Sadako Akashi-Tanaka

Identification of 20 genes aberrantly methylated in human breast cancers.

Aberrant methylation of CpG islands (CGI) not only plays a role in gene silencing, but is also a potential cancer biomarker. To identify more CGI aberrantly methylated in human breast cancers, we carried out a genome‐wide search for aberrant methylation, using methylation‐sensitive‐representational difference analysis. CGI in 5′ upstream regions of 20 genes, TSPAN‐2, AK5, LOC284999, HOXD11, FLJ25161, XT3, PCDH10, PCDHGB6, SIM1, LOC346978, COE2, TDH (FLJ25033), LOC346419, FLJ33790, GJB2, AMN, LOC201164, DLX4, DCC and FOXA2, were found to be methylated in at least one of 8 breast cancer cell lines. Fifteen of the 20 genes were methylated in more than one of 21 primary breast cancers in Stages I or II, and especially, those of LOC346978, HOXD11, SIM1, PCDHGB6 and FLJ25161 were methylated in more than 10 cancers. All the breast cancers had some aberrant methylation. Among the 13 genes whose CGI were completely methylated in one or more cell lines, FOXA2 and XT3 were expressed in normal human mammary epithelial cells (HMEC) and were not expressed in cancer cell lines with complete methylation. The other 11 genes examined were barely expressed, or not expressed even in HMEC. Our results showed that breast cancer cells accumulate aberrant methylation of the CGI identified here. This may serve as markers for early‐stage breast cancers and suggests that aberrant methylation targets transcriptionally inactive genes in vivo.

c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues.

We investigated whether expression levels of c‐erbB‐2 and p53 proteins in breast cancer tissues differ in primary and metastatic lesions.

Histopathological criteria for assessment of therapeutic response in breast cancer (2007 version)

In preoperative drug therapy (chemo-, endocrine, molecular-targeting, and other therapies) and/or radiotherapy for breast cancer, various degrees of histological changes of cancer tissue occur depending on the sensitivity of cancer cells to the particular treatment, kinds of therapeutic agents, dosage of drugs, method of administration, kind of combination, type and dosage of isotope, method of irradiation, duration of treatment, interval from the last treatment, and resection of cancer tissue. Histopathological criteria for assessment of response to neoadjuvant therapy for breast cancer have been established according to the degree of histological change of cancer tissue as described below. Histological diagnosis should be confirmed before treatment using biopsy materials, and it is important to compare the histopathological findings of cancer tissues before and after treatment for the assessment of response to therapy. Pathological response should be evaluated only from histological changes in the invasive area, and the presence of residual ductal components should be described. If only ductal components remain, the pathological response is evaluated as Grade 3.

Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer

BackgroundTumor markers are frequently used for screening and monitoring in oncology. We investigated the use of preoperative tumor marker (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA] 15-3) levels in estimating the prognosis of breast cancer patients.MethodsWe conducted a retrospective study in patients who underwent breast cancer surgery at National Cancer Center Hospital between 1975 and 1994 and whose serum CEA (n = 1663) and CA 15-3 (n = 1500) levels were measured prior to operation. When we excluded patients with stage IV disease from the study, the CEA level was within the normal range in 1470 patients, while 150 patients had an elevated CEA level. For CA 15-3, 1395 patients were within the normal range, while 70 patients exhibited an elevated level.ResultsThe 5-year and 10-year survival rates for patients with normal CEA levels were 87% and 76%, respectively. However, the 5-year and 10-year survival rates for patients with elevated CEA levels were 76% and 65%, respectively. At both time points, patients with normal CEA levels had higher survival rates (P < 0.05). The 5-year and 10-year survival rates for the patients with normal CA 15-3 levels were 86% and 76%, respectively, while only 71% and 52% patients with elevated CA 15-3 levels survived at 5 and 10 years, respectively. These differences were also significant (P < 0.05). However, there were no significant differences in disease-free survival (DFS) according to CEA or CA 15-3 levels.ConclusionThere was a positive correlation between CEA levels and CA 15-3 levels and patient prognosis. Thus, the levels of these tumor markers may help to determine prognosis in breast cancer patients.

Diagnostic value of contrast-enhanced computed tomography for diagnosing the intraductal component of breast cancer

Background: It is important to reduce local residual cancer to avoid local recurrence after breast conserving treatment. We therefore tried to detect the Backgroundintraductal components and small invasive foci of breast cancers by contrast-enhanced helical computed tomography (CE-CT). Methods: In 122 women whose breasts were examined by CE-CT preoperatively, intraductal spread detected on ultrasound (US), mammography (MMG), and CE-CT, and extensive intraductal components (EICs) detected by histological examination were analyzed for correlations among the extent and subtypes of intraductal components, and deviations in tumor size. Results: EICs were present in 44 patients. The sensitivities of EIC detection by US, MMG, and CE-CT were 35%, 61%, and 88%, respectively, and the corresponding specificities were 83%, 86%, and 79%, respectively. The sensitivities of detecting EIC and small invasive foci were 34%, 57%, and 91%, respectively. In 5 patients, EIC could only be visualized by CE-CT. The median deviation of the size of intraductal spread revealed by CE-CT from pathological EIC was 0.0 cm (range + 3.0 to − 1.7 cm. Conclusions: CE-CT is useful for visualizing intraductal spread and small invasive foci of breast cancer.

Prognosis of a series of 763 consecutive node-negative invasive breast cancer patients without adjuvant therapy: Analysis of clinicopathological prognostic factor

The objectives of this study were to confirm the favorable outcome of Japanese invasive breast cancer patients without lymph node metastasis, after treatment with surgery alone, and to evaluate clinicopathological prognostic factors in this population.

Metaplastic carcinoma of the breast

The purposes of this study were to investigate whether the biological characteristics or outcomes of patients with metaplastic carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma of the breast differ; to determine whether the metaplastic carcinoma subtypes have similar malignant potentials; and to identify accurate predictors of outcome in patients with metaplastic carcinoma. The subject comprised 6137 invasive ductal carcinoma patients, 301 invasive lobular carcinoma patients, and 46 metaplastic carcinoma patients of the breast. The metaplastic carcinomas were classified according to the World Health Organization classification. Multivariate analyses clearly demonstrated that the metaplastic carcinoma patients had a significantly poorer outcome than the invasive ductal carcinoma patients or the invasive lobular carcinoma patients independent of the nodal status or age not exceeding 39 years, whereas patients with triple-negative metaplastic carcinomas or triple-negative invasive lobular carcinomas had a poorer outcome than those with triple-negative invasive ductal carcinomas. Although no significant differences in clinical outcome were observed among the metaplastic carcinoma subtypes in multivariate analyses, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant outcome predictors for metaplastic carcinoma patients. In conclusion, the results of this study clearly demonstrated that metaplastic carcinoma is more aggressive than invasive ductal carcinoma or invasive lobular carcinoma. Although the metaplastic carcinoma subtypes had no prognostic significance, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant predictors of outcome among metaplastic carcinoma patients.

Histological and immunohistochemical analysis of apocrine breast carcinoma

BackgroundThere are few data regarding the biological characteristics of apocrine breast carcinoma in the literature due to its rarity and controversy over its definition. We analyzed the histopathological characteristics and tumor biology of apocrine breast carcinomas with regard to histological grade, p53, HER2, bcl-2, MIB-1 and hormone receptor status.Patients and MethodsA consecutive series of 24 female apocrine breast carcinoma patients were the primary source of these retrospective data. Background factors including histological grade, nodal status and lymphatic invasion by tumor cells were analyzed. Immunohistochemical staining for p53, HER2, MIB-1, bcl-2, estrogen receptor (ER) and progesterone receptor (PR) was carried out on formalin-fixed, paraffin embedded specimens.ResultsOlder age and postmenopausal status were observed more frequently in patients with apocrine breast carcinoma than those with invasive ductal carcinoma. Apocrine breast carcinoma also showed relatively lower histological grade than invasive ductal carcinoma. Nuclear accumulation of p53, HER2 overexpression, bcl-2 and MIB-1 index were observed in 29% (7/24), 33%(8/24), 25%(6/24) and 29% (7/24) of cases, respectively. Positivity for ER and PR was present in 17% (4/24) and 17% (4/24) of cases, respectively.ConclusionsApocrine breast carcinoma tended to show low MIB-1 index, low bcl-2 expression and low positive rate of hormone receptors. There was no correlation between the three types of apocrine carcinoma and the positivity rate of p53, HER2, bcl-2, MIB-1 and hormone receptor status.

Association between frequent CpG island methylation and HER2 amplification in human breast cancers

The presence of frequent methylation of CpG islands (CGIs), designated as the CpG island methylator phenotype in some cancers, is associated with distinct clinicopathological characteristics, including gene amplification, in individual tumor types. Amplification of HER2 in human breast cancers is an important prognostic and therapeutic target, but an association between HER2 amplification and frequent CGI methylation is unknown. To clarify the association, we here quantified methylation levels of promoter CGIs of 11 genes, which are unlikely to confer growth advantage to cells, in 63 human breast cancers. The number of methylated genes in a cancer did not obey a bimodal distribution, and the 63 cancers were classified into those with frequent methylation (n = 16), moderate methylation (n = 26) and no methylation (n = 21). The incidence of HER2 amplification was significantly higher in the cancers with frequent methylation (11 of 16) than in those with no methylation (2 of 21, P = 0.001). Also, the number of methylated genes correlated with the degree of HER2 amplification (r = 0.411, P = 0.002). Correlation analysis with clinicopathological characteristics and methylation of CDKN2A, BRCA1 and CDH1 revealed that frequent methylation had significant correlation with higher nuclear grades (P = 0.001). These showed that frequent methylation had a strong association with HER2 amplification in breast cancers and suggested that frequent methylation can be a determinant of various characteristics in a fraction of human breast cancers.

The Use of Contrast-Enhanced Computed Tomography Before Neoadjuvant Chemotherapy to Identify Patients Likely to Be Treated Safely With Breast-Conserving Surgery

Objective:To select suitable candidates for breast-conserving treatment (BCT) after neoadjuvant chemotherapy (NAC), based on the classification of tumors into localized or diffuse types using contrast-enhanced computed tomography (CE-CT). Summary Background Data:A relatively high rate of loco-regional failure after BCT has been reported with breast cancer downstaged by NAC. Accurate assessment of the suitability of BCT and the response to NAC, before the initiation of NAC, will allow the optimal selection of an appropriate therapeutic course. Methods:We evaluated 110 consecutive patients with operable breast carcinomas measuring 3-cm or more in diameter by CE-CT after NAC treatment with doxorubicin and docetaxel at National Cancer Center Hospital, Tokyo, from May 1998 to November 2001. Lesions were classified as either localized or diffuse types by mammography (MMG), ultrasonography (US), and CE-CT. Results:Tumors designated as localized type by MMG, US, and CE-CT were reduced to tumors less than 3.0 cm (P < 0.0001) in a concentric circle (P < 0.0001). Localized tumors by CE-CT were treated safely with BCT maintaining a negative margin status (P = 0.01). In contrast, diffuse type tumors shrunk into a mosaic pattern consisting of tumors larger than 3.1 cm. Tumors classified as localized by CE-CT responded better pathologically than diffuse tumors (P = 0.0365). Multivariate analysis demonstrated that morphologic type by CE-CT and histologic type were significant predictors of candidates for safe BCT. Conclusions:The classification of tumors into either localized or diffuse types, using CE-CT before NAC administration, accurately predicts which tumors will be suitable candidates for BCT after NAC.