2001: Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer.
Cancer Res 2001 Jan 15;61(2):445-51, Shirakawa K, et al.
“We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The graft was transplantable in BALB/c nude and severe combined immunodeficient (SCID) mice. WIBC-9 was frequently accompanied by lung metastasis and exhibited erythema of the overlying skin, reflecting its human counterpart. Histological study of the original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, absence of endothelial cells, central necrosis, and fibrosis were observed. In vitro, WIBC-9 formed tube-like structures and loops, reflecting its in vivo feature and its human counterpart. WIBC-9 exhibited aneuploidy, ErbB-2 gene amplification, and an absence of estrogen receptor and progesterone receptor, which is consistent with IBC. Comparative studies of WIBC-9, three established non-IBC xenografts, and a human breast cancer cell line (SK-BR3) by reverse transcription-PCR, ELISA, and immunohistochemistry indicated that certain human genes (interleukin 8, vascular epidermal growth factor, basic fibroblast growth factor, angiopoietin 13, Flt-1, Tie-2, and Tie-1) and certain murine genes (integrin alpha(v)beta3, flt-1, tie-2, vascular epidermal growth factor, and CD31) were overexpressed in exposure to tumor cells. The molecular basis and these unique histological features may be associated with aggressive IBC on angiogenic and nonangiogenic pathways.“
2001: Congestive heart failure mimicking inflammatory breast carcinoma: a case report and review of the literature.
Breast J 2001 Mar-Apr;7(2):117-9, Oraedu CO, et al.
“Inflammatory breast cancer is a rare but highly malignant form of breast cancer. Biopsy and histologic examination usually confirm the diagnosis. There are rare reports of difficulties in differentiating this particular type of breast malignancy from congestive heart failure (CHF). This difficulty arises when CHF is associated with unilateral breast edema and skin thickening. However, inflammatory breast carcinoma has distinctive histologic and microscopic characteristics allowing the establishment of a proper diagnosis. We report the case of a 65-year-old woman with CHF associated with unilateral breast edema and skin thickening simulating inflammatory breast carcinoma on mammography.“
2001: Inflammatory Breast Cancer (IBC) is Associated with an Increased Microvessel Density (MVD) Compared with Non-Inflammatory Breast Cancer.
2001 ASCO poster 3078, McCarthy NJ, et al.
“IBC is a rare clinicopathologic entity characterized by lymphatic invasion and angioinvasive features. We studied 58 archival tumors, obtained prior to chemotherapy, by immunohistochemistry (Br. .J. Cancer 1982:45:367-74). Patients (pts) were categorized according to PEV (pousse evolutive) status: PEV 0 - tumor without recent increase in volume or inflammatory signs; PEV 1 - tumor with marked increase in volume in the last 2 months without inflammatory signs; PEV 2 - tumor showing inflammation and edema involving < ” breast surface and PEV 3 - tumor with inflammation and edema involving > ” breast surface. Epithelial membrane antigen staining was used to confirm the diagnosis. Greater than 80% of all tumors were infiltrating ductal. Tumors were considered positive for p53 (NCL-p53-DO7) when >10% tumor cells stained. CD31 (DAKO JC/70A) was used as a marker for microvessel density (MVD) in a high power field. Scores were low (<25), mod (26-50) and high (>50). Results: see table below. We conclude that there is an apparent increase in p53 positivity and MVD in pts with IBC. Further studies with other angiogenesis markers will be presented.“
| PEV 0 (n=17) | PEV 1 (n=9) | PEV 2/3 (n=32) | |
| Median age years (range) | 48 (18-73) | 45 (34-56) | 48 (32-72) |
| Nuclear grade 3 | 15/17 (88%) | 7/8 (88%) | 27/28 (96%) |
| Histologic grade poor | 13/17 (77%) | 7/9 (78%) | 28/31 (90%) |
| p53 + | 5/16 (31%) | 3/9 (33%) | 17/32 (53%) |
| c-erbB-2 0-1+ | 8/17 (47%) | 6/9 (67%) | 20/32 (63%) |
| c-erbB-2 3+ | 8/17 (47%) | 2/9 (22%) | 11/32 (34%) |
| MVD | |||
| 0-low | 12/13 (92%) | 3/4 (75%) | 8/20 (40%) |
| mod-high | 1/13 (8%) | 1/4 (25%) | 12/20 (60%) |
2001: Congestive heart failure mimicking inflammatory breast carcinoma: a case report and review of the literature.
Breast J 2001 Mar-Apr;7(2):117-9, Oraedu CO, et al.
“Inflammatory breast cancer is a rare but highly malignant form of breast cancer. Biopsy and histologic examination usually confirm the diagnosis. There are rare reports of difficulties in differentiating this particular type of breast malignancy from congestive heart failure (CHF). This difficulty arises when CHF is associated with unilateral breast edema and skin thickening. However, inflammatory breast carcinoma has distinctive histologic and microscopic characteristics allowing the establishment of a proper diagnosis. We report the case of a 65-year-old woman with CHF associated with unilateral breast edema and skin thickening simulating inflammatory breast carcinoma on mammography.“
2001: Persistent E-cadherin expression in inflammatory breast cancer.
Mod Pathol 2001 May;14(5):458-64, Kleer CG, et al.
“E-cadherin is a transmembrane glycoprotein that mediates epithelial cell-to-cell adhesion. Because loss of E-cadherin expression results in disruption of cellular clusters, it has been postulated that E-cadherin functions as a tumor suppressor protein. The role of E-cadherin in inflammatory breast cancer (IBC), a distinct and highly aggressive form of breast cancer, is largely unknown. The aim of our study was to elucidate whether E-cadherin expression contributes to the development and progression of the IBC phenotype and to investigate any differences in E-cadherin expression between IBC and stage-matched non-IBC. Forty-two breast cancer cases (20 IBC and 22 non-IBC) were identified. Strict and well-accepted criteria were used for the diagnosis of IBC. Clinical and pathologic features were studied, and formalin-fixed, paraffin-embedded tissue sections were immunostained for E-cadherin, estrogen and progesterone receptors (ER and PR, respectively), and HER2/neu. Statistical analysis was performed using Fisher’s exact test. All IBC uniformly expressed E-cadherin, whereas 15 of the 22 (68%) of the non-IBC expressed the protein (P = .006). Intralymphatic tumor emboli in the IBC cases were also all E-cadherin positive. Two IBC tumors demonstrated invasive lobular histology, and both cases were positive for E-cadherin. Of the non-IBC cases, three were invasive lobular carcinomas, and all were positive for E-cadherin. No association was found between E-cadherin expression and ER, PR status, or HER2/neu overexpression. Our study demonstrates that there is a strong association between E-cadherin expression and IBC and suggests that E-cadherin may be involved in the pathogenesis of this form of advanced breast cancer. In our study, we demonstrate that circulating IBC tumor cells strongly express E-cadherin, thereby providing an important exception to the positive association between E-cadherin loss and poor prognosis in breast cancer.“
2001: An intact overexpressed E-cadherin/alpha,beta-catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma.
Cancer Res 2001 Jul 1;61(13):5231-41, Tomlinson JS, et al.
“The step of intravasation (lymphovascular invasion), a rate-limiting step in metastasis, is greatly exaggerated in inflammatory breast carcinoma (IBC). Comparing MARY-X with common non-IBC cell lines/xenografts, we discovered an overexpressed and overfunctioning E-cadherin/alpha,beta-catenin axis. In MARY-X, the E-cadherin and catenins were part of a structurally and functionally intact adhesion axis involving the actin cytoskeleton. In vitro, MARY-X grew as round compact spheroids with a cell density 5-10-fold higher than that of other lines. The spheroids of MARY-X completely disadhered when placed in media containing absent Ca(2+) or anti-E-cadherin antibodies or when retrovirally transfected with a dominant-negative E-cadherin mutant (H-2K(d)-E-cad). Anti-E-cadherin antibodies injected i.v. immunolocalized to the pulmonary lymphovascular emboli of MARY-X and caused their dissolution. A total of 90% of human IBCs showed increased membrane E-cadherin/alpha,beta-catenin immunoreactivity. These findings indicate that it is the gain and not the loss of the E-cadherin axis that contributes to the IBC phenotype.“
2001: Expression of amphiregulin and epidermal growth factor receptor in human breast cancer: analysis of autocriny and stromal-epithelial interactions.
J Pathol 2001 Aug;194(4):413-9, Ma L, et al.
“Amphiregulin (AR) and its receptor, epidermal growth factor receptor (EGFR), were evaluated by dual immunostaining in a series of 84 invasive ductal breast carcinoma specimens, 33 of which were from locally advanced inflammatory (T4d) cancer. Co-expression of AR and EGFR was always found in non-malignant breast tissues adjacent to tumours (24/24). Alternatively, expression of AR and EGFR was found in invasive epithelial tumour cells in 50% and 17.8% of specimens, respectively. In tumour stroma, 59.5% and 30.9% of specimens, respectively, were positively stained. By univariate analysis, AR and EGFR expression in invasive carcinomas was correlated with large tumour size, inflammatory carcinoma, node involvement, Bloom-Richardson (SBR) grade III, and absence of oestrogen receptor. EGFR expression in stromal cells was correlated with non-inflammatory carcinoma. A putative autocrine loop with AR and EGFR expression in invasive carcinoma was detected in 14.3% of cases. Stromal expression of AR and EGFR expression in invasive tumour cells was detected in 11.9% of cases and related to poor prognostic parameters. By multivariate analysis, AR expression in invasive tumour was strongly related to inflammatory carcinoma (p=0.005) and marginally related to SBR grade III (p=0.07). EGFR expression in invasive tumour and stromal cells was correlated with absence of oestrogen receptor and non-inflammatory carcinoma (p=0.002 and p=0.015, respectively). Copyright 2001 John Wiley & Sons, Ltd.“
2001: Allelic loss detection in inflammatory breast cancer: improvement with laser microdissection.
Lab Invest 2001 Oct;81(10):1397-402, Bertheau P, et al.
“SUMMARY: Solid tumors are composed not only of tumor cells but also of stromal nonneoplastic cells. In whole tumor samples, stromal cells retaining their alleles may therefore obscure detection of loss of heterozygosity (LOH) in tumor cells. An increasing number of studies have used laser-assisted tissue microdissection to improve LOH detection, but the real gain in sensitivity has been poorly quantified. We studied a group of 16 inflammatory breast carcinomas that were submitted to both standard DNA extraction from frozen whole tumor samples and laser microdissection performed on paraffin-embedded tumor samples. Using PCR with fluorescence-labeled primers, we comparatively analyzed ten polymorphic markers with both sources of DNA. With the LOH detection threshold set at -25%, we showed that 25 LOHs could not be diagnosed with whole tumor samples out of 73 LOHs positively diagnosed in microdissected samples (34%). With the LOH detection threshold set at -50%, the respective figures were 39 LOHs not diagnosed out of 55 LOHs (71%). Measuring the intensity of the allelic decrease, we showed that the mean decrease of the lost allele is -34% with whole tumor samples and -67% with microdissected samples. The increase in sensitivity of LOH detection with microdissection is associated with the density of stromal cells. This strong improvement in LOH detection in this aggressive type of breast cancer indicates that many other molecular studies performed on heterogeneous solid tumors may benefit from a first step of laser microdissection.“
2001: Case control study of prognostic markers and disease outcome in inflammatory carcinoma breast: a unique clinical experience.
Breast J 2001 Nov-Dec;7(6):398-404, Aziz SA, et al.
“Inflammatory breast carcinoma (IBC) is a rare but aggressive form of breast cancer. In this first-ever study, we investigated the role of nine prognostic markers’ expression (estrogen receptor [ER], progesterone receptor [PR], p53, C-erbB-2, epidermal growth factor receptor [EGFR], cathepsin D [CD], proliferating cell nuclear antigen [PCNA], DNA ploidy, and S-phase fraction [SPF]) and disease outcome in IBC cases compared with the control group. A case control study of IBC was conducted on 40 test cases with two controls per case matching age, grade, and number of axillary lymph nodes sampled. During 7 years of this study, 10% of all patients with breast cancer had IBC. In this study, 84% of IBC cases showed positive axillary lymph nodes compared with 63% in control group. The expression of nine prognostic markers, that is, ER, PR, p53, C-erbB-2, EGFR, CD, PCNA, SPF, and DNA ploidy, was studied by immunohistochemistry and flow cytometry. Hormone receptor status showed an inverse correlation (p < 0.05). Among p53, C-erbB-2, EGFR, and CD in the IBC group, only p53 showed a significant correlation, with 70% positivity in IBC versus 48% positivity in the control group (p < 0.05). Much higher SPF and PCNA positivity was seen in the IBC group compared with the control group (p < 0.05). DNA ploidy also showed a significant correlation compared with the control group (p < 0.05). After a median follow up of 18 months, median overall survival in the IBC group was 1.8 years (range 0.6-5.8 years) compared with 3.0 years (range 2.5-7.0 years), with a p value of 0.0001.“
2001: Farnesyltransferase inhibitors: mechanism and applications.
Expert Opin Investig Drugs 2001 Dec;10(12):2105-16, Prendergast GC, et al.
“Farnesyltransferase (FT) inhibitors (FTIs) are among the first wave of signal transduction inhibitors to be clinically tested for antitumour properties. FTIs were designed to attack Ras oncoproteins, the function of which depends upon post-translational modification by farnesyl isoprenoid. Extensive preclinical studies have demonstrated that FTIs compromise neoplastic transformation and tumour growth. In preclinical models, FTIs display limited effects on normal cell physiology and in Phase I human trials FTIs have been largely well tolerated. Exactly how FTIs selectively target cancer cells has emerged as an important question, one which has become more pressing with the somewhat disappointing results from initial Phase II efficacy trials. Although FTI development was predicated on Ras inhibition, it has become clear that the drugs’ antineoplastic properties are based to a large degree on altering the prenylation and function of proteins other than Ras. One key candidate that has emerged is RhoB, an endosomal protein that has been implicated in selective growth inhibition and apoptosis in neoplastic cells. On the basis of mechanistic studies and other recent developments, we propose that FTIs may be useful to treat a unique spectrum of diseases including not only inflammatory breast cancer and melanoma but also non-neoplastic diseases such as diabetic retinopathy and macular degeneration.“
