Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment.

BACKGROUND: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. METHODS: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. RESULTS: Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. CONCLUSION: These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

Correlation of three-dimensional magnetic resonance imaging with precise histopathological map concerning carcinoma extension in the breast.

This study was initiated to clarify the ability of magnetic resonance imaging (MRI) in defining breast carcinoma extension by comparing MRI to detailed histopathological analysis. Mastectomy (n = 14) or quadrantectomy (n = 44) specimens were sub-serially sectioned and mapped in detail in 58 breast cancer patients. Morphologically, we classified the lesions utilizing MRI into three patterns in relation to their histology. Numerically, we assessed the maximum distance of carcinoma extension using MRI, mammography, and ultrasonography (US). Linear regression was calculated for each of the three imaging measurements versus histopathological measurements. Three imaging patterns were observed by MRI, (1) localized (n = 30), (2) segmentally extended (n = 19), and (3) irregularly extended (n = 5). The localized pattern showed a distinct focal mass, but in 10 cases, microscopic ductal carcinoma in situ (DCIS), or invasive lobular carcinoma, which were not depicted by MRI, existed. The segmentally extended pattern showed diffuse enhancement along duct-lobular segments, forming a 'cone' shape. Histologically, pure (n = 4) or predominant (n = 10) DCIS was distributed segmentally. The irregularly extended pattern showed thick branches extending out from the index tumor which were histologically revealed to be stromal invasion of ductal carcinoma. From the results of linear regressions, MRI was the most accurate modality in histologically measuring the extent of the cancer. When cases were limited to patients who were classified into segmentally or irregularly extended pattern by MRI (n = 24), MRI was more accurate than mammography and US, even if they were combined (P < 0.05). MRI may provide additional information concerning carcinoma extension prior to surgery, especially in patients classified into 'extended patterns' by MRI.

[Clinical efficacy of low-dose weekly docetaxel combined with oral 5'-deoxy-5-fluorouridine (5'-DFUR) in advanced or metastatic breast cancer: a pilot trial].

Docetaxel (TXT) has been shown to be an up-regulator of human pyrimidine nucleoside phosphorylase (PyNPase) in tumors. We have tried to use the combination of low-dose weekly TXT with 5'-DFUR (LD + D) in patients with advanced or metastatic breast cancer. In this study, we compared the clinical efficacy of LD + D with that of conventional full-dose TXT (FD) and that of low-dose weekly TXT (LD). Twenty-one patients received 3 or 4 cycles of FD 60 mg/m2 every 3 or 4 weeks (group I), 14 patients received 8 cycles of LD 20-30 mg/m2 every week (group II) and 25 patients received 8 cycles of LD 20-30 mg/m2 weekly with oral 5'-DFUR 600-1,200 mg per day (group III). The overall response rates of groups I, II and III were 29%, 29% and 52% (p = 0.24), respectively. Grade 3-4 neutropenia was observed in 91% of group I, 6% of group II and 3% of group III. Nausea was present in 27% of group I, 28% of group II and 40% of group III. Higher incidence of gastrointestinal symptoms was found in LD + D, but the symptoms abated when the doses of 5'-DFUR were reduced. Low-dose weekly TXT with oral 5'-DFUR produced a higher response rate, but less hematologic toxicity than full-dose TXT, suggesting that this combination therapy is clinically useful and may be effective for patients with advanced or metastatic breast cancer.

[Magnetic resonance imaging of breast cancer: correlation between contrast enhancement and tumor angiogenesis].

PURPOSE: To evaluate the association between enhancement characteristics of breast cancers obtained by three-dimensional dynamic MRI and histopathologic findings, especially tumor angiogenesis. MATERIALS AND METHODS: Forty-four women with invasive breast cancer under went preoperative MR imaging. Three-dimensional fast low angle shot (3D-FLASH) images of the whole breast (section thickness, 2 mm; gap, 0 mm; number of sections, 50; acquisition time, 87 sec) were obtained at 90-second intervals for three images (the first image before the injection of Gd-DTPA). Microvessel densities were evaluated in specimens immunohistochemically stained with anti-CD34 antibody. Pearson correlation tests were used to determine the strength of the relationships between enhancement parameters and microvessel densities. Univariate and multivariate analyses were performed to explore the associations with histopathologic factors, including histological grade. RESULTS: The enhancement parameters were correlated with microvessel densities (p < 0.0001). The peripheral microvessel densities were significantly higher than central microvessel densities (p < 0.0001). A significant association with histological grade was observed for the steepest slopes of the dynamic curve and microvessel densities (p < 0.05). CONCLUSION: A correlation between three-dimensional dynamic MRI parameters and microvessel densities, and associations with histological grade were seen. This may allow MRI to be used in the prediction of tumor angiogenesis and tumor grade.

LOH analyses of premalignant and malignant lesions of human breast: frequent LOH in 8p, 16q, and 17q in atypical ductal hyperplasia.

The number of breast cancer patients is increasing yearly, and it is important to establish effective methods for clinical management. We investigated loss of heterozygosity (LOH) in tumors derived from 23 patients that harbored synchronous lesions of atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Fourteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOH in breast cancer. Our results suggested that i) losses of chromosomal regions 8p, 16q, and 17q are early genetic changes, and ii) ADH is a premalignant lesion for the development of breast cancer.