from all IBC with all non-IBC, we found no significant differences after adjusting for multiple testing. When IBC and non-IBC tumors were compared by clinical subtype, however, significant differences emerged. Complement and immune system-related pathways were overexpressed in ER-positive/HER2-normal IBC. Protein translation and mTOR signaling were overexpressed in HER2-amplified IBC. Apoptosis-, neural-, and lipid metabolism-related pathways were overexpressed in ER-negative/HER2-normal IBC compared with non-IBC of the same receptor phenotype. In this T stage-matched case-control study, the survival curves of patients with IBC and non-IBC were similar for all three clinical subtypes. IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC.

Girardi, V., et al. (2011). Inflammatory breast carcinoma and locally advanced breast carcinoma: characterisation with MR imaging. La Radiologica Medica, 116(1), 71-83. Abstract below, free full text not available.

PURPOSE: This study was done to identify the typical magnetic resonance (MR) imaging findings of inflammatory breast carcinoma (IBC) in comparison with noninflammatory locally advanced breast carcinoma (LABC). MATERIALS AND METHODS: MR images of 30 patients with IBC (T4d) were compared with those of a cohort of 30 patients with LABC (T3/T4a-c). The age distribution was approximately equal in the two groups. MR images were assessed for the following features: skin thickening (>4 mm), skin oedema, architectural distortion, enhancement pattern (mass-like/non-mass-like), time-signal intensity curve (continuous-persistent type/wash-out type), skin enhancement. Fisher’s exact text was used to compare MR imaging appearances of IBC and LABC (significant p value <0.05). RESULTS: Skin involvement and enhancement pattern differed between groups: skin thickening was present in 16/30 IBC (53%) vs 8/30 LABC cases (27%, p=0.06), skin oedema was present in 26/30 IBC (87%) vs 8/30 LABC (27%, p < 0.0001), and skin enhancement in 10/30 IBC (33%) vs 2/30 LABC (7%, p=0.02); non-mass-like enhancement was present in 22/30 IBC (73%) vs 12/30 LABC (40%, p=0.02). CONCLUSIONS: IBC is a distinct clinical and pathological entity resulting in typical MR imaging features. Skin changes (thickening, oedema, enhancement) related to neoplastic involvement of the dermal lymphatics are suggestive of IBC and should prompt a skin biopsy to confirm or rule out the diagnosis.

Xiao, Y., et al. (2011). The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction. Oncogene, 30(3), 287-300. Abstract below, free full text not available.

Inflammatory breast carcinoma (IBC) is characterized by exaggerated lymphovascular invasion (LVI), recapitulated in our human xenograft, MARY-X. This model exhibited lymphovascular emboli in vivo and corresponding spheroids in vitro. Owing to the morphological and gene profile resemblance of these spheroids to embryonal blastocysts, we wondered whether they might exhibit embryonic stem cell signaling. Specifically we investigated Notch and observed selective Notch 3 activation by expression profiling, reverse transcriptase- and real-time PCR, western blot and immunofluorescence in vitro, and immunohistochemistry in vivo. Notch 3 intracellular domain (N3icd) and six target genes, HES-5, HEY-1, c-Myc, Deltex-1, NRARP and PBX1, markedly increased in MARY-X. In addition, a significant percentage of MARY-X cells expressed aldehyde dehydrogenase (ALDH), a stem cell marker. Only the ALDH(+) cells were capable of secondary spheroidgenesis, tumorigenicity and self-renewal. Inhibiting Notch 3 activation in vitro with ?-secretase inhibitors (GSIs) or small interfering RNA resulted in a downregulation of Notch target genes, including CD133, and an induction of caspase 3-mediated apoptosis. Transfection of N3icd but not Notch 1 intracellular domain into normal human mammary epithelial cells resulted in increased expression of Notch target genes and induction of spheroidgenesis. GSI in vivo resulted in inhibitory but diffusion-limited effects on Notch 3 signaling, resulting in xenograft growth reduction. The lymphovascular emboli of human IBC exhibited dual N3icd and ALDH1 immunoreactivities independently of molecular subtype. This Notch 3 addiction of lymphovascular emboli might be exploited in future therapeutic strategies.

Dawood, S., et al. (2011). International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Annals of Oncology, 22(3), 515-23. Abstract below, free full text not available.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.