Selected 2006 Inflammatory Breast Cancer published research.

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Van Laere, SJ., et al. (2006). Nuclear factor-kappaB signature of inflammatory breast cancer by cDNA microarray validated by quantitative real-time reverse transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding. Clinical Cancer Research, 12(11 part 1), 3249-56. Abstract below, free full text at link above.

PURPOSE: Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer with high metastatic potential. In a previous study, we showed that IBC is a different form of breast cancer compared with non-IBC by cDNA microarray analysis. A list of 756 genes with significant expression differences between IBC and non-IBC was identified. In-depth functional analysis revealed the presence of a high number of nuclear factor-kappaB (NF-kappaB) target genes with elevated expression in IBC versus non-IBC. This led to the hypothesis that NF-kappaB contributes to the phenotype of IBC. The aim of the present study was to further investigate the role of NF-kappaB in IBC. EXPERIMENTAL DESIGN: Immunohistochemistry and NF-kappaB DNA-binding experiments were done for all NF-kappaB subunits (RelA, RelB, cRel, NFkB1, and NFkB2) using IBC and non-IBC specimens. Transcriptionally active NF-kappaB dimers were identified by means of coexpression analysis. In addition, quantitative real-time reverse transcription-PCR for eight NF-kappaB target genes, selected upon a significant, 3-fold gene expression difference between IBC and non-IBC by cDNA microarray analysis, was done. RESULTS: We found a significant overexpression for all of eight selected NF-kappaB target genes in IBC compared with non-IBC by quantitative real-time reverse transcription-PCR. In addition, we found a statistically elevated number of immunostained nuclei in IBC compared with non-IBC for RelB (P = 0.038) and NFkB1 (P < 0.001). Immunohistochemical data were further validated by NF-kappaB DNA-binding experiments. Significant correlations between immunohistochemical data and NF-kappaB DNA binding for RelA, RelB, NFkB1, and NFkB2 were found. Transcriptionally active NF-kappaB dimers, composed of specific combinations of NF-kappaB family members, were found in 19 of 44 IBC specimens compared with 2 of 45 non-IBC specimens (P < 0.001). In addition, we found evidence for an estrogen receptor (ER)-mediated inhibition of the NF-kappaB signaling pathway. NF-kappaB target genes were significantly elevated in ER- versus ER+ breast tumors. Also, the amount of immunostained nuclei for RelB (P = 0.025) and NFkB1 (P = 0.031) was higher in ER- breast tumors versus ER+ breast tumors. CONCLUSIONS: The NF-kappaB transcription factor pathway probably contributes to the phenotype of IBC and possibly offers new options for treatment of patients diagnosed with this aggressive form of breast cancer.

Kim, T., Lau, J., & Erban, J. (2006). Lack of uniform diagnostic criteria for inflammatory breast cancer limits interpretation of treatment outcomes: a systematic review. Clinical Breast Cancer, 7(5), 386-95. Abstract below, free full text not available.

PURPOSE: Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. No randomized controlled trial or systematic review with an IBC-only cohort that evaluates interventions has been published. We conducted a systematic review of the literature to characterize the reporting of clinical criteria and response to neoadjuvant therapy for IBC. PATIENTS AND METHODS: We searched MEDLINE and other sources for the following: previously untreated patients with IBC without metastasis in cohort studies; utilized chemotherapy; and reported clinical outcomes. The following 4 groups were analyzed: no anthracycline induction, low-dose anthracycline induction, moderate-dose anthracycline induction, and high-dose chemotherapy requiring stem cell support. Weighted averages for the overall response rates were calculated using a random effects model. RESULTS: Twenty-seven studies met all criteria, totaling 1232 patients. Clinical description of IBC eligibility criteria and reported response assessments varied significantly among studies. The response rates and 3- and 5-year overall survival for all 27 studies ranged from 14% to 100%, 22% to 84%, and 32% to 75%, respectively. Pathologic complete response rates after no anthracycline induction, low-dose anthracycline induction, moderate-dose anthracycline induction, and neoadjuvant high-dose chemotherapy subgroups were 4% (95% confidence interval [CI], 1%-18%), 11% (95% CI, 7%-17%), 14% (95% CI, 8%-22%), and 32% (95% CI, 24%-41%), respectively. CONCLUSION: The criteria and reporting of IBC and treatment response was notably variable, with significant potential for subject heterogeneity. Pathologic complete response rates appear to be related to intensity of neoadjuvant treatment; however, this analysis is not based on randomized data. Future clinical trials should define and report the criteria for IBC diagnosis and response assessment to enhance interstudy comparisons.

Gonzalez-Angulo, AM., et al. (2006). Downregulation of the cyclin-dependent kinase inhibitor p27kip1 might correlate with poor disease-free and overall survival in inflammatory breast cancer. Clinical Breast Cancer, 7(4), 326-30. Abstract below, free full text not available.

The objective of this study was to evaluate whether p27kip1 downregulation is a prognostic factor in patients with inflammatory breast carcinoma (IBC). PATIENTS AND METHODS: Fifty-eight patients with IBC were treated between January 1994 and July 2002. Median age was 49 years. Thirty-eight patients had baseline biopsy specimens. Patients received preoperative chemotherapy with FAC (5-fluorouracil/doxorubicin/cyclophosphamide; 34%) or FAC followed by a taxane (66%). All patients underwent mastectomies. All patients received radiation therapy and hormonal treatment when indicated. Expression level of p27kip1 was evaluated by indirect immunoperoxidase procedure. The p27kip1 was considered downregulated if nuclear staining was present in < 50% of the neoplastic cells. RESULTS: Thirty-two patients (84%) had p27kip1-downregulated tumors, and 6 patients (17%) had p27kip1-normal tumors. Six patients (16%) exhibited a pathologic complete response. At a median follow-up of 43 months, 25 recurrences (66%) and 27 deaths (71%) occurred. Patients with p27kip1-downregulated tumors had fewer pathologic complete responses (9% vs. 50%; P = 0.03) and had lower 4-year recurrence-free survival (23% vs. 83%; P = 0.03) and overall survival rates (36% vs. 83%; P = 0.01). CONCLUSION: The p27kip1 deregulation manifested by low protein cellular concentration might represent an adverse prognostic marker in IBC and could provide a valuable tool for selecting treatment for this aggressive disease.

Veyret, C., et al. (2006). Inflammatory breast cancer outcome with epirubicin-based induction and maintenance chemotherapy: ten-year results from the French Adjuvant Study Group GETIS 02 Trial. Cancer, 107(11), 2535-44. Abstract below, free full text at link above.

The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen. METHODS: One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed. RESULTS: The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome. CONCLUSIONS: FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC.

Nguyen, DM., et al. (2006). Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype. Clinical Cancer Research, 12(17), 5047-54. Abstract below, free full text at link above.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.