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Find video protocols related to scientific articles indexed in Pubmed.
[Efficacy and Safety of TS-1Monotherapy for Advanced/Metastatic Breast Cancer - An Observational Study by the Kumamoto Breast Cancer Cooperative Group(KBCCG)].
Gan To Kagaku Ryoho
PUBLISHED: 10-23-2014
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TS-1, an oral fluoropyrimidine, is known to be effective for the treatment of various carcinomas including advanced/metastatic breast cancer.The Kumamoto Breast Cancer Cooperative Group(KBCCG)conducted an observational study, wherein, the efficacy and safety of TS-1 monotherapy was analyzed in 35 patients with recurrent or metastatic breast cancer.The median time to cancer progression was 3.7 months, overall response rate was 12%, and clinical benefit rate was 32%. Adverse events were observed in 27 patients(77%), and adverse events of Grade >3 were observed in 7 patients(20%). The rate of treatment-related Grade 3 and 4 adverse events increased, and was associated with poor levels of creatinine clearance(Ccr)ie <60mL/min.This study suggests that TS-1 monotherapy can potentially be used as a salvage treatment for advanced/metastatic breast cancer owing to its safety and efficacy.Measuring the level of Ccr before TS-1 therapy should be considered to avoid severe adverse events.
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The localization of HER4 intracellular domain and expression of its alternately-spliced isoforms have prognostic significance in ER+ HER2- breast cancer.
Oncotarget
PUBLISHED: 07-09-2014
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Human epidermal growth factor receptors (HERs) are known to play a pivotal role in breast cancer, both as prognostic markers and as therapeutic targets. The importance of Her4 expression is, however, still controversially discussed; there are few reports on the clinical significance of HER4, its splice variants, and cleaved HER4 intracellular domains (4ICD) which function differently depending on their localization in breast cancer. In 238 primary invasive breast cancer patients, we analyzed the expression levels of HER4 extracellular (JM-a and JM-b) and intracellular (CYT-1 and CYT-2) domains as well as 4ICD localization, and tested the relationship with clinicopathological characteristics and prognosis. The predominantly-expressed extracellular domain was JM-a, and lower CYT-2 dominance was a factor related to better relapse-free survival. CYT-2-dominance with higher nuclear 4ICD expression was a favorable prognostic marker especially in patients with the ER+ HER2- subtype treated with endocrine therapy. The absence of cytoplasmic 4ICD staining was related to better prognosis in CYT-1-dominant patients. In conclusion, analysis of splicing variants and 4ICD localization should be considered when targeting HER4 as a novel ER+/HER2- breast cancer treatment.
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C6ORF97-ESR1 breast cancer susceptibility locus: influence on progression and survival in breast cancer patients.
Eur. J. Hum. Genet.
PUBLISHED: 03-22-2014
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Genome-wide association studies have identified a single-nucleotide polymorphism (SNP) to be associated with an increased risk of breast cancer. The biology of one of the susceptibility locus C6ORF-ESR1 and whether it also contributes to progression of established disease has not yet been ascertained. We examined the association of rs2046210 and its six linkage disequilibrium SNPs with clinicopathological characteristics, prognosis, and gene expression levels of ESR1 and the C6ORFs (C6ORF97:CCDC170, C6ORF211, C6ORF96:RMND1) in 344 breast cancer tissue samples and 253 corresponding samples of adjacent normal tissue. Tumor genotypes with homozygous risk alleles were more frequent than normal tissues. The tumor genotypes of rs2046210 and rs6929137 with homozygous risk alleles showed worse relapse-free survival (RFS, P=0.038 and P=0.031, respectively), whereas no notable associations were observed with either clinicopathological characteristics or expression of the peripheral genes. Higher C6ORF97 expression correlated with ER negativity (P<0.0001), highly proliferative characteristics (P=0.0005 for Ki67, P<0.0001 for nuclear grade) and worse RFS in the ER+/HER2- cohort (P=0.013), whereas the other two C6ORFs showed the inverse associations. Furthermore, C6ORF97 showed significant worse prognostic values especially in luminal B subtype in the publically available data sets. rs2046210 and the upstream gene C6ORF97 might have substantial roles not only in carcinogenesis but also in progression toward a more aggressive phenotype in breast cancer patients, which suggests that functional studies of this locus are imperative.European Journal of Human Genetics advance online publication, 5 November 2014; doi:10.1038/ejhg.2014.219.
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Serum ANGPTL2 levels reflect clinical features of breast cancer patients: implications for the pathogenesis of breast cancer metastasis.
Int. J. Biol. Markers
PUBLISHED: 02-27-2014
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Breast cancer is a leading cause of cancer-related death in women worldwide, and its metastasis is a major cause of disease mortality. Therefore, identification of the mechanisms underlying breast cancer metastasis is crucial for the development of therapeutic and diagnostic strategies. Our recent study of immunodeficient female mice transplanted with MDA-MB231 breast cancer cells demonstrated that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates metastasis through both increasing tumor cell migration in an autocrine/paracrine manner, and enhancing tumor angiogenesis. To determine whether ANGPTL2 contributes to its clinical pathogenesis, we asked whether serum ANGPTL2 levels reflect the clinical features of breast cancer progression.
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Clinical significance of pretherapeutic Ki67 as a predictive parameter for response to neoadjuvant chemotherapy in breast cancer: is it equally useful across tumor subtypes?
Surgery
PUBLISHED: 01-31-2014
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Ki67 has been identified as a prognostic and predictive marker for breast cancer and it was suggested that it may contribute to pathologic complete response (pCR) after neoadjuvant chemotherapy. It is unclear whether expression of Ki67 is particularly helpful for prediction of pCR across tumor subtypes.
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Differential expression of estrogen receptor ?, ?1, and ?2 in lobular and ductal breast cancer.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 01-21-2014
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The role of estrogen receptor (ER) ? as a target in treatment of breast cancer is clear, but those of ER?1 and ER?2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ER? was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ER?. We found that whereas ductal cancer is a highly proliferative, ER?-positive, ER?-negative disease, lobular cancer expresses both ER? and ER? but with very few Ki67-positive cells. ER?2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ER?2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1?. ER?2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ER? nor ER? was expressed, but in the high-grade lobular cancer ER? was lost and ER? and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ER? agonists in preventing in situ ductal cancers from becoming invasive.
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Clinical significance of CYLD downregulation in breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 01-08-2014
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Cylindromatosis (CYLD) is a tumor suppressor gene that is mutated in familial cylindromatosis, a rare autosomal dominant disorder associated with numerous benign skin adnexal tumors. CYLD is now known to regulate various signaling pathways, including transforming growth factor-? signaling, Wnt/?-catenin signaling, and NF-?B signaling by deubiquitinating upstream regulatory factors. Downregulation of CYLD has been reported in several malignancies; however, the clinical significance of CYLD expression in many malignancies, including breast cancer, remains to be elucidated. This study investigated the clinical significance of CYLD in breast cancer and its roles in tumor progression. We evaluated CYLD expression in matched normal breast tissue samples and tumor breast tissue samples from 26 patients with breast cancer and in a series of breast cancer cell lines. In addition, by means of immunohistochemistry, we investigated CYLD protein expression and its clinical significance in 244 breast cancer cases. We also analyzed the effects of CYLD repression or overexpression on breast cancer cell viability, cell migration, and NF-?B activity with or without receptor activator of NF-?B ligand (RANKL) stimulation. Breast cancer tissues demonstrated significantly reduced CYLD mRNA expression compared with normal breast tissues. Downregulation of CYLD promoted cell survival and migratory activities through NF-?B activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells. As an important finding, CYLD overexpression also inhibited RANKL-induced NF-?B activation. Our immunohistochemical analysis revealed that reduced CYLD protein expression was significantly correlated with estrogen receptor negativity, high Ki-67 index, high nuclear grade, decreased disease-free survival, and reduced breast cancer-specific survival in primary breast cancer. Moreover, reduced CYLD expression was an independent factor for poor prognosis in breast cancer. CYLD downregulation may promote breast cancer metastasis via NF-?B activation, including RANKL signaling.
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A case of synchronous bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character.
Springerplus
PUBLISHED: 12-01-2013
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We report a case of synchronous locally advanced bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character. The patient had presented bilateral breast cancer: the left breast cancer was hormone receptor negative, human epidermal growth factor receptor-2 (HER2) positive, and classified as T4bN1M0, stage IIIb, while the right was hormone receptor positive, HER2-negative, and classified as T4bN0M0, stage IIIb. We administered four cycles of anthracycline-based therapy followed by 12 weekly cycles of taxane with trastuzumab for neoadjuvant chemotherapy. We had achieved a significant left tumor reduction after each chemotherapy, but not right tumor. Bilateral modified radical mastectomies with axillary lymph-node dissection were performed. The therapeutic effect in the left was determined as a pathological complete response, in contrast to the right side. She has no recurrence for more than five years, though she had advanced cancer with oncologic emergency. This case could be an informative experience to understand the relation of tumor biology and response to systemic therapy.
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Breast cancers with high DSS1 expression that potentially maintains BRCA2 stability have poor prognosis in the relapse-free survival.
BMC Cancer
PUBLISHED: 06-26-2013
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Genetic BRCA2 insufficiency is associated with breast cancer development; however, in sporadic breast cancer cases, high BRCA2 expression is paradoxically correlated with poor prognosis. Because DSS1, a mammalian component of the transcription/RNA export complex, is known to stabilize BRCA2, we investigated how the expression of DSS1 is associated with clinical parameters in breast cancers.
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Divisional role of quantitative HER2 testing in breast cancer.
Breast Cancer
PUBLISHED: 03-28-2013
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BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is amplified in human breast cancers in which therapy targeted to HER2 significantly improves patient outcome. We re-visited the use of real-time quantitative polymerase chain reaction (qPCR)-based assays using formalin-fixed paraffin-embedded (FFPE) tissues as alternative methods and investigated their particular clinical relevance. METHODS: DNA and RNA were isolated from FFPE specimens and HER2 status was assessed by qPCR in 249 consecutive patients with primary breast cancer. Concordance with results forg immunohistochemistry (IHC) and in situ hybridization (ISH), clinical characteristics and survival was assessed. RESULTS: HER2 gene copy number had a stronger correlation with clinicopathological characteristics and excellent concordance with IHC/ISH results (Sensitivity: 96.7 %; concordance: 99.2 %). HER2 gene expression showed inadequate sensitivity, rendering it unsuitable to determine HER2 status (Sensitivity: 46.7 %; concordance: 92.1 %), but lower HER2 gene expression, leading to the classification of many cases as "false negative", contributed to a prediction of better prognosis within the HER2-amplified subpopulation. CONCLUSION: Quantitative HER2 assessments are suggested to have evolved their accuracy in this decade, which can be a potential alternative for HER2 diagnosis in line with the in situ method, while HER2 gene expression levels could provide additional information regarding prognosis or therapeutic strategy within a HER2-amplified subpopulation.
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Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer.
BMC Cancer
PUBLISHED: 01-26-2013
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BACKGROUND: After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. METHODS: Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. RESULTS: When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. CONCLUSIONS: TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE.Trial registration number: UMIN000001841 URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000001797&language=J.
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A comprehensive analysis of Aurora A; transcript levels are the most reliable in association with proliferation and prognosis in breast cancer.
BMC Cancer
PUBLISHED: 01-08-2013
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Aurora A kinase, a centrosomal serine/threonine kinase which plays an essential role in chromosome segregation during cell division, is commonly amplified and/or over expressed in human malignancies. Aurora A is suggested to be one of the proliferation parameters which is an independent prognostic factor for early invasive breast cancer patients; however the individual clinical or prognostic relevance of this gene has been a matter of debate.
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Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.
Breast Cancer
PUBLISHED: 01-08-2013
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BACKGROUND: The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. METHODS: Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. RESULTS: Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. CONCLUSION: Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.
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PTIP Associated protein 1, PA1, Is an Independent Prognostic Factor for Lymphnode Negative Breast Cancer.
PLoS ONE
PUBLISHED: 01-01-2013
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Pax transactivation domain interacting protein (PTIP) associated protein 1, PA1, was a newly found protein participating in the modulation of transactivity of nuclear receptor super family members such as estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR). Breast cancer is one of the most life threatening diseases for women and has tight association with estrogen and ER. This study was performed to understand the function of PA1 in breast cancer. The expression of PA1 had been evaluated in a total of 344 primary invasive breast cancer samples and examined the relationship with clinical output, relapse free survival (RFS), breast cancer-specific survival (BCSS). PA1 expression was observed in both nucleus and cytoplasm, however, appeared mainly in nuclear. PA1 nuclear expression was correlated with postmenopausal (P = 0.0097), smaller tumor size (P = 0.0025), negative Ki67 (P = 0.02), positive AR (P = 0.049) and positive ER? (P = 0.0020). Kaplan-Meier analysis demonstrated PA1 nuclear positive cases seemed to have a longer survival than negative ones for RFS (P = 0.023) but not for BCSS (P = 0.23). In the Cox hazards model, PA1 nuclear protein expression proved to be a significant prognostic univariate parameter for RFS (P = 0.03), but not for BCSS (P = 0.20). In addition, for those patients without lymphnode metastasis PA1 was found to be an independent prognostic factor for RFS (P = 0.025), which was verified by univariate and multivariate analyses. These investigations suggested PA1 expression could be a potential prognostic indicator for RFS in breast cancer.
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A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population.
Breast Cancer Res. Treat.
PUBLISHED: 10-06-2011
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Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 23 genetic variants identified in previous GWASs and conducted a case-control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Eleven single-nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4-5, 6-7, 8-9, and 10 or more were 1.33 (95% confidence interval, 1.00-1.80), 1.71 (1.26-2.30), 3.01 (1.97-4.58), and 8.69 (2.75-27.5), respectively (P (trend) = 1.9 × 10(-9)). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.6933, versus 0.6652 with the conventional risk factors only (P = 1.3 × 10(-4)). Population-attributable fraction of the risk score was 33.0%. In conclusion, we identified a genetic risk predictor of breast cancer in a Japanese population. Risk models which include a genetic risk score are possibly useful in distinguishing women at high risk of breast cancer from those at low risk, particularly in the context of targeted prevention.
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Establishment of a standardized gene-expression analysis system using formalin-fixed, paraffin-embedded, breast cancer specimens.
Breast Cancer
PUBLISHED: 09-20-2011
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It has recently being emphasized that gene-expression profiles are important clinical decision-making tools, and as such must be standardized across hospital laboratories in the same way as pathological investigations. In this study our objective was to independently establish a standardized gene-expression assay system using routinely processed, formalin-fixed, paraffin-embedded (FFPE) tissues.
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Stromal sarcoma of the breast with lung metastases showing a clinical complete response to doxorubicin plus ifosfamide treatment: report of a case.
Surg. Today
PUBLISHED: 07-20-2011
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A 29-year-old woman presented with a painful right breast tumor, measuring 15 cm in diameter, which had progressed rapidly over 3 months. Core needle biopsy of the tumor revealed a malignant mesenchymal tumor. A mastectomy was performed, and pathological examination of the tumor showed stromal sarcoma. Solitary pleural dissemination in the right lung was suspected, based on the computed tomography image taken before the operation. Two months after surgery, bilateral multiple lung nodules were demonstrated. Systemic chemotherapy with doxorubicin plus ifosfamide was performed, and 3 months later the lung metastases had disappeared. Moreover, there is still no sign of recurrence at 5 months after the initiation of the chemotherapy. Breast stromal sarcoma is very rare, accounting for less than 1% of mammary neoplasms, and the treatment strategy is not well established, especially regarding chemotherapy. This case demonstrates the effectiveness of chemotherapy with doxorubicin plus ifosfamide for lung metastases from breast stromal sarcoma.
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Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval.
Onco Targets Ther
PUBLISHED: 07-18-2011
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Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m(2) with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m(2) over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m(2) over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nabpaclitaxel was also more active and displayed less toxicity compared with 100 mg/m(2) docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent.
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Quantitative determination of insulin-like growth factor 1 receptor mRNA in formalin-fixed paraffin-embedded tissues of invasive breast cancer.
Breast Cancer
PUBLISHED: 07-14-2011
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Insulin-like growth factor 1 receptor (IGF1R) has recently received much attention due to its role in initiation and progression of breast cancer. Previously analysis of its gene expression has been restricted to fresh-frozen (FF) samples, but application of this technique to routinely processed formalin-fixed paraffin-embedded (FFPE) samples could facilitate larger retrospective studies correlating IGF1R expression with prognosis and therapeutic response.
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Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression.
Breast Cancer Res. Treat.
PUBLISHED: 03-31-2011
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Insulin-like growth factor-1 receptor (IGF1R) plays a key role in the initiation and progression of breast cancer. However, its prognostic relevance to breast cancer patients has long been a matter of debate. In a series of 325 primary invasive breast cancer patients, we performed a comprehensive analysis of IGF1R at the levels of gene copy number, mRNA expression and protein expression. The relationship between the IGF1R status and the clinicopathological characteristics and prognosis was evaluated. IGF1R mRNA levels not only correlated with protein expression, but also were significantly associated with several clinicopathological parameters and prognosis. Patients with low nuclear grade, negative axillary lymph nodes, positive hormone receptor, negative Her2, negative Ki67, and luminal subtype tumors showed higher expression levels of IGF1R mRNA, which was shown to be a significant univariate parameter for both relapse-free survival and breast cancer-specific survival (BCSS) as well as a significant multivariate parameter for BCSS. IGF1R protein expression showed an association with a prolonged BCSS in univariate analysis. In contrast, IGF1R gene copy number was not correlated with mRNA and protein expression, and harbored no prognostic value. When studied in the luminal tumor subtype groups, IGF1R mRNA level was still significantly associated with a better BCSS. Overall, our data indicated a correlation between IGF1R mRNA expression and protein expression in primary breast cancer. In particular, IGF1R mRNA expression appeared to be a good prognostic marker both in the entire cohort and in the luminal subtype group. These data may serve as background information for IGF1R-targeted therapy.
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Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor 2-positive metastatic breast cancer.
Int. J. Clin. Oncol.
PUBLISHED: 03-19-2011
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Trastuzumab demonstrates significant clinical benefits in HER2-positive metastatic breast cancer (MBC), and recent clinical trials suggest that trastuzumab should be continued in combination with other chemotherapy beyond progression. There is an urgent need to assess if patients could substantially benefit from continuing trastuzumab-based therapy.
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Shift in cytotoxic target from estrogen receptor-positive to estrogen receptor-negative breast cancer cells by trastuzumab in combination with taxane-based chemotherapy.
Oncol Lett
PUBLISHED: 01-11-2011
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Trastuzumab has shown significant clinical benefits in patients with operable and metastatic HER2-positive breast cancer. However, the biological mechanism of the additional effect of trastuzumab administered in combination with conventional chemotherapy is poorly understood. We performed a retrospective analysis of 55 patients with HER2-positive breast cancer treated with anthracycline and taxane (chemotherapy alone; CT), or trastuzumab in combination with taxane-based chemotherapy (CT+T) for neoadjuvant chemotherapy. We determined the therapeutic efficacies [clinical (CR) and pathological complete responses (pCR)] and changes in the proportion of positive cells for each biomarker pre- to post-neoadjuvant chemotherapy for each treatment regimen. Clinical-CR and quasi-pCR rates defined as the absence of invasive tumors or only a few remaining invasive tumor cells were 6.9 and 31.0% in the CT group and 46.2 and 65.4% in the CT+T group, respectively. In the CT group, the proportion of estrogen receptor (ER)-/progesterone receptor (PgR)-positive cells decreased significantly following treatment (ER, 73.5 vs. 50.9%; P=0.02). Changes in the proportion of ER-/PgR-positive cells were not noted in the CT+T group (ER, 81.9 vs. 80.3%; P=0.61), although a relatively greater decrease in the proportion of Ki-67-positive cells was found in the CT+T group than that in the CT group (-26.5 vs. -13.7%). These findings indicate that CT+T inhibits ER-negative and Ki-67-positive breast cancer cells. In conclusion, trastuzumab sensitized ER-negative proliferative cells to cytotoxic chemotherapy. This finding may indicate an additional clinical effect of trastuzumab when administered in combination with conventional chemotherapy as neoadjuvant chemotherapy for HER2-positive breast cancer.
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Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients.
Cancer Sci.
PUBLISHED: 12-07-2010
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FBXW7 is a cell cycle regulatory gene that ubiquitinates positive cell cycle regulators such as c-Myc and cyclin E, allowing for cell cycle exit. Defects in the FBXW7 gene that lead to cell cycle re-entry and expedite the G1-S transition is thought to be one of the causes of cancer development. However, its clinical importance for breast cancer patients remains undetermined. This prompted us to investigate its expression level in breast cancer patients to establish its clinical significance. The expression level of FBXW7 mRNA was assessed in 186 cases of primary invasive breast cancer. Correlations between FBXW7 mRNA expression and clinicopathological factors, prognoses and immunohistochemical expression levels of Ki-67, FBXW7, c-Myc and cyclin E were analyzed. In vitro investigation of FBXW7 gene silencing in a breast cancer cell line was conducted. FBXW7 mRNA was expressed at significantly lower levels in patients with high histological grade and hormone receptor-negative tumors. Patients with lower FBXW7 mRNA expression had a poorer prognosis for breast cancer-specific survival than those with higher expression. A high Ki-67 labeling index and positive cyclin E protein expression were significantly correlated with lower FBXW7 mRNA expression. In vitro, silencing FBXW7 enhanced expression of c-Myc and cyclin E proteins and upregulated both cell proliferation and G1-S transition. In breast cancer, reduced FBXW7 mRNA expression may have independent prognostic potential through the enhanced function of cell cycle regulatory proteins.
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Clinicopathological features and treatment strategy for triple-negative breast cancer.
Int. J. Clin. Oncol.
PUBLISHED: 06-11-2010
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Breast cancers are divided into at least 4 subtypes on the basis of gene expression profiles and expression of receptors (hormone receptors (HR) and HER2) as measured by immunohistochemistry. These subtypes have different prognoses and responses to treatments such as endocrine manipulation, anti-HER2 therapy, and chemotherapy. Triple-negative breast cancer (TNBC) is immunohistochemically defined as lacking estrogen and progesterone receptors and not overexpressing HER2. TNBC accounts for approximately 15% of breast cancer patients, and is more chemosensitive but has a worse prognosis than the HR-positive/HER2-negative phenotype. TNBC is a heterogeneous disease that does not offer specific targets in the same way as HR-positive and HER2-positive breast cancers, and is similar to basal-like breast cancer and BRCA1-related breast cancer. At present, the lack of highly effective therapeutic targets for TNBC leaves standard chemotherapy, for example the combination of anthracycline and taxane, as the only medical treatment, but this is insufficiently efficacious. Novel approaches for TNBC, for example DNA damaging agents, PARP-1 inhibitors, receptor tyrosin kinase inhibitors (TKIs), and antiangiogenesis agents, have been examined in clinical settings. Concerning therapeutic strategies for TNBC, it is most important to develop novel effective approaches for TNBC treatment and high-throughput predictive tools for standard chemotherapy and novel agents.
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Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins.
Breast Cancer Res.
PUBLISHED: 01-07-2010
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Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer.
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Nuclear corepressor 1 expression predicts response to first-line endocrine therapy for breast cancer patients on relapse.
Chin. Med. J.
PUBLISHED: 09-29-2009
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Estrogen receptor alpha (ER alpha) is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 (NCOR1) is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy.
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Maintenance of HCT116 colon cancer cell line conforms to a stochastic model but not a cancer stem cell model.
Cancer Sci.
PUBLISHED: 08-19-2009
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The cancer stem cell (CSC) model, in which a small population of cells within a tumor possesses the ability to self-renew and reconstitute the phenotype of primary tumor, has gained wide acceptance based on evidence over the past decade. It has also been reported that cancer cell lines contain a CSC subpopulation. However, phenotypic differences between CSCs and non-CSCs in cancer cell lines are not better defined than in primary tumors. Furthermore, some cell lines do not have a CSC population, revealed as a side population and expression of CD133. Thus, the identification of CSCs in cancer cell lines remains elusive. Here, we investigated the CSC hierarchy within HCT116 colon cancer cells, which do not have a CD133-positive subpopulation. We examined the expression of alternative CSC markers epithelial specific antigen (ESA) and CD44 in floating-sphere-derived cells, which are known to be the cells of enriching CSCs. Sphere-derived HCT116 cells exhibited heterogeneous expression of ESA and CD44. The two major subpopulations of HCT116 sphere cells (ESA(low)CD44(-/low) and ESA(high)CD44(high)) exhibited a biological/proliferative hierarchy of sphere-forming and soft agar colony-forming activity. However, there was no difference between the two subpopulations in the incidence of xenograft tumors. When ESA(low)CD44(-/low) cells were allowed to aggregate and re-form floating-spheres, the biological/proliferative hierarchy of parental HCT116 spheres was reconstituted, in terms of ESA and CD44 expression. Thus, HCT116 cells have plasticity when they are set in floating-spheres, suggesting that maintenance of the HCT116 cell line conforms to a stochastic model, not a CSC model.
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No association between CYP2D6*10 genotype and survival of node-negative Japanese breast cancer patients receiving adjuvant tamoxifen treatment.
Jpn. J. Clin. Oncol.
PUBLISHED: 07-11-2009
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The CYP2D6 enzyme plays a major role in converting tamoxifen to its active metabolites. We investigated whether there is an association between the CYP2D6*10 allele and clinical outcome in node-negative Japanese breast cancer patients.
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Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer.
Cancer Sci.
PUBLISHED: 07-06-2009
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Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERalpha-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERalpha, ERbeta, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin-like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERalpha serine (Ser) 118, ERalpha Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post-treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERalpha, ERbeta, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERalpha Ser118, ERalpha Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post-treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.
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[A case of spindle cell carcinoma of the breast including metaplastic lesion with poor prognosis].
Gan To Kagaku Ryoho
PUBLISHED: 06-23-2009
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A 57-year-old woman complained of a huge and rapid growing mass with bleeding in the left breast. Breast imaging (CT and MRI)showed a large, irregular and unevenly enhanced tumor with lymph node swelling in the left axilla. Mastectomy and axillary lymph node dissection were performed for control of bleeding from the tumor in the left breast. Pathological diagnosis was spindle cell carcinoma of the breast with transition from papillotubular carcinoma. Although the patient was treated with adjuvant chemotherapy and trastuzumab according to the treatment guideline for conventional breast cancer, she had an early relapse with mediastinal metastasis and died 9 months after operation. The tumor showed metaplastic change from epithelial tumor to spindle cell carcinoma. Because the epithelial part expressed weakly positive estrogen receptor(ER), progesterone receptor(PgR)-negative and HER2-positive, we used trastuzumab for adjuvant therapy. However, part of the spindle cell tumor mainly showed triple-negative, and ER, PgR and HER2 expression were negative, which might explain her poor prognosis for resistance to trastuzumab.
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Triple negative breast cancer: clinicopathological characteristics and treatment strategies.
Breast Cancer
PUBLISHED: 06-10-2009
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Triple negative breast cancer (TNBC) is defined as a subtype that is negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. We introduce the theme of the special issue concerning clinicopathological characteristics and prospective treatment strategies of TNBC. This special issue consists of five conference papers that have been agreed on by the speakers and the commentator of the symposium of the 16th Annual Meeting of the Japanese Breast Cancer Society in September 2008 in Osaka.
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Clinical usefulness of high-dose toremifene in patients relapsed on treatment with an aromatase inhibitor.
Breast Cancer
PUBLISHED: 06-04-2009
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Aromatase inhibitors (AIs) have been employed as adjuvant therapy or as treatment for recurrent cases. However, when AI treatment fails, it is unclear which endocrine therapy is the most appropriate to introduce at this point and how effective it will be. In this study, we investigated the efficacy and safety of toremifene (TOR, Fareston(®)), a selective estrogen receptor modulator (SERM).
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Midkine in plasma as a novel breast cancer marker.
Cancer Sci.
PUBLISHED: 06-01-2009
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Midkine, a heparin-binding growth factor, is up-regulated in many types of cancer. The aim of this study was to measure plasma midkine levels in patients with breast cancer and to assess its clinical significance. We examined plasma midkine levels in 95 healthy volunteers, 11 patients with ductal carcinoma in situ (DCIS), 111 patients with primary invasive breast cancer without distant metastasis (PIBC), and 25 patients with distant metastatic breast cancer (MBC), using an automatic immunoasssay analyzer (TOSOH AIA system). In PIBC, we studied the correlation between plasma midkine levels and clinicopathological factors. Immunoreactive midkine was detectable in the plasma of healthy volunteers, and a cut-off level of 750 pg/mL was established. In breast cancer patients, plasma midkine levels were increased above normal values. These elevated levels of midkine were seen in one (9.1%) of 11 patients with DCIS, 36 (32.4%) of 111 patients with PIBC, and 16 (64.0%) of 25 patients with MBC. Increased levels of midkine were correlated with menopausal status (P = 0.0497) and nuclear grade (P = 0.0343) in PIBC. Cancer detection rates based on midkine levels were higher than those based on three conventional markers including CA15-3 (P < 0.0001), CEA (P = 0.0077), and NCCST-439 (P < 0.0001). Detection rates of breast cancer using a combination of two conventional tumor markers (CA15-3/CEA, CA15-3/NCCST-439, or CEA/NCCST-439) with midkine is significantly higher than those using combination of three conventional tumor markers. Midkine may be a useful novel tumor marker for detection of breast cancer, superior to conventional tumor markers.
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Advantage of sentinel lymph node biopsy before neoadjuvant chemotherapy in breast cancer treatment.
Surg. Today
PUBLISHED: 04-30-2009
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Lymph node status is a key factor in determining the stage of breast cancer and the most appropriate therapy and for predicting the outcome of patients. Accurate identification of sentinel lymph nodes (SLNs) preoperatively is of clinical importance. Sentinel lymph node biopsy (SLNB) causes less lymph edema of the upper arm than axillary lymph node dissection (ALND) with a high accuracy rate and low false-negative rate (FNR). Neoadjuvant chemotherapy (NAC) can be given not only to patients with locally advanced breast cancer, but also to those with axillary lymph node metastasis and an operable tumor. However, SLNB after NAC results in a lower identification rate and a higher FNR than SLNB before treatment. Recently, a hybrid imaging device has been developed, which consists of single photon emission computed tomography (CT, SPECT) and a low-dose CT installed on the same platform. This imaging system offers an easy and safe method of performing SLNB under local anesthesia. To identify the initial cancer stage in patients who will be treated by systemic therapy before surgery, SLNB should be performed prior to systemic treatments, using a well-developed navigating tool, such as SPECT/CT.
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Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance.
Breast Cancer Res. Treat.
PUBLISHED: 04-14-2009
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Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-alpha (ERalpha) promote the proliferation of breast cancer cells. Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription. Here, we show that menin expressed in breast cancer cell line MCF-7 is colocalized with ERalpha and functions as a direct coactivator of ER-mediated transcription in breast cancer cells. In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner. Cells knocked down for ERalpha exhibited impaired ERE-luciferase activity induced by menin. Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ERalpha. These results indicate that menin is a direct activator of ERalpha function. Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7. In a clinical study with 65 ER-positive breast cancer samples-all of which had been treated with tamoxifen for 2-5 years as adjuvant therapies--menin-positive tumors had a worse outcome than menin-negative ones. These indicated that menin can function as a transcriptional regulator of ERalpha and is a possible predictive factor for tamoxifen resistance.
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Potential advantage of preoperative three-dimensional mapping of sentinel nodes in breast cancer by a hybrid single photon emission CT (SPECT)/CT system.
Surg Oncol
PUBLISHED: 03-06-2009
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This study aims to assess the role of three-dimensional single-photon emission computed tomography (3D-SPECT/CT) in sentinel node (SN) identification, and to analyze the impact of such information on estimating metastases to SNs.
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Estrogen receptor alpha gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients.
Cancer Sci.
PUBLISHED: 02-25-2009
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Estrogen receptor (ER) alpha plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, the molecular mechanisms controlling the expression of ERalpha are as yet not fully understood. Gene amplification is one of the important factors regulating protein expression. Recent studies on the amplification of the ESR1 gene, which encodes ERalpha, have presented conflicting data. Using fluorescence in situ hybridization and real-time quantitative polymerase chain reaction analysis, we examined the ESR1 status in a series of breast cancer tissues and analyzed its clinical importance. ESR1 gene amplification and gain were found in 22.6 and 11.3% of samples, respectively, as determined by three-dimensional fluorescence in situ hybridization assay. Moreover, ESR1 amplification and amplification plus gain were significantly negatively correlated with tumor size, number of positive lymph nodes, negative ERalpha, and positive human epidermal growth factor receptor 2 status. It has also been shown that ESR1 amplification strongly correlates with higher expression levels of ER protein and that patients with ESR1 amplification in their tumors apparently experience longer disease-free survival than those without. Our data suggest that ESR1 amplification might prove to be helpful in selecting patients who may potentially benefit from endocrine therapy.
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Pathological lymph node involvement at surgery is a significant predictive factor of recurrence in locally advanced breast cancer treated with concomitant epirubicin-docetaxel neoadjuvant chemotherapy: a cohort study.
Breast Cancer
PUBLISHED: 02-12-2009
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Neoadjuvant chemotherapy (NAC) is the standard therapy for locally advanced breast cancer. Recently, several studies have revealed that clearance of axillary lymph node involvement is an independent factor for survival irrespective of the response of the primary lesion. However, in daily practice, it is difficult to fully examine every lymph node that has been surgically sampled, in view of pathology laboratory workload and cost. Therefore, in the present study, we adopted the more clinically relevant categorization of evaluating postoperative axillary lymph node status and retrospectively studied its significance in predicting patients survival.
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Clinical significance of basal-like subtype in triple-negative breast cancer.
Breast Cancer
PUBLISHED: 01-22-2009
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No clinically useful target molecule has been identified for triple-negative (TN) breast cancer, i.e., estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, human epidermal growth factor receptor-2 (HER2)-negative phenotype, and its prognosis is poor. Triple-negative cancer consists of two subtypes: basal-like and non-basal-like. The aim of this study is to clarify the clinical and biological characteristics of these two subtypes of TN cancer.
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Clinicopathological analyses of triple negative breast cancer using surveillance data from the Registration Committee of the Japanese Breast Cancer Society.
Breast Cancer
PUBLISHED: 01-15-2009
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Triple negative (TN) breast cancer is defined as a subtype that is negative for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). To clarify the characteristics of TN breast cancer, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed.
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Differential impact of body mass index and its change on the risk of breast cancer by molecular subtype: A case-control study in Japanese women.
Springerplus
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Body mass index (BMI) is an independent risk factor for luminal-type breast cancer in Western populations. However, it is unclear whether the impact of BMI differs according to breast cancer subtype in Japanese populations. We conducted a case-control study with 715 cases and 1430 age- and menopausal status-matched controls to evaluate the associations of BMI and its change (from age 20 years to the current age) with breast cancer risk. We applied conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tumor subtypes were divided into four subtypes, namely the luminal, luminal/HER2, HER2-rich, and triple-negative subtypes. Current BMI and BMI change were positively associated with postmenopausal breast cancer risk. On stratified analysis by tumor subtype, we observed associations between current BMI and BMI change and postmenopausal breast cancer risk for the luminal subtype, with OR for each 1 kg/m(2) increase in current BMI of 1.14 (95% CI: 1.07 - 1.20) and the corresponding OR of BMI change of 1.16 (1.09 - 1.23) (each P(trend) < 0.001). Additionally, we found the same tendency for the triple-negative subtype, with the OR for a 1 kg/m(2) increase in current BMI of 1.21 (1.05 - 1.39) and that for BMI change of 1.18 (1.02 - 1.36) (P(trend) was 0.008 and 0.024, respectively). In premenopausal women, a suggestive inverse association was observed between BMI change and breast cancer risk for the luminal subtype only, with OR of BMI change of 0.93 (0.87 - 1.00, P(trend) = 0.054). No association was seen between BMI at age 20 years and risk of any tumor subtype. In conclusion, BMI and its change are associated with the risk of both luminal and triple-negative breast cancer among postmenopausal Japanese women. These findings suggest the etiological heterogeneity of breast cancer among tumor subtypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-1-39) contains supplementary material, which is available to authorized users.
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Association of ErbB1-4 expression in invasive breast cancer with clinicopathological characteristics and prognosis.
Breast Cancer
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BACKGROUND: Human epidermal growth factor receptor type 2 (Her2)/ErbB2 plays a key role in the initiation and progression of invasive breast cancer. However, the prognostic relevance to breast cancer patients of the other ErbB family members has long been a matter of debate. METHODS: In a series of 250 primary invasive breast cancer patients, we performed a comprehensive analysis of ErbB1-4 at the levels of mRNA expression and gene copy number using real-time quantitative PCR. The relationship between the status of ErbB1-4 and the clinicopathological characteristics or prognosis was evaluated. RESULTS: The mRNA expression of ErbB2, but not the other ErbB genes, was significantly correlated to copy number (P = 0.0005). ErbB3 and ErbB4 mRNA expression were positively correlated to each other (P < 0.0001). The mRNA expression of ErbB1/2 was inversely correlated to estrogen receptor (ER) and progesterone receptor (PgR) positivity, although mRNA expression of ErbB3/4 was positively correlated to ER and PgR positivity. Kaplan-Meier survival analysis showed that ErbB1 mRNA expression was associated with reduced survival. Neither ErbB2 nor ErbB3 mRNA expression had any association with survival, because half of the patients with Her2-positive tumors were treated with trastuzumab. High ErbB4 mRNA expression showed good prognosis with respect to breast cancer-specific survival CONCLUSIONS: ErbB3 and ErbB4 mRNA expression, as well as well as that of ErbB1 and ErbB2, could be histopathological factors. ErbB3 mRNA was highly expressed in ER-positive tumors and has controversial prognostic value. ErbB4 mRNA expression was well correlated with ER positivity and good prognosis, indicating that ErbB4 may contribute to ER-dependent growth.
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Analysis of Ki-67 expression with neoadjuvant anastrozole or tamoxifen in patients receiving goserelin for premenopausal breast cancer.
Cancer
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The increasing costs associated with large-scale adjuvant trials mean that the prognostic value of biologic markers is increasingly important. The expression of nuclear antigen Ki-67, a marker of cell proliferation, has been correlated with treatment efficacy and is being investigated for its value as a predictive marker of therapeutic response. In the current study, the authors explored correlations between Ki-67 expression and tumor response, estrogen receptor (ER) status, progesterone receptor (PgR) status, and histopathologic response from the STAGE study (S_tudy of T_amoxifen or A_rimidex, combined with G_oserelin acetate to compare E_fficacy and safety).
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High survivin mRNA expression is a predictor of poor prognosis in breast cancer: a comparative study at the mRNA and protein level.
Breast Cancer
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BACKGROUND: Survivin plays a key role in the initiation and progression of breast cancer. However, its prognostic relevance to breast cancer patients has long been a matter of debate. The purpose of this study was to examine the expression of survivin and its role in predicting clinical outcome in a series of human breast cancer cases both at the mRNA and protein level. METHODS: Formalin-fixed paraffin-embedded tumor tissues from 245 female patients with invasive breast cancer and 13 patients with ductal carcinoma in situ were examined for survivin mRNA by quantitative real-time RT-PCR (RT-qPCR). In addition, 237 of these tumors with invasive breast cancer were available for immunohistochemistry (IHC). The relationship between survivin status and clinicopathological characteristics and prognosis was evaluated. RESULTS: RT-qPCR revealed that high levels of survivin mRNA were strongly associated with high nuclear grade, positive axillary lymph nodes, negative hormone receptor status, positive Her2 amplification, higher Ki67 labeling index, and presence of vascular invasion. In the Cox proportional regression model analysis, survivin mRNA was shown to be a significant univariate parameter for relapse-free survival (RFS), distant relapse-free survival (DRFS), and breast cancer-specific survival (BCSS) as well as a significant multivariate parameter for RFS, DRFS, and BCSS. In hormone receptor (HR)-positive/Her2-negative subtype cases, survivin mRNA expression was also an independent predictor in terms of DRFS. Immunohistochemically, positive staining was seen in the cytoplasm and/or nucleus of cancer cells, although this did not correlate with the mRNA level, and harbored no prognostic value. CONCLUSIONS: High mRNA expression of survivin was an independent marker of poor prognosis both in the entire cohort and in the HR-positive/Her2-negative subtype, whereas the protein expression of survivin was not. These findings suggest that RT-qPCR can provide more reliable data than IHC in validating the prognostic significance of survivin for breast cancer patients.
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Comparison of prognostic values between combined immunohistochemical score of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67 and the corresponding gene expression score in breast cancer.
Mod. Pathol.
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In the clinical diagnosis of breast cancer, immunohistochemistry panels with estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 are routinely used, and they have been proposed for the classification of breast tumors into distinct subtypes. Gene expression analysis with formalin-fixed paraffin-embedded material have also become widely available recently, but the prognostic values of corresponding gene panels compared with these four immunohistochemical panels had never tested. We independently evaluated the 5-year relapse risk-estimation scores using semiquantitative data of four immunohistochemical panels (Ku-IHC4 score) and compared these with the results of four-gene expression profiling of formalin-fixed paraffin-embedded specimens (Ku-FFPE4 score) in a consecutive series of 235 primary invasive breast cancer patients. Ku-IHC4 score was revealed to be an independent predictor of recurrence other than Ku-FFPE4 score in a multivariate model analyzed by classical clinical parameters (Ku-IHC4 score vs Ku-FFPE4 score; ?(2): 14.2 vs 2.5, P: 0.0002 vs 0.11). When patients were trichotomized into high-, intermediate- and low-risk groups using the thresholds determined from the approximately calculated 5-year relapse rate, Kaplan-Meier analyses showed a significant difference among the three groups in Ku-IHC4 score (log-rank, P<0.0001), but not in Ku-FFPE4 score. The high-risk group according to Ku-FFPE4 score showed contradictory low recurrence rates (Ku-IHC4 score vs Ku-FFPE4 score, 53.1 vs 24.8%), which might be caused by risk-dependently extended error ranges. We show that the Ku-IHC4 score, consisted with semiquantitative measures of immunohistochemistry, provides better prognostic information than the corresponding quantitative RNA measurements. Prognostication tools such as the Ku-IHC4 score may be potentially useful in screening which patients had better be assessed by further testing using other genes rather than ER, PgR, HER2 and Ki-67 to determine critical aspects of therapeutic decision making.
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Evaluation of tumor stiffness by elastography is predictive for pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer.
Ann. Surg. Oncol.
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Breast elastography (EG), which can objectively evaluate tumor stiffness, has been useful for differentiation of benign and malignant breast lesions. However, the value of EG for prediction of response to systemic therapy is poorly understood.
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Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens.
Breast Cancer
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Ki67 is a protein associated with cell cycle activity and shows a good correlation with the growth fraction, which has been proposed as a prognostic or predictive marker in breast cancer. In this study, we aimed to analyze the expression levels of Ki67 (MKI67) messenger RNA (mRNA) derived from formalin-fixed paraffin-embedded (FFPE) tissues for comparison with the immunohistochemical Ki67 labeling index, and investigate the correlation coefficients with clinical outcomes.
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Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis.
Cancer Res.
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Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here, we report evidence of critical role for the angiopoietin-like protein 2 (ANGPTL2) in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In patients with lung cancer, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor cell-derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor cell-derived ANGPTL2 accelerated metastasis and shortened survival whereas attenuating ANGPTL2 expression in tumor cells-blunted metastasis and extended survival. Overall, our findings showed that tumor cell-derived ANGPTL2 drives metastasis and provided an initial proof of concept for blockade of its action as a strategy to antagonize the metastatic process.
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Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial.
Lancet Oncol.
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Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.