40 results on '"Kurebayashi J"'
Search Results
2. Effects of long-term hypoxia and/or endocrine manipulation on endocrine sensitivity in MCF-7 cells
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Kurebayashi, J., primary, Kishino, E., additional, Ogata, R., additional, Saitoh, W., additional, Koike, Y., additional, Ohta, Y., additional, Kanomata, N., additional, and Moriya, T., additional
- Published
- 2019
- Full Text
- View/download PDF
3. Anti-cancer stem cell activity of the hedgehog inhibitor GANT61 in triple-negative breast cancer cells
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Koike, Y., primary, Ohta, Y., additional, Saitoh, W., additional, Yamashita, T., additional, Kanomata, N., additional, Moriya, T., additional, and Kurebayashi, J., additional
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- 2017
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4. Anti-cancer stem cell activity of the hedgehog inhibitor GANT61 in ER-positive breast cancer cells
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Kurebayashi, J., primary, Koike, Y., additional, Ohta, Y., additional, Saitoh, W., additional, Yamashita, T., additional, Kanomata, N., additional, and Moriya, T., additional
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- 2017
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5. P038 - Anti-cancer stem cell activity of the CDK4/6 inhibitor palbociclib in breast cancer cells
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Kishino, E., Ogata, R., Saitoh, W., Koike, Y., Ohta, Y., Kanomata, N., Moriya, T., and Kurebayashi, J.
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- 2019
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- View/download PDF
6. P039 - Effects of long-term hypoxia and/or endocrine manipulation on endocrine sensitivity in MCF-7 cells
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Kurebayashi, J., Kishino, E., Ogata, R., Saitoh, W., Koike, Y., Ohta, Y., Kanomata, N., and Moriya, T.
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- 2019
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7. Abstract P5-12-07: Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer
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Kurebayashi, J, primary, Toyama, T, additional, Sumino, S, additional, and Fujimoto, T, additional
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- 2016
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8. P083 Anti-tumor and anti-cancer stem cell activities of eribulin and anti-estrogens in breast cancer cells
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Kurebayashi, J., primary, Kanomata, N., additional, Yamashita, T., additional, Shimo, T., additional, and Moriya, T., additional
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- 2015
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9. P092 QOL score changes in breast cancer patients: 2-year vs. 3-or-more-year administration of leuprorelin
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Ohashi, Y., primary, Shiba, E., additional, Toyama, T., additional, Kurebayashi, J., additional, Noguchi, S., additional, and Iwase, H., additional
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- 2015
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10. P050 - Anti-cancer stem cell activity of the hedgehog inhibitor GANT61 in ER-positive breast cancer cells
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Kurebayashi, J., Koike, Y., Ohta, Y., Saitoh, W., Yamashita, T., Kanomata, N., and Moriya, T.
- Published
- 2017
- Full Text
- View/download PDF
11. P051 - Anti-cancer stem cell activity of the hedgehog inhibitor GANT61 in triple-negative breast cancer cells
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Koike, Y., Ohta, Y., Saitoh, W., Yamashita, T., Kanomata, N., Moriya, T., and Kurebayashi, J.
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- 2017
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12. [Neoadjuvant Epirubicin-Cyclophosphamide Therapy followed by Nab-Paclitaxel in Patients with Operable Breast Cancer-A Single-Center Phase Ⅱ Trial].
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Ogata R, Yamamoto Y, Jo A, Fukuma Y, Mikami T, Kawano S, Kishino E, Saito W, Koike Y, Soda M, Nomura T, Tanaka K, and Kurebayashi J
- Subjects
- Albumins, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide, Epirubicin, Female, Humans, Middle Aged, Paclitaxel, Receptor, ErbB-2, Trastuzumab therapeutic use, Treatment Outcome, Breast Neoplasms drug therapy, Breast Neoplasms surgery, Neoadjuvant Therapy
- Abstract
Clinical studies have confirmed that nab-paclitaxel(nab-PTX)therapy is effective and safe in patients with metastatic breast cancer. Neoadjuvant chemotherapy(NAC) with nab-PTX has resulted in a pathological complete response (pCR) rate of 29% in all cases and 58% in HER2-positive cases. However, these data were obtained from an overseas study, and the effectiveness and safety of NAC with nab-PTX remain unclear in Japan. Thus, the present study was conducted to investigate these aspects. In patients with T1-3, N0-2, M0 breast cancer, 4 cycles of 260 mg/m2 nab-PTX were administered every 3 weeks after 4 cycles of EC therapy(100 mg/m2 of epirubicin and 600 mg/m2 of cyclophosphamide)as NAC. In HER2- positive patients, trastuzumab was used in combination with nab-PTX. Overall, 14 patients were registered between October 2014 and October 2018. One patient who had requested for another drug after providing informed consent was excluded, and the remaining 13 patients were analyzed. The primary endpoint was pCR rate. The median age of the subjects was 57 years, and the median tumor diameter was 35 mm. There were 7 cases of Stage Ⅱ disease and 6 cases of Stage Ⅲ disease. As for tumor subtype, there were 7 cases of Luminal-type, 2 cases of Luminal- HER2-type, 4 cases of HER2-type, and no triple negative-type tumors(the cut-off values for estrogen receptor [ER] and progesterone receptor were both 1%). The objective response rate to NAC was 77%(10/13 cases), and no PD was observed. The pCR rate was 54%(7/13 cases): 2 patients had Luminal-type tumors, 1 had a Luminal-HER2-type tumor, and 4 had HER2-type tumors. Predictive factors for pCR were ER negativity and HER2 positivity. Common adverse events of chemotherapy were hair loss, pain, malaise, anemia, dysgeusia, constipation, itchiness, and numbness, but their severity was modest, and they were manageable. This study suggests the efficacy and safety of nab-PTX after EC therapy in Japanese patients with operable breast cancer.
- Published
- 2022
13. A Case of Rare Matrix-producing Triple-negative Breast Carcinoma for Which Drug Response in a Patient-derived Orthotopic Xenograft Mouse Model Was Correlated With Patient Response.
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Nomura T, Kurebayashi J, Moriya T, Saito W, Murata T, Yamamoto J, Hozumi C, and Hoffman RM
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- Adult, Animals, Disease Models, Animal, Female, Humans, Mice, Triple Negative Breast Neoplasms mortality, Xenograft Model Antitumor Assays, Triple Negative Breast Neoplasms drug therapy
- Abstract
Background: Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents., Case Report: A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence., Conclusion: The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2021
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14. A case of human breast sparganosis diagnosed as Spirometra Type I by molecular analysis in Japan.
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Okino T, Yamasaki H, Yamamoto Y, Fukuma Y, Kurebayashi J, Sanuki F, Moriya T, Ushirogawa H, and Saito M
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- Aged, 80 and over, Animals, Breast Diseases diagnostic imaging, Breast Diseases parasitology, Breast Diseases pathology, Female, Humans, Japan, Mammary Glands, Human diagnostic imaging, Mammary Glands, Human pathology, Sparganosis diagnostic imaging, Sparganosis parasitology, Sparganum isolation & purification, Breast Diseases diagnosis, Mammary Glands, Human parasitology, Sparganosis diagnosis, Spirometra isolation & purification
- Abstract
A 92-year-old Japanese woman presented with a mass in the left breast, and sparganosis was suspected by biopsy of the mass. The mass disappeared once, but it reappeared at the same site one year later. For a definitive diagnosis, the mass was surgically removed, and a sparganum-like worm was detected. The causative agent was confirmed as Spirometra Type I (most probably Spirometra mansoni) by mitochondrial DNA analysis. The serological examination also proved the case as sparganosis. Considering the presence of two Spirometra species (Type I and II) in Asia, particularly Japan, molecular analysis of the causative agents is highly recommended to understand the epidemiology, infection sources, and pathogenicity in humans in both species, if the parasite specimens are available., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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15. A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.
- Author
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Kurebayashi J, Shiba E, Toyama T, Matsumoto H, Okazaki M, Nomizu T, Ohtake T, Fujii T, and Ohashi Y
- Subjects
- Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Follow-Up Studies, Humans, Leuprolide adverse effects, Premenopause, Tamoxifen adverse effects, Time Factors, Breast Neoplasms drug therapy, Chemotherapy, Adjuvant methods, Leuprolide administration & dosage, Tamoxifen administration & dosage
- Abstract
Background: Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study., Methods: Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS., Results: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486-1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397-1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011-0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups., Conclusions: Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment., Trial Registration Number: Not applicable. This was an observational study.
- Published
- 2021
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16. Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells.
- Author
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Ogata R, Kishino E, Saitoh W, Koike Y, and Kurebayashi J
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- Aminopyridines pharmacology, Aminopyridines therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Biomarkers, Tumor analysis, Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Down-Regulation drug effects, Drug Resistance, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Phosphorylation drug effects, Piperazines pharmacology, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Receptors, Estrogen antagonists & inhibitors, Receptors, Estrogen metabolism, Retinoblastoma Binding Proteins metabolism, Ubiquitin-Protein Ligases metabolism, Antineoplastic Agents, Hormonal pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms drug therapy, Drug Resistance, Neoplasm drug effects, Protein Kinase Inhibitors pharmacology
- Abstract
Background: Combined endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor has been indicated to improve not only progression-free survival, but also overall survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, resistance to this combination therapy inevitably develops. How to manage this resistant breast cancer is one of the most important clinical issues. To investigate the mechanisms of action responsible for resistance, we developed breast cancer cells resistant to CDK4/6 inhibitors, and analyzed their biological characteristics and sensitivity to different anticancer agents., Methods: HR-positive, HER2-negative MCF-7 and KPL-1 breast cancer cells were cultivated in palbociclib (PAL) or abemaciclib (ABE)-added culture medium for over 5 months, and we successfully developed PAL- or ABE-resistant cells. The effects of PAL or ABE on the cell growth, basal RB expression, RB phosphorylation, cell cycle and cell senescence were compared between resistant and parental cells. Effects of the other CDK4/6 inhibitor, different chemotherapeutic agents and estrogen on the cell growth were also examined. The expression levels of cyclin D1, CDK2, CDK4, CDK6, cyclin E1 and estrogen receptor (ER)-ɑ were measured using RT-PCR., Results: Long-term exposure to up to 200 nM PAL or ABE resulted in the development of PAL- or ABE-resistant MCF-7 or KPL-1 breast cancer cells. Basal expression levels of RB in both resistant cells were down-regulated. Inhibitory effects of either PAL or ABE on RB phosphorylation were reduced in both resistant cells. Accordingly, G1-S cell cycle retardation and cell senescence induced by either inhibitor were also attenuated in both resistant cells. Both resistant cells were cross-resistant to the other CDK4/6 inhibitor but almost as equally sensitive to different chemotherapeutic agents (5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin and eribulin) as the parental cells. The mRNA expression level of CDK6 significantly increased in the resistant MCF-7 cells and that of Rb1 significantly decreased in the resistant KPL-1 cells. Although both resistant cells were less sensitive to estrogen than the parental cells, the expression levels of ER-ɑ did not significantly change in either., Conclusions: Our study suggests that acquired resistance to PAL or ABE confers cross-resistance to the other CDK4/6 inhibitor but not to chemotherapeutic agents in HR-positive, HER2-negative breast cancer cells. Down-regulation of basal RB expression and normalized RB phosphorylation reduced by CDK4/6 inhibitors may be responsible for the attenuated anti-cell growth effects of the inhibitors.
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- 2021
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17. Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions.
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Akahane T, Kanomata N, Harada O, Yamashita T, Kurebayashi J, Tanimoto A, and Moriya T
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- Adult, Aged, Breast Neoplasms pathology, Class I Phosphatidylinositol 3-Kinases genetics, DNA Copy Number Variations genetics, Female, Genomics, Germ-Line Mutation genetics, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local pathology, Receptor, ErbB-2 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Neoplasm Proteins genetics, Neoplasm Recurrence, Local genetics
- Abstract
Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions., Methods: Triplet samples of genomic DNA were extracted from each patient's normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis., Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions., Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.
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- 2020
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18. Automated assessment of Ki-67 in breast cancer: the utility of digital image analysis using virtual triple staining and whole slide imaging.
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Hida AI, Omanovic D, Pedersen L, Oshiro Y, Ogura T, Nomura T, Kurebayashi J, Kanomata N, and Moriya T
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- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Breast pathology, Cell Proliferation, Cohort Studies, Female, Humans, Immunohistochemistry methods, Middle Aged, Neoplasm Grading, Prognosis, Reproducibility of Results, Retrospective Studies, Staining and Labeling methods, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Image Processing, Computer-Assisted methods, Ki-67 Antigen metabolism
- Abstract
Aims: Precise evaluation of proliferative activity is essential for the stratified treatment of luminal-type breast cancer (BC). Immunohistochemical staining of Ki-67 has been widely used to determine proliferative activity and is recognised to be a useful prognostic marker. However, there remains discussion concerning the methodology. We aimed to develop an automated and reliable Ki-67 assessment approach for invasive BC., Materials and Results: A retrospective study was designed to include two cohorts consisting of 152 and 261 consecutive patients with luminal-type BC. Representative tissue blocks following surgery were collected, and three serial sections were stained automatically with Ki-67, pan-cytokeratin and p63. The whole slides were scanned digitally and aligned using VirtualTripleStaining - an extension to the VirtualDoubleStaining™ technique provided by Visiopharm software. The aligned files underwent automated invasive cancer detection, hot-spot identification and Ki-67 counting. The automated scores showed a significant positive correlation with the pathologists' scores (r = 0.82, P < 0.0001). Among selected patients with curative surgery and standard adjuvant therapies (n = 130), the digitally assessed low Ki-67 group (<20%) demonstrated a significantly better prognosis (breast cancer-specific survival, P = 0.030; hazard ratio = 0.038) than the high Ki-67 group., Conclusions: Digital image analysis yielded similar results to the scores determined by experienced pathologists. The prognostic utility was verified in our cohort, and an automated process is expected to have high reproducibility. Although some pitfalls were confirmed and thus need to be monitored by laboratory staff, the application could be utilised for the assessment of BC., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
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19. Anti-cell growth and anti-cancer stem cell activity of the CDK4/6 inhibitor palbociclib in breast cancer cells.
- Author
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Kishino E, Ogata R, Saitoh W, Koike Y, Ohta Y, Kanomata N, and Kurebayashi J
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- Apoptosis, Biomarkers, Tumor metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Movement, Cell Proliferation, Female, Humans, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Tumor Cells, Cultured, Breast Neoplasms pathology, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Neoplastic Stem Cells pathology, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology
- Abstract
Background: A cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib, has been used to treat patients with estrogen receptor (ER)-positive (+) and human epidermal growth factor receptor (HER) 2-negative (-) advanced breast cancer. To investigate the mechanisms underlying the antitumor activity of palbociclib, we conducted a preclinical study on the anti-cell growth and anti-cancer stem cell (CSC) activity of palbociclib in breast cancer cells., Methods: The effects of palbociclib on Rb phosphorylation, cell growth, cell cycle progression, apoptosis, cell senescence and the proportion of CSCs were investigated in five human breast cancer cell lines of different subtypes. To investigate the mechanisms of the anti-CSC activity of palbociclib, small-interfering RNAs for CDK4 and/or CDK6 were used. Palbociclib dose-dependently reduced Rb phosphorylation and cell growth in association with G1-S cell cycle blockade and the induction of cell senescence, but without increased apoptosis, in all breast cancer cell lines., Results: The anti-cell growth activity of palbociclib widely differed among the cell lines. Palbociclib also dose-dependently reduced the CSC proportion measured by three different assays in four of five cell lines. The inhibition of CDK4 expression, but not CDK6 expression, reduced the increased proportion of putative CSCs induced by estradiol in ER (+)/HER2 (-) cell lines., Conclusions: These results suggest that palbociclib exhibits significant anti-cell growth and anti-CSC activity in not only ER (+) breast cancer cell lines but also ER (-) cell lines. CDK4 inhibition induced by palbociclib may be responsible for its anti-CSC activity.
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- 2020
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20. Eribulin Regresses a Cisplatinum-resistant Rare-type Triple-negative Matrix-producing Breast Carcinoma Patient-derived Orthotopic Xenograft Mouse Model.
- Author
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Yamamoto J, Murata T, Sugisawa N, Higuchi T, Tashiro Y, Nishino H, Inubushi S, Sun YU, Lim H, Miyake K, Shimoya K, Nomura T, Kurebayashi J, Tanino H, Hozumi C, Bouvet M, Singh SR, Endo I, and Hoffman RM
- Subjects
- Animals, Biomarkers, Tumor, Cisplatin therapeutic use, Disease Models, Animal, Female, Furans therapeutic use, Humans, Ketones therapeutic use, Mice, Paclitaxel pharmacology, Treatment Outcome, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms etiology, Triple Negative Breast Neoplasms metabolism, Tumor Burden drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Cisplatin pharmacology, Drug Resistance, Neoplasm drug effects, Furans pharmacology, Ketones pharmacology, Triple Negative Breast Neoplasms pathology
- Abstract
Background/aim: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model., Materials and Methods: The PDOX model was established in the left 2
nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3 : G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week., Results: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001)., Conclusion: Eribulin has clinical potential for triple-negative MPBC patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2020
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21. Multiplex PCR analysis of apocrine lesions shows frequent PI3K-AKT pathway mutations in both benign and malignant apocrine breast tumors.
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Kanomata N, Yamaguchi R, Kurebayashi J, and Moriya T
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- Adult, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Diagnosis, Differential, F-Box Proteins genetics, Female, Gene Expression, Humans, Multiplex Polymerase Chain Reaction, Mutation, Neoplasms diagnosis, Neoplasms pathology, Papilloma, Intraductal diagnosis, Papilloma, Intraductal pathology, Tumor Suppressor Protein p53 genetics, Breast Neoplasms genetics, Class I Phosphatidylinositol 3-Kinases genetics, Neoplasm Proteins genetics, Neoplasms genetics, Papilloma, Intraductal genetics, Proto-Oncogene Proteins c-akt genetics
- Abstract
Pathological diagnosis of intraductal apocrine lesions can be challenging, because even benign apocrine lesions often show atypical cytology, and immunohistochemistry is of little assistance. A new diagnostic method for apocrine lesions is desirable. The mutations present in apocrine lesions have not been well studied. We performed a MassARRAY multiplex polymerase chain reaction (PCR) study of benign and malignant apocrine lesions, which included 152 mutations of 18 genes. We found that four of 11 benign lesions showed AKT1 or PIK3CA mutations, one of four noninvasive apocrine carcinomas showed a FBX4 mutation, two of 15 invasive apocrine carcinomas showed a PIK3CA mutation, and one invasive apocrine carcinoma showed both PIK3CA and TP53 mutations. The mutation frequency did not differ significantly between benign and malignant lesions (p = 0.683). We demonstrated that both benign and malignant apocrine lesions may contain mutations of genes in the PI3K-AKT pathway, this pathway could be a good therapeutic target of these diseases.
- Published
- 2020
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22. Phosphorylated HER3 and FITC-labeled trastuzumab immunohistochemistry in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.
- Author
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Kanomata N, Kurebayashi J, and Moriya T
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- Adult, Antineoplastic Agents, Immunological chemistry, Antineoplastic Agents, Immunological therapeutic use, Breast Neoplasms metabolism, Breast Neoplasms pathology, Chemotherapy, Adjuvant, Female, Fluorescein-5-isothiocyanate chemistry, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Phosphorylation, Prognosis, Retrospective Studies, Trastuzumab chemistry, Breast Neoplasms drug therapy, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 metabolism, Trastuzumab therapeutic use
- Abstract
The development of trastuzumab has significantly improved the prognosis of HER2-positive breast cancer. However, disease recurs in some patients with HER2-positive breast cancer. A new strategy for treating HER2-positive breast cancer is necessary. Although several studies have reported that HER3 is a prognostic factor for HER2-positive breast cancers, phosphorylated HER3 (pHER3) has not been well studied. There has been no survival analysis including immunohistochemistry with trastuzumab as the primary antibody. We analyzed immunohistochemistry using anti-pHER3 antibody and FITC-labeled trastuzumab (FITC-tra). Of 78 patients enrolled in the study, we could evaluate the immunohistochemistry for pHER3 in 71 cases and that for FITC-tra in 72 cases. Sixteen cases were positive for pHER3 (16/71, 22.5%), and 19 positive for FITC-tra (19/72, 26.4%). Kaplan-Meier analysis showed a significant association of pHER3 positivity (p = 0.011) but not HER3 positivity or FITC-tra positivity with disease-free survival. Therefore, immunohistochemical evaluation of pHER3 in HER2-positive breast cancer may provide a useful biomarker. An expanded study of pHER3 involving standardization of the pHER3 test to be encouraged.
- Published
- 2019
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23. CD1d- and PJA2-related immune microenvironment differs between invasive breast carcinomas with and without a micropapillary feature.
- Author
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Kanomata N, Kurebayashi J, Koike Y, Yamaguchi R, and Moriya T
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- Antigens, CD1d immunology, Breast immunology, Breast pathology, Breast surgery, Breast Neoplasms immunology, Breast Neoplasms mortality, Breast Neoplasms surgery, Carcinoma, Ductal, Breast immunology, Carcinoma, Ductal, Breast mortality, Carcinoma, Ductal, Breast surgery, Carcinoma, Papillary immunology, Carcinoma, Papillary mortality, Carcinoma, Papillary surgery, Down-Regulation, Female, Follow-Up Studies, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Oligonucleotide Array Sequence Analysis, Survival Analysis, Tissue Array Analysis, Tumor Microenvironment, Ubiquitin-Protein Ligases immunology, Up-Regulation, Antigens, CD1d metabolism, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Papillary pathology, Ubiquitin-Protein Ligases metabolism
- Abstract
Background: Invasive micropapillary carcinoma (IMPC) of the breast is characterized by its unique morphology and frequent nodal metastasis. However, the mechanism for development of this unique subtype has not been clearly elucidated. The aim of this study was to obtain a better understanding of IMPC., Methods: Using representative cases of mixed IMPC, mRNA expression in the micropapillary area and usual invasive area was compared. Then, immunohistochemical analyses for 294 cases (76 invasive carcinomas with a micropapillary feature [ICMF] and 218 invasive carcinomas without a micropapillary feature [ICNMF]) were conducted. Clinicopathological analyses were also studied., Results: DNA microarray analyses for mixed IMPC showed that BC-1514 (C21orf118) was commonly upregulated in the micropapillary area. CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4, and TXNIP were commonly downregulated in the micropapillary area. Immunohistochemically, we confirmed that BC-1514 was more upregulated in ICMF than in ICNMF. CD1d and PJA2 were more downregulated in ICMF than ICNMF. All patients with cases of PJA2 overexpression survived without cancer recurrence during the follow-up period, although the differences for disease-free (p = 0.153) or overall survival (p = 0.272) were not significant., Conclusions: The CD1d- and PJA2-related tumour microenvironment might be crucial for IMPC. Further study of the immune microenvironment and micropapillary features is warranted.
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- 2019
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24. Comprehensive immunohistochemical analyses on expression levels of hedgehog signaling molecules in breast cancers.
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Kurebayashi J, Kanomata N, Koike Y, Ohta Y, Saitoh W, and Kishino E
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms mortality, Breast Neoplasms pathology, Female, Humans, Immunohistochemistry, Lymphatic Metastasis, Middle Aged, Neoplasm Grading, SOXB1 Transcription Factors analysis, Signal Transduction, Breast Neoplasms chemistry, Hedgehog Proteins analysis, Nuclear Proteins analysis, Zinc Finger Protein GLI1 analysis, Zinc Finger Protein Gli2 analysis
- Abstract
Background: The hedgehog (Hh) signaling pathway plays important roles in cell proliferation, malignant progression, invasion and metastasis, and the expansion of cancer stem cells (CSCs). Comprehensive immunohistochemical (IHC) analyses have not yet been conducted on the expression levels of Hh signaling molecules in breast cancer tissues., Methods: A total of 204 patients with invasive breast cancer treated in our institute were study subjects. IHC analyses on the expression levels of the Hh signaling molecules, sonic Hh (SHH), PTCH1, GLI1, GLI2, and GLI3 and the CSC-related factor, SOX2, were investigated., Results: Positive correlations were observed among all of the Hh signaling molecules tested. SOX2 expression correlated with the expression levels of all Hh signaling molecules. SHH expression positively correlated with tumor size, the Ki-67 labeling index, histological grade, estrogen receptor negativity, progesterone receptor negativity, and HER2 positivity. GLI1 expression positively correlated with the histological grade. GLI2 expression positively correlated with the histological grade, Ki-67 labeling index, and HER2 positivity. Univariate analyses revealed that a younger age, larger tumor size, positive lymph node metastasis, higher histological grade, positive lymphatic invasion, and higher Ki-67 labeling index were related to poor relapse-free survival (RFS). The positivity of all Hh signaling molecules and SOX2 did not correlate with poor RFS. A multivariate analysis revealed that positive lymphatic invasion and a younger age were independent worse prognostic factors for RFS., Conclusions: This comprehensive analysis demonstrated for the first time that SHH, GLI1, and GLI2 expression levels positively correlated with the malignant phenotypes of tumor cells.
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- 2018
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25. [A Case Report of Surgery and Chemotherapy for a Patient with Rapidly Progressing Breast Cancer during Pregnancy].
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Hazama Y, Nakai Y, Sugawara S, Nomura T, Matsumoto K, Matsumoto R, Sugihara M, Ishida T, Murata S, Murata T, Nakamura T, Moriya T, Kurebayashi J, and Shimoya K
- Subjects
- Adult, Biopsy, Breast Neoplasms pathology, Breast Neoplasms surgery, Carcinoma, Ductal, Breast surgery, Chemotherapy, Adjuvant, Disease Progression, Epirubicin administration & dosage, Female, Humans, Mastectomy, Radical, Paclitaxel administration & dosage, Pregnancy, Pregnancy Complications, Neoplastic surgery, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Carcinoma, Ductal, Breast drug therapy, Pregnancy Complications, Neoplastic drug therapy
- Abstract
A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed.
- Published
- 2018
26. Comparison of quality of life between 2-year and 3-or-more-year administration of leuprorelin acetate every-3-months depot in combination with tamoxifen as adjuvant endocrine treatment in premenopausal patients with endocrine-responsive breast cancer: a randomized controlled trial.
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Ohashi Y, Shiba E, Yamashita H, Kurebayashi J, Noguchi S, Iwase H, Yoshida M, and Fujimoto T
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms pathology, Female, Humans, Leuprolide administration & dosage, Leuprolide pharmacology, Middle Aged, Premenopause, Tamoxifen administration & dosage, Tamoxifen pharmacology, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Chemotherapy, Adjuvant methods, Leuprolide therapeutic use, Quality of Life psychology, Tamoxifen therapeutic use
- Abstract
Background: We conducted an open-label, randomized controlled trial evaluating the appropriate treatment duration of leuprorelin acetate 3-month depot, TAP-144-SR (3M), administered postsurgically every 3 months for 2 years versus 3 or more (up to 5) years, in combination with tamoxifen, for 5 years in premenopausal endocrine-responsive breast cancer patients and reported similar survival benefit in the two treatment groups. We hereby present patient-reported quality of life (QOL) data obtained from this trial., Methods: Three self-administered QOL questionnaires (QOL-ACD, QOL-ACD-B, FACT-ES subscale) were used, and the difference in QOL score changes between the two groups was analyzed using a mixed-effects model for repeated measures., Results: Eligible patients (N = 222) were randomly assigned to a 2-year (2YG, N = 112) or 3-or-more-year treatment group (3YG, N = 110). The time courses of the three QOL scores during the trial period were similar in the two groups. The mean changes in the QOL scores from week 96 were largely stable through week 240 in the 3YG, but showed significantly greater improvement in the score changes from week 96 in the 2YG than the 3YG. Symptoms associated with menopause such as hot flashes and sweating contributed to these results. Menstruation recovery was associated with significantly greater improvement of these symptoms in the 2YG than the 3YG., Conclusions: Patient-reported menopause-associated symptoms and QOL improved after discontinuation of the LH-RH agonist administration and menstruation recovery. QOL information should be a consideration in long-term treatment.
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- 2018
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27. Cost analysis of leuprorelin acetate in Japanese pre-menopausal breast-cancer patients: comparison between 6-month and 3-month depot formulations.
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Goto R, Uda A, Hiroi S, Iwasaki K, Takashima K, and Kurebayashi J
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- Adult, Age Factors, Antineoplastic Agents, Hormonal administration & dosage, Cost of Illness, Costs and Cost Analysis, Delayed-Action Preparations, Drug Administration Schedule, Female, Health Expenditures, Humans, Insurance Claim Review, Japan, Leuprolide administration & dosage, Middle Aged, Premenopause, Antineoplastic Agents, Hormonal economics, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Leuprolide economics, Leuprolide therapeutic use
- Abstract
Aims: The aim in this study is to evaluate economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot in Japanese pre-menopausal breast cancer patients from a societal perspective., Methods: The cost analysis was conducted by estimating direct and indirect cost, and intangible costs associated with one 6-month injection compared with two 3-month injections. Claims data were used for the analyses of direct and indirect cost and Medical Fee Schedule Table for direct cost. Discrete choice experiments were conducted by web-based survey to determine the intangible costs. Another web-based survey was also conducted on premenopausal breast cancer patients with injections of leuprorelin acetate, to calibrate the results of discrete choice experiments., Results: The medical costs saved for having one less injection in pre-menopausal breast cancer patients with leuprorelin acetate injection were JPY 6,183. The productivity loss saving was JPY 1,419. An estimation of intangible costs saved for having one less injection of leuprorelin acetate was JPY 58,430, which included the disbenefit due to pain (JPY 8,535), injection site reactions (JPY 44,051), waiting time (JPY 9,595), and subtracting value in medical consultation (JPY 3,751). The total cost saved for having one less injection was JPY 66,032., Limitations: The respondents from the internet panel provided by a survey company do not necessarily reflect a population of Japanese society., Conclusions: Leuprorelin acetate 6-month depot demonstrates a higher value than leuprorelin acetate 3-month depot through saving medical costs and loss of productivity, as well as intangible costs saved for having one less injection when treating pre-menopausal breast cancer patients. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.
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- 2017
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28. Anti-cell growth and anti-cancer stem cell activities of the non-canonical hedgehog inhibitor GANT61 in triple-negative breast cancer cells.
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Koike Y, Ohta Y, Saitoh W, Yamashita T, Kanomata N, Moriya T, and Kurebayashi J
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- Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Cell Cycle drug effects, Cell Line, Tumor, Drug Synergism, Female, Fluorescent Antibody Technique, Hedgehog Proteins metabolism, Humans, Molecular Targeted Therapy methods, Neoplastic Stem Cells pathology, Nuclear Proteins metabolism, Paclitaxel pharmacology, Paclitaxel therapeutic use, Pyridines therapeutic use, Pyrimidines therapeutic use, Signal Transduction drug effects, Spheroids, Cellular, Triple Negative Breast Neoplasms pathology, Zinc Finger Protein GLI1 metabolism, Zinc Finger Protein Gli2 metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Proliferation drug effects, Hedgehog Proteins antagonists & inhibitors, Neoplastic Stem Cells drug effects, Pyridines pharmacology, Pyrimidines pharmacology, Triple Negative Breast Neoplasms drug therapy
- Abstract
Background: Triple-negative breast cancer (TNBC) exhibits biologically aggressive behavior and has a poor prognosis. Novel molecular targeting agents are needed to control TNBC. Recent studies revealed that the non-canonical hedgehog (Hh) signaling pathway plays important roles in the regulation of cancer stem cells (CSCs) in breast cancer. Therefore, the anti-cell growth and anti-CSC effects of the non-canonical Hh inhibitor GANT61 were investigated in TNBC cells., Methods: The effects of GANT61 on cell growth, cell cycle progression, apoptosis, and the proportion of CSCs were investigated in three TNBC cell lines. Four ER-positive breast cancer cell lines were also used for comparisons. The expression levels of effector molecules in the Hh pathway: glioma-associated oncogene (GLI) 1 and GLI2, were measured. The combined effects of GANT61 and paclitaxel on anti-cell growth and anti-CSC activities were also investigated., Results: Basal expression levels of GLI1 and GLI2 were significantly higher in TNBC cells than in ER-positive breast cancer cells. GANT61 dose-dependently decreased cell growth in association with G1-S cell cycle retardation and increased apoptosis. GANT61 significantly decreased the CSC proportion in all TNBC cell lines. Paclitaxel decreased cell growth, but not the CSC proportion. Combined treatments of GANT61 and paclitaxel more than additively enhanced anti-cell growth and/or anti-CSC activities., Conclusions: The non-canonical Hh inhibitor GANT61 decreased not only cell growth, but also the CSC population in TNBC cells. GANT61 enhanced the anti-cell growth activity of paclitaxel in these cells. These results suggest for the first time that GANT61 has potential as a therapeutic agent in the treatment of patients with TNBC.
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- 2017
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29. Correction: Preparation of a novel antiserum to aromatase with high affinity and specificity: Its clinicopathological significance on breast cancer tissue.
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Kanomata N, Matsuura S, Nomura T, Kurebayashi J, Mori T, Kitawaki J, and Moriya T
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0177439.].
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- 2017
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30. Preparation of a novel antiserum to aromatase with high affinity and specificity: Its clinicopathological significance on breast cancer tissue.
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Kanomata N, Matsuura S, Nomura T, Kurebayashi J, Mori T, Kitawaki J, and Moriya T
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- Adult, Aged, Aged, 80 and over, Animals, Breast immunology, Breast Neoplasms immunology, Female, Humans, Hybridomas, Mice, Inbred BALB C, Middle Aged, Rabbits, Aromatase analysis, Aromatase immunology, Breast physiology, Breast Neoplasms pathology, Immune Sera immunology
- Abstract
Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated with pT (p = 0.019), pN (p = 0.001), stage (p < 0.001), histologic grade (p = 0.003), lymphatic infiltration (p < 0.001), venous infiltration (p < 0.001), and Ki-67 index (p < 0.001). However, cancer aromatase expression was independent of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 statuses. This antiserum will be applicable to clinicopathological examination of aromatase in addition to ER and PgR for an appropriate use of aromatase inhibitor on the treatment of breast cancer. Further studies on the relationship between Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated with pT (p = 0.019), pN (p = 0.001), stage (p < 0.001), histologic grade (p = 0.003), lymphatic infiltration (p < 0.001), venous infiltration (p < 0.001), and Ki-67 index (p < 0.001). However, cancer aromatase expression was independent of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 statuses. This antiserum will be applicable to clinicopathological examination of aromatase in addition to ER and PgR for an appropriate use of aromatase inhibitor on the treatment of breast cancer. Further studies on the relationship between aromatase expression and aromatase inhibitors are warranted.
- Published
- 2017
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31. Anti-cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor-positive breast cancer cells.
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Kurebayashi J, Koike Y, Ohta Y, Saitoh W, Yamashita T, Kanomata N, and Moriya T
- Subjects
- Apoptosis drug effects, Breast Neoplasms metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Estradiol metabolism, Estrogen Antagonists pharmacology, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Neoplastic Stem Cells metabolism, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Hedgehog Proteins antagonists & inhibitors, Neoplastic Stem Cells drug effects, Pyridines pharmacology, Pyrimidines pharmacology, Receptors, Estrogen metabolism
- Abstract
Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2017
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32. Efficacy and safety of leuprorelin acetate 6-month depot, TAP-144-SR (6M), in combination with tamoxifen in postoperative, premenopausal patients with hormone receptor-positive breast cancer: a phase III, randomized, open-label, parallel-group comparative study.
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Kurebayashi J, Toyama T, Sumino S, Miyajima E, and Fujimoto T
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asian People, Breast Neoplasms mortality, Breast Neoplasms surgery, Disease-Free Survival, Estradiol blood, Female, Humans, Leuprolide administration & dosage, Leuprolide pharmacokinetics, Menstruation drug effects, Middle Aged, Premenopause, Tamoxifen administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy
- Abstract
Background: Leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, is used worldwide in premenopausal women with hormone receptor-positive breast cancer. This study was conducted to assess the non-inferiority of the 6-month depot formulation, TAP-144-SR (6M) 22.5 mg to the 3-month depot formulation, TAP-144-SR (3M) 11.25 mg in postoperative, premenopausal patients with hormone receptor-positive breast cancer., Methods: This was a 96-week phase III, randomized, open-label, parallel-group comparative study. All patients concomitantly received oral tamoxifen (20 mg daily). The primary endpoint was the suppression rate of serum estradiol (E
2 ) to the menopausal level (≤30 pg/mL) from Week 4 through Week 48., Results: In total, 167 patients were randomized to receive TAP-144-SR (6M) (n = 83) or TAP-144-SR (3M) (n = 84) and the E2 suppression rate was 97.6 and 96.4 %, respectively. The estimated between-group difference was 1.2 % (95 % confidence interval -5.2 to 7.8). The non-inferiority of TAP-144-SR (6M) to TAP-144-SR (3M) for E2 suppression was confirmed. As for safety, common adverse events were hot flush and injection site reactions including induration, pain, and erythema in both treatment groups, which were of ≤Grade 2 in severity and not serious. No significant between-group differences in safety profiles and tolerability were observed., Conclusions: TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for its suppressive effect on serum E2 . TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M)., Competing Interests: J. Kurebayashi received advisory/consultation fees from Takeda Pharmaceutical Company Limited and research funding from Takeda Pharmaceutical Company Limited, Eisai Company Limited, Chugai Pharmaceutical Company Limited and AstraZeneca K.K. T. Toyama received a research funding from Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Healthcare Co., Ltd. and Novartis Pharma K.K. S. Sumino, E. Miyajima and T. Fujimoto are employees of Takeda Pharmaceutical Company Limited. This work was supported by Takeda Pharmaceutical Company Limited.- Published
- 2017
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33. Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity.
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Shi G, Yoshida Y, Yuki K, Nishimura T, Kawata Y, Kawashima M, Iwaisako K, Yoshikawa K, Kurebayashi J, Toi M, and Noda M
- Subjects
- Azacitidine analogs & derivatives, Azacitidine pharmacology, Benzamides pharmacology, Breast Neoplasms pathology, Decitabine, Dose-Response Relationship, Drug, Exons, Female, Histone Deacetylase Inhibitors pharmacology, Humans, MCF-7 Cells, Methotrexate pharmacology, Middle Aged, Neoplasm Grading, Neoplasm Staging, Promoter Regions, Genetic, Pyridines pharmacology, Time Factors, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms genetics, CpG Islands, DNA Methylation drug effects, Epigenesis, Genetic drug effects, GPI-Linked Proteins genetics
- Abstract
The membrane-anchored glycoprotein RECK negatively regulates multiple metalloproteinases and is frequently downregulated in tumors. Forced RECK expression in cancer cells results in suppression of tumor angiogenesis, invasion, and metastasis in xenograft models. A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation (in an intron-1 region) and relapse-free survival. In this study, we focused on another region of the RECK CpG island (a promoter/exon-1 region) and found an inverse correlation between its methylation and RECK-inducibility by an HDAC inhibitor, MS275, among a panel of breast cancer cell lines (n=15). In clinical samples (n=62), RECK intron-1 methylation was prevalent among luminal breast cancers as reported previously (26 of 38 cases; 68%) and particularly enriched in tumors of the ER+PR- subclass (10 of 10 cases) and of higher histological grades (Grade 2 and 3; 28 of 43 cases; P=0.006). In about a half of these cases, promoter/exon-1 methylation was absent, and hence, RECK may be inducible by certain drugs such as MS275. Our results indicate the value of combined use of two RECK methylation markers for predicting prognosis and drug-sensitivity of breast cancers.
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- 2016
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34. A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.
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Shiba E, Yamashita H, Kurebayashi J, Noguchi S, Iwase H, Ohashi Y, Sasai K, and Fujimoto T
- Subjects
- Adult, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Density drug effects, Breast Neoplasms mortality, Chemotherapy, Adjuvant methods, Disease-Free Survival, Estradiol blood, Female, Humans, Leuprolide administration & dosage, Leuprolide adverse effects, Middle Aged, Premenopause, Survival Rate, Tamoxifen administration & dosage, Tamoxifen adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Leuprolide therapeutic use
- Abstract
Background: Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin., Methods: We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety., Results: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2., Conclusions: Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.
- Published
- 2016
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35. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells.
- Author
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Kurebayashi J, Kanomata N, Yamashita T, Shimo T, and Moriya T
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Breast Neoplasms pathology, Cell Cycle drug effects, Cell Line, Tumor, Estradiol administration & dosage, Estradiol analogs & derivatives, Estrogen Antagonists administration & dosage, Female, Fulvestrant, Furans administration & dosage, Humans, Ketones administration & dosage, Neoplastic Stem Cells pathology, Tamoxifen administration & dosage, Tamoxifen analogs & derivatives, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Estrogen Antagonists pharmacology, Furans pharmacology, Ketones pharmacology, Neoplastic Stem Cells drug effects
- Abstract
Background: Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens., Methods: A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4-hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays., Results: The 50% growth inhibitory concentrations of eribulin were 0.38-2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43-1.46 for ER-positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1-S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines., Discussion: The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells.
- Published
- 2016
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36. Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model.
- Author
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Duquette M, Sadow PM, Husain A, Sims JN, Antonello ZA, Fischer AH, Song C, Castellanos-Rizaldos E, Makrigiorgos GM, Kurebayashi J, Nose V, Van Hummelen P, Bronson RT, Vinco M, Giordano TJ, Dias-Santagata D, Pandolfi PP, and Nucera C
- Subjects
- Animals, Apoptosis drug effects, Blotting, Western, Carcinoma, Papillary, Cell Survival drug effects, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Heterografts, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Neovascularization, Pathologic, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins B-raf genetics, Thyroid Cancer, Papillary, Transfection, Vemurafenib, Antineoplastic Agents pharmacology, Carcinoma genetics, Drug Resistance, Neoplasm genetics, Gene Dosage, Genes, p16, Indoles pharmacology, Myeloid Cell Leukemia Sequence 1 Protein genetics, Sulfonamides pharmacology, Thyroid Neoplasms genetics
- Abstract
BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAF(V600E)-positive PTC.
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- 2015
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37. Prognostic value of phosphorylated HER2 in HER2-positive breast cancer patients treated with adjuvant trastuzumab.
- Author
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Kurebayashi J, Kanomata N, Yamashita T, Shimo T, Mizutoh A, Moriya T, and Sonoo H
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms mortality, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast mortality, Carcinoma, Lobular drug therapy, Carcinoma, Lobular metabolism, Carcinoma, Lobular mortality, Chemotherapy, Adjuvant, ErbB Receptors metabolism, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Lymphatic Metastasis, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local mortality, Phosphorylation, Prognosis, Receptor, ErbB-2 genetics, Receptor, ErbB-3 metabolism, Receptor, ErbB-4 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Retrospective Studies, Survival Rate, Tumor Suppressor Protein p53 metabolism, Young Adult, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular pathology, Neoplasm Recurrence, Local pathology, Receptor, ErbB-2 metabolism, Trastuzumab therapeutic use
- Abstract
Background: Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab., Patients and Methods: The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively., Results: The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors., Conclusions: This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.
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- 2015
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38. Clinicopathological characteristics of breast cancer and trends in the management of breast cancer patients in Japan: Based on the Breast Cancer Registry of the Japanese Breast Cancer Society between 2004 and 2011.
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Kurebayashi J, Miyoshi Y, Ishikawa T, Saji S, Sugie T, Suzuki T, Takahashi S, Nozaki M, Yamashita H, Tokuda Y, and Nakamura S
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms metabolism, Combined Modality Therapy, Disease Management, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Japan, Middle Aged, Neoplasm Staging, Prognosis, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Young Adult, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Breast Neoplasms therapy, Registries
- Abstract
Purposes: We conducted a study to analyze the clinicopathological characteristics of breast cancer in Japan registered to the Japanese Breast Cancer Registry of the Japanese Breast Cancer Society (JBCS). Trends in the management of breast cancer patients in Japan were also analyzed., Patients and Methods: More than 250,000 breast cancer patients were registered to the JBCS registry between 2004 and 2011. Demographic and clinicopathological factors in newly diagnosed primary breast cancer patients were registered to the JBCS through the Web-based system from affiliated institutes nationwide., Results: Two distinct peaks were observed, in patients in their late 40s and early 60s, in the population-adjusted age distribution of breast cancer patients. An increased rate of screen-detected breast cancer may contribute to an earlier detection of breast cancer and increased rate of non-invasive ductal carcinoma. The positive rate of either ER or PgR appears to have increased in recent years. The annual rates of patients treated with breast-conserving surgery increased until 2006, but these increases stopped in 2007 and thereafter plateaued at approximately 60 %. The annual rates of patients treated with sentinel lymph node dissection alone have steadily increased. The annual rates of patients treated with preoperative trastuzumab plus chemotherapy have also increased, as well as those treated with postoperative aromatase inhibitors. The annual rates of patients treated with postoperative anthracycline-containing regimens have decreased, whereas those treated with postoperative taxane-containing regimens have increased. The postoperative use of trastuzumab has markedly increased since 2007., Conclusion: Although this study was based on the registry database, several unique clinicopathological characteristics of breast cancer in Japan have been unveiled. Our results suggest that recent trends in the management of breast cancer patients in Japan were strongly followed by clinical evidence that originated from a number of clinical trials worldwide.
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- 2015
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39. 2013 clinical practice guidelines (The Japanese Breast Cancer Society): history, policy and mission.
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Mukai H, Noguchi S, Akiyama F, Inaji H, Iwase H, Horiguchi J, Kurebayashi J, Hirata K, Toi M, Kurosumi M, Kohno N, Nishimura R, Nakamura S, Imoto S, Iwase T, Endo T, Saeki T, Ogawa Y, Ito Y, Tokuda Y, and Ikeda T
- Subjects
- Breast Neoplasms epidemiology, Female, Humans, Japan, Breast Neoplasms diagnosis, Breast Neoplasms therapy, Practice Guidelines as Topic, Societies, Medical organization & administration
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- 2015
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40. The cell cycle profiling-risk score based on CDK1 and 2 predicts early recurrence in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy.
- Author
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Kim SJ, Masuda N, Tsukamoto F, Inaji H, Akiyama F, Sonoo H, Kurebayashi J, Yoshidome K, Tsujimoto M, Takei H, Masuda S, Nakamura S, and Noguchi S
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms genetics, Breast Neoplasms pathology, CDC2 Protein Kinase, Cell Cycle genetics, Chemotherapy, Adjuvant methods, Cyclin-Dependent Kinase 2 genetics, Cyclin-Dependent Kinases genetics, Disease-Free Survival, Female, Humans, Middle Aged, Neoplasm Recurrence, Local enzymology, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Prognosis, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Retrospective Studies, Risk, Young Adult, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Cycle physiology, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinases metabolism, Neoplasm Recurrence, Local metabolism
- Abstract
The Cell Cycle Profiling - Risk Score (C2P-RS) based on CDK1 and CDK2 specific activities was significantly associated with relapse in breast cancers. We evaluated the prognostic value of the C2P-RS classification using a Japanese cohort including node-negative, hormone receptor-positive breast cancers treated with adjuvant endocrine therapy alone as systemic therapy. Of 266 patients, 22 (8.3%) relapsed within 5 years after surgery. The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The 5-year relapse-free survival rate in the low C2P-RS group (97.3%) was significantly higher than that in the intermediate C2P-RS group (84.3%) or the high C2P-RS group (74.4%) (P < 0.001). The univariate analysis demonstrated that age, tumor size, histologic grade, and HER2 had no significant correlations with relapse but the C2P-RS classification (P < 0.001) and Ki-67 (P = 0.009) were significantly associated with relapse. Multivariate analysis showed only that the C2P-RS classification was a significant independent prognostic indicator. The C2P-RS classification might be a significant predictor of earlier recurrence in node-negative, hormone receptor-positive breast cancers treated with endocrine therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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