Shinzaburo Noguchi

The detection of breast carcinoma micrometastases in axillary lymph nodes by means of reverse transcriptase‐polymerase chain reaction

Background. The development of a sensitive method for the detection of breast carcinoma micrometastases in axillary lymph nodes is reported.

Involvement of up-regulation of 17β-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers

Estradiol (E2) and estrone (E1) levels as well as mRNA expression levels of aromatase, sulfatase and 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) in breast cancer tissues were studied to elucidate the mechanism involved in the maintenance of the intratumoral high E2 levels in postmenopausal patients with very low serum E2 levels. Intratumoral E2 levels of postmenopausal patients (127.2 ± 17.5 pg/g) (mean ± SE) were not significantly different from those of premenopausal patients (110.1 ± 10.1 pg/g) (p = 0.36). The mRNA expression levels of aromatase and sulfatase, determined by a quantitative real‐time PCR, were not significantly different between premenopausal and postmenopausal breast cancers, but 17β‐HSD1 mRNA expression levels were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.05). Intratumoral E2/E1 ratios were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.01). These results demonstrate that the increased conversion from E1 to E2 catalyzed by 17β‐HSD1 may play an important role in the maintenance of the intratumoral high E2 levels in postmenopausal patients.

Quantitative analysis of estrogen receptor‐β mRNA and its variants in human breast cancers

We have carried out a quantitative analysis of ER‐α and ER‐β mRNA expression in normal (n = 11) and breast cancer (n = 112) tissues using a real‐time (Taq‐Man) PCR assay. Expression of ER‐β mRNA variants has also been studied by triple‐primer PCR assay. ER‐α mRNA levels in normal breast tissues were significantly (p < 0.01) lower than those in ER‐positive breast cancers but not significantly different from those in ER‐negative breast cancers. However, ER‐β mRNA levels in normal breast tissues were significantly (p < 0.01) higher than those in ER‐positive and ER‐negative breast cancers. Proportions of ER‐β1 and ER‐β2 mRNA expression among total ER‐β mRNA expression were significantly higher and those of ER‐β5 and ER‐β5` mRNA were significantly lower in normal breast tissues than in ER‐positive and ER‐negative breast cancers. ER‐β mRNA levels and proportions of ER‐β mRNA variants did not show any significant correlation with age, tumor size, lymph node status and histological grade. Our results demonstrate that ER‐α mRNA is up‐regulated and ER‐β mRNA is down‐regulated during carcinogenesis of breast cancers. Changes in proportions of ER‐β mRNA variants are also implicated in this process. Int. J. Cancer 88:733–736, 2000.

Fibroadenoma and Phyllodes Tumor

Background. The histogeneses of fibroadenoma and phyllodes tumor of the breast appear to be closely related, but it is still unclear whether fibroadenoma can progress directly to phyllodes tumor.

Predictive factors for response to docetaxel in human breast cancers

Docetaxel has come into wide use recently for the treatment of breast cancer in neoadjuvant, adjuvant and metastatic settings. Docetaxel binds to β‐tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization, resulting in elevated levels of microtubule formation. During metaphase, defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest, culminating in apoptosis. However, docetaxel is not effective for all breast cancers. For example, in metastatic settings, the response rate to docetaxel reportedly ranges from 30 to 50%. It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment. Currently it is impossible to identify, before the initiation of therapy, the patients for whom docetaxel will be effective. Various biological parameters have been studied clinically for their ability to predict response to docetaxel, such as parameters related to: (1) efflux (p‐glycoprotein) and metabolism (CYP3A4); (2) β‐tubulin (somatic mutation of β‐tubulin and changes in β‐tubulin isotypes levels); (3) cell cycle (HER2, BRCA1 and Aurora‐A); and (4) apoptosis (p53, BCL2 and thioredoxin). More recently, gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel. In the present paper, clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field. (Cancer Sci 2006; 97: 813–820)

Combination technique is superior to dye alone in identification of the sentinel node in breast cancer patients.

The purpose of the present study was to evaluate whether the combination of dye and radioisotope would improve the detection rate of sentinel nodes (SN) and the diagnostic accuracy of axillary lymph node status over dye alone in patients with breast cancer.

Abnormal expression of BRCA1 and BRCA1‐interactive DNA‐repair proteins in breast carcinomas

Breast cancer is one of the most common malignancies among women. The molecular mechanisms involved in breast carcinogenesis, however, remain to be elucidated. Although somatic mutation of BRCA1 is rare, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas (Yoshikawa et al., Clin. Cancer Res., 5:1249–1261, 1999), indicating its possible involvement even in sporadic breast carcinogenesis. Among the BRCA1‐interactive proteins are hRAD51 (a human homologue of Escherichia coli rec A protein), BARD1 (BRCA1‐associated RING domain 1) and p53, all of which are involved in DNA repair. We have analyzed the expression patterns of the hRAD51, BARD1 and p53 proteins in five breast cancer cell lines, including a BRCA1‐deficient cell line, and in 179 breast cancer tissue samples from Japanese women, including 113 sporadic, 47 hereditary (i.e., BRCA1 status unknown), and 19 BRCA1‐associated cases. Of the 179 breast carcinomas, fifty‐four (30%) exhibited reduced hRAD51 expression, and sixty‐two (35%) exhibited p53 overexpression. On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch‐repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases. The overall frequency of sporadic breast carcinomas with abnormal expression of either BRCA1 or the BRCA1‐interactive proteins was 67% (76/113). These results indicate that there may be an important role for the BRCA1‐associated DNA‐repair pathway, not only in BRCA1‐associated breast carcinomas, but also in sporadic breast carcinomas. Int. J. Cancer 88:28–36, 2000.

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

BACKGROUND Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. METHODS In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0-2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. FINDINGS Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637-0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83-20·99) in the fulvestrant group versus 13·8 months (11·99-16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. INTERPRETATION Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. FUNDING AstraZeneca.

Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene

To investigate the clonality of uterine leiomyomas, we developed a PCR-based method involving the differential inactivation of the X-chromosome-linked phosphoglycerokinase (PGK) gene. Small DNA samples of 22 leiomyomas from 9 Japanese patients, showing heterozygosity at the BstXI site of the PGK gene, were digested with the methylation-sensitive restriction enzyme HpaII. Only the inactive (methylated) PGK gene allele was selectively amplified by PCR followed by digestion with BstXI and electrophoresis. All leiomyoma samples consisted of a single type of inactive allele, even though alleles were detected that were specific to each nodule. The results indicated that all leiomyoma nodules were unicellular in origin but independently generated in the uterus.

Preoperative evaluation of prognosis in breast cancer patients by [18F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography

Purpose [18F]2-Deoxy-2-fluoro-D-glucose (FDG)-positron emission tomography (PET) was applied to breast cancer patients for the purpose of preoperative evaluation of patient prognosis with more accuracy than conventional TNM staging.Methods FDG-PET was performed preoperatively in 81 patients with breast cancer, and the maximum standardized uptake value (SUVmax) of tumors as well as the focal accumulation of FDG in the axillary region (PET-N status) were investigated in their association with patient prognosis.Results The SUVmax high group (n=40) showed a significantly (P=0.011) poorer prognosis than the SUVmax low group (n=41) (5-year disease-free survival (DFS) rates; 75.0% vs 95.1%). FDG-PET was more accurate in the diagnosis of axillary lymph node status than physical examination, i.e., diagnostic accuracy was 80% and 70% for FDG-PET and physical examination, respectively. The combination of high SUVmax and positive PET-N (+) was shown to be a highly significant risk factor being independent of the clinical T and N factors, i.e., patients with high SUVmax and positive PET-N (+) showed a significantly (P<0.001) poorer prognosis than the other patients (5-year DFS rates; 44.4% vs 96.8%).Conclusions These results suggest that FDG-PET is useful in the preoperative evaluation of prognosis in breast cancer patients with more accuracy than conventional TNM staging. It is expected that the indication of neoadjuvant chemotherapy can be decided more precisely by the preoperative evaluation of patient prognosis with FDG-PET due to a possible elimination of overtreatment for those who have good prognosis and, thus, need not to be treated with chemotherapy.