bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomics of basal breast carcinomas: a potential target for treatment intervention.
Authors: Thor AD , Edgerton SM , Fan Z , Lind SE , Liu B 
Published: December 2010

Abstract
Abstract #6026
Breast cancers of the basal subtype (ER, PR and HER2 negative; EGFR and/or CK5/6 positive) are typically high grade, rapidly proliferative, associated with a poor outcome and are resistant to many chemotherapeutic regimens. They occur more frequently in women with BRCA-1 mutations, African Americans and obese individuals. At the molecular level, basal cancers have impairment of BRCA-1 and p53 signaling and are driven, in part, through EGFR which activates the PI3K/AKT/mTOR pathways. Treatment of basal carcinoma cell lines with the FDA approved anti-diabetic drug metformin significantly reduces cellular proliferation, induces cell cycle arrest (late G1/S phase) and apoptosis in vivo and in vitro. Similar effects were not observed in breast cancer cells of the luminal A, B or HER2 subtypes. Metformin induces a wide spectrum of metabolic and molecular changes in basal carcinoma cell lines in vitro, including: a reduction in glucose uptake, enhanced lactate release, a decrease in cellular proliferation and colony formation, a decrease in EGFR, phospho-EGFR and downstream signaling including pAKT, pMAPK and psrc, inhibition of cyclins D1 and E, reduced E2F1, PARP cleavage and activation of caspases 3, 8 and 9 in a dose and time dependent manner. Nude mice with basal cell line MDA-MB-231 xenografts treated with metformin showed significantly reduced tumor growth and prolonged survival as compared to control untreated mice. Pre-treatment with metformin prior to xenograft inoculation reduced both tumor formation and growth as compared to mice treated with metformin after implantation or untreated control mice, suggesting that metformin may have some use in basal cancer prevention. Epidemiologic data has shown that women treated with metformin have a reduced rate of breast cancer and, for those patients with breast cancer, an improved disease free and overall survival. In aggregate, these data suggest that further study of metformin to prevent or treat breast cancer in some patient subgroups may be indicated.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6026.
Expression of prostaglandin metabolizing enzymes in correlation with vitamin D receptor in benign and malignant breast cell lines and breast tissue and regulation of prostaglandin metabolism by calcitriol.
Authors: Thill M , Fischer D , Becker S , Tim C , Diedrich K , Friedrich M 
Published: December 2010

Abstract
Abstract #6028
Backround: The antiproliferative effects of calcitriol [1,25(OH)2D3] make the biologically active form of vitamin D to a promising target in breast cancer therapy. It is well known, that these effects are mediated via the vitamin D3 receptor (VDR). Furthermore breast cancer is associated with inflammatory processes based on an upregulation of cyclooxygenase-2 (COX-2) expression, the prostaglandin E2 (PGE2) synthesizing enzyme. The PGE2 metabolizing enzyme, 15 hydroxyprostaglandin dehydrogenase (15 PGDH) is described as a tumor suppressor in cancer. First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 on the expression of COX-2 and 15 PGDH. Thus we evaluated the expression of COX-2 and 15 PGDH with VDR and the influence of calcitriol on COX-2 and 15 PGDH.&#x2028; Materials and methods: The Expression of VDR, COX-2 and 15 PGDH in MCF10F, a human benign epithelial cell line and the breast cancer cell line MCF-7 was determined by real time PCR and western blot analysis. Furthermore, we determined mRNA level of COX-2 and 15 PGDH and VDR in healthy and malignant breast sample tissues. In addition we examined the effect of calcitriol on COX-2 and 15 PGDH mRNA levels.&#x2028; Results: Although our data from real time pCR were divergent from those obtained from the western blot analysis, we showed, that COX-2 protein expression is increased in MCF-7 2-fold compared to MCF10F. These data were confirmed in breast cancer tissue samples, where COX-2 mRNA level increased to 1,44 in comparison to healthy tissues. No correlation of 15 PGDH was detected in both cell lines, but in malignant tissues 15 PGDH expression increase dramatically compared to healthy tissue samples. The expression of VDR we found differs in protein and mRNA level in benign and malign cell lines. VDR protein levels were inverse correlated to 15 PGDH expression and reveal that the benign tissue as well as the MCF10F cells have the highest VDR expression. Furthermore we demonstrated a downregulation of cyclooxygenase and an up-regulation of 15 PGDH by calcitriol.&#x2028; Conclusion: We found a basically inverse correlation between VDR and 15 PGDH protein level expression. These findings suggest a possible link between VDR, associated target genes and the prostaglandin metabolism. The influence of calcitriol on COX-2 and 15 PGDH might lead to an additional novel pathway of calcitriol action mediating its antiproliferative effects in breast cancer and might open new therapeutic approaches in breast cancer therapy.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6028.
HOXB13 protein expression predicts the benefit of tamoxifen treatment in breast cancer patients.
Authors: Jerevall P , Jansson A , Fornander T , Skoog L , Nordenskjöld B , Stål O 
Published: December 2010

Abstract
Abstract #6038
Background: The two-gene expression ratio HOXB13:IL17BR, originally from a microarray analysis, has been shown to be indicative of clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer, with a high ratio associated with decreased disease-free survival. Analysis of a cohort of breast cancer patients randomized to 2 or 5 years of adjuvant tamoxifen therapy showed that the two-gene ratio and expression of the HOXB13 gene alone were predictive of the benefit of prolonged tamoxifen treatment. Patients with tumors expressing HOXB13 at high levels were unresponsive to prolonged adjuvant treatment, suggesting that this gene is involved in tamoxifen resistance. It is suggested that a high two-gene ratio may indicate impaired ER signaling, which is known to predict resistance to tamoxifen. To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer.&#x2028; Methods: We have analyzed the protein expression of HOXB13 with immunohistochemistry in tumor samples from 912 postmenopausal node negative breast cancer patients randomized to 2 years of tamoxifen or no endocrine treatment. After 2 years, recurrence-free patients were randomized to 3 more years of tamoxifen, or no further therapy. This selection enabled us to investigate the treatment predictive value of HOXB13.&#x2028; Results: Data on HOXB13 protein expression were obtained from 866 patients (see table). Tamoxifen treated patients with estrogen receptor (ER) positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (hazard ratio (HR) 0.37, 95% CI 0.23-0.60, p=0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the distant recurrence-free survival compared to the untreated patients (HR=0.83, 95% CI 0.45-1.54, p=0.55). The interaction between HOXB13 expression and benefit from tamoxifen was statistically significant (p=0.046). HOXB13 did not have any prognostic value among systemically untreated patients.&#x2028; &#x2028; Conclusions: HOXB13 protein level may be used as a predictive marker for tamoxifen treatment, but does not have any prognostic value. Patients with a high expression of HOXB13 do not seem to benefit from tamoxifen.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6038.
Prognostic algorithm identified in node-negative early breast cancer patients predicts outcome also in node-positive patients treated with adjuvant chemotherapy.
Authors: Kronenwett R , Kalogeras KT , Stropp U , Weber K , Dafni U , Gehrmann M , Pectasides D , von Toerne C , Papakostas P , Wirtz RM , Fountzilas G 
Published: December 2010

Abstract
Abstract #6044
Background: Recently, we identified and validated a prognostic multigene score, which predicted outcome in early node-negative breast cancer patients that did not receive systemic therapy. The aim of this study was to examine the performance of our prognostic multigene algorithm in node-positive patients treated with adjuvant chemotherapy.&#x2028; Patients and Methods: Patients were treated with adjuvant anthracycline-based chemotherapy in the context of a randomized Phase III study. This was a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was isolated from 222 formalin-fixed, paraffin-embedded tumor tissue samples, using a Siemens proprietary automated method based on silica-coated magnetic beads, followed by kinetic one-step RT-PCR for mRNA expression analysis of 9 informative genes and 2 normalization genes. For each patient a risk score was calculated using a linear combination of expression values. Patients were separated into high, intermediate and low risk by applying two thresholds of the score. As used in node-negative patients, distant metastasis-free survival (MFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox analysis for MFS and OS was also performed.&#x2028; Results: The prognostic score could be calculated for 213 patients (102 E-T-CMF; 111 E-CMF). Looking at all patients independently of type of chemotherapy, the score could classify the patients into three distinct risk groups, which were significantly different in terms of MFS (log-rank test, p=0.004) and OS (p=0.01). The separation of the risk groups was even better when focusing on patients with more than three involved lymph nodes (MFS: p=0.0001; OS: p=0.0015; n=166). The respective analysis of the two treatment arms showed that the separation of the risk groups was only significant in E-CMF-treated patients (E-CMF: p=0.002; E-T-CMF: p=0.37). Interestingly, the subgroup of patients with more than three involved lymph nodes and classified as intermediate or high risk (n=77) had a nearly significant better MFS when treated with E-T-CMF in comparison with E-CMF (p=0.07; HR: 0.53; 95% CI: 0.2685 to 1.060).&#x2028; Conclusions: Our prognostic algorithm, identified and validated in node-negative patients that had not been systemically treated, predicts outcome also in node-positive chemotherapy-treated patients. Our findings suggest that the prognostic score may also be predictive of benefit from the addition of taxanes to adjuvant chemotherapy. This hypothesis needs to be confirmed in a larger cohort of samples from an independent clinical study.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6044.
Predicting response to alkylating chemotherapy in breast cancer patients using array comparative genomic hybridization.
Authors: Vollebergh MA , Nederlof PM , Wessels LF , Schmidt MK , Joosse SA , van Beers E , Froklage F , Holtkamp M , Schrama JG , Wesseling J , Hauptmann M , de Bruin M , Rodenhuis S , Linn SC 
Published: December 2010

Abstract
Abstract #6050
Background: Breast cancer cells lacking the DNA repair mechanism Homologous Recombination (HR) have recently been shown to be hypersensitive to bifunctional alkylating agents such as carboplatin and poly(ADP-ribose)polymerase(PARP)-inhibitors, a novel class of targeted agents. We have previously reported the construction of an array Comparative Genomic Hybridization (aCGH) classifier that detects the characteristic copy number aberrations of BRCA1-mutated tumors which are thought to be caused by HR deficiency. We hypothesized that metastatic breast cancer patients with tumors harboring such a BRCA1-profile may specifically benefit (longer progression-free survival (PFS)) from intensive treatment with bifunctional alkylating agents compared to patients without this tumor-profile.&#x2028; Methods: We isolated DNA from formalin-fixed paraffin-embedded primary tumor tissue collected from 3 prior studies carried out in our institute, in which metastatic breast cancer patients received intensive alkylating chemotherapy with carboplatin, thiotepa and cyclophosphamide (CTC). DNA from 40 tumors was tested for the presence of the BRCA1-profile by aCGH. Furthermore, we screened for the majority of BRCA1 and BRCA2 mutations that frequently occur in Dutch BRCA1 and BRCA2 families.&#x2028; Results: Sixteen patients had a tumor with a BRCA1-profile and had a better response to CTC-treatment, defined by achievement of a complete remission (p=0.01) and longer PFS (p=0.001, figure 1), with a hazard ratio for progression of 0.30 (p=0.002).&#x2028; &#x2028; All 6 patients who remain in continuous complete remission (56+ to 150+ months) had a tumor with a BRCA1 profile. Two BRCA1 and 2 BRCA2 mutations were found in 4 patients of whom 3 had a BRCA1-profile and a long PFS (&gt; 30months), linking HR deficiency (BRCA1 and BRCA2 mutations) in breast cancer patients to good outcome on platinum-based chemotherapy.&#x2028; Discussion: Using an aCGH classifier initially constructed to identify BRCA1-mutated tumors we were able to identify a group of metastatic breast cancer patients treated with platinum-based chemotherapy with a high complete remission-rate and long progression free survival. Moreover, this group contained all patients who were apparently cured by intensive alkylating chemotherapy. Our aCGH assay may represent an effective test for BRCA-ness and could be important to select patients with sporadic tumors for therapy targeted at cells deficient in Homologous Recombination.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6050.
Ratio of cyclin-dependent kinase 1 (CDK1) activity to CDK2 activity after ex vivo paclitaxel treatment predicts response to paclitaxel in human breast cancer.
Authors: Kim S , Taguchi T , Tamaki Y , Tsukamoto F , Akazawa K , Ueno NT , Hortobagyi GN , Nakayama S , Torikoshi Y , Gohda K , Ishihara H , Noguchi S 
Published: December 2010

Abstract
Abstract #6065
Background: Increased CDK1 activity and reduced CDK2 activity reflect paclitaxel sensitivity in vitro. We have developed a novel assay that measures CDK1 and CDK2 activity in small tissue samples (“C2P assay”). The aim of this study was to determine whether the CDK1/2 ratio after ex vivo paclitaxel treatment correlates with response to paclitaxel in human breast cancer.&#x2028; Material and Methods: This study included 38 patients with primary breast cancer. The median age was 50 years. Twenty-five patients (66%) had stage II, 12 (32%) stage III, and 1 (3%) stage IV. Thirty-three patients (87%) had invasive ductal and four (11%) invasive lobular cancer: 1 patient (3%) had mucinous disease. Histologic grade was II in 33 patients (87%) and III in 5 patients (13%). Twenty-one patients (55%) had ER-positive and 11 (29%) HER2-positive disease. All patients received preoperative chemotherapy - paclitaxel (80 mg/m2, weekly for 12 weeks) followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) (500/75/500 mg/m2, every 3 weeks for 4 cycles) in 34 patients (89%) and paclitaxel alone in 4 patients (11%). Tumor tissues obtained by core needle biopsy before chemotherapy were treated ex vivo with paclitaxel (100 nM) for 24 h, and then had CDK1/2 activity measured using the C2P assay. Clinical responses were evaluated with magnetic resonance imaging after paclitaxel treatment, and tumors that showed equal and more than 80 % shrinkage were defined as responders. The cutoff value for distinguishing between high and low CDK1/2 ratio was identified as 5.2 to best separate the responders and non-responders to paclitaxel.&#x2028; Results: Of the 23 tumors with a high CDK1/2 ratio, 18 responded to paclitaxel. On the other hand, of the 15 tumors with a low CDK1/2 ratio, 10 did not respond to paclitaxel (positive predictive value, 78%; negative predictive value, 67%; p = 0.006). Of the 34 patients who were treated with paclitaxel followed by FEC and underwent surgery, 9 (26%) had a pathologic complete response (pCR). Eight of 21 tumors in the high CDK1/2 ratio group but only 1 of 13 tumors in the low CDK1/2 ratio group had a pCR (positive predictive value, 38%; negative predictive value, 92%; p = 0.05).&#x2028; Discussion: The CDK1/2 ratio is significantly associated with response to paclitaxel and also with pCR after treatment with paclitaxel followed by FEC. The CDK1/2 ratio after ex vivo paclitaxel treatment might be a useful test to predict paclitaxel sensitivity in breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6065.
Prevalence of fibroadenomas in kidney-transplanted patients using cyclosporine A.
Authors: Machado JN , Vieira Jr. LA , Araujo Neto JT , Kemp C , Facina G , Nazario AC 
Published: December 2010

Abstract
Abstract #6078
Background: Fibroadenoma is the commonest benign tumor of female breast, classified as fibroepithelial neoplasia. It is frequent during reproductive years mainly in the 2nd and 3rd decades of life, coinciding with follicular maturation and steroidogenesis. With the beginning of the era of transplants the use of cyclosporine A was accepted by the medical community as potential lymphocyte T suppressant. In 1980 the first report on multiple breast fibroadenomas in renal transplant patients taking cyclosporine A was published. The imaging standard of fibroadenomas also seems to differ from usually found in asymptomatic patients: diameters are notably larger, lower longitudinal / anteroposterior diameter ratio and are more hyperechogenic.&#x2028; Objetive: To define the prevalence of breast fibroadenomas in kidney-transplanted patients taking cyclosporine A.&#x2028; Materials and Methods: Prevalence of breast fibroadenomas was determined in three groups of patients: 50 women with renal transplant taking cyclosporine A (Group 1); 51 women with renal transplant not taking cyclosporine A (Group 2) and 181 women without renal transplant (Control Group). Evaluation was performed by anamnesis, physical examination and breast ultrasonography. In the case of clinical or imaging suspicion of fibroadenoma, the diagnosis was confirmed by core needle biopsy or lumpectomy.&#x2028; Results: The groups were homogeneous regarding age, menstrual status and former breast cancer family history. Fourteen percent fibroadenomas were found in the renal transplant patient group taking cyclosporine A versus 2.0% in the renal transplant patient group not taking cyclosporine A, and 2.8% in the control group. Prevalence of breast fibroadenomas in renal transplant patients taking cyclosporine A was significantly higher than in those not taking the drug and than in the control group (p=0.001). Frequency of fibroadenomas of the control group and renal transplant patients not taking cyclosporine was similar (p=0.073). Multiplicity, bilaterality and greater nodule dimensions were observed more in renal transplant patients taking cyclosporine A, but there was no statistical significance among the groups.&#x2028; &#x2028; Conclusion: Breast fibroadenomas are more prevalent in the renal transplant patients taking cyclosporine A.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6078.
Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients.
Authors: Yin W , Di G , Lin Y , Lu J , Liu G , Wu J , Shen Z , Shao Z 
Published: December 2010

Abstract
Abstract #6080
Background: Triple negative breast cancers are defined by a lack of expression of estrogen, progesterone, and Her-2 receptors. A number of studies suggested that the triple-negative phenotype could contribute to an aggressive behavior and a poor prognosis. However, similar data is still not available for Chinese populations. We sought to analyze the clinicopathological features of this subgroup in our hospital in order to get characteristics for Chinese breast cancer.&#x2028; Methods: We performed a retrospective study of 2028 female unilateral breast cancer patients undergoing surgery in our hospital from February 1991 to December 2003. ER, PR and Her-2 status were assessed using immunohistochemical staining. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function.&#x2028; Results: According to different combinations of hormone receptor (HR) and Her-2 status, 2028 patients were categorized into the three subgroups as follows: Her-2+ (32.25%), HR+/Her-2- (48.92%) and triple-negative (18.83%). Triple-negative tumors were larger (greater than 2 cm in diameter) than HR+/Her-2- tumors, but smaller than Her-2+ tumors (70.03%, 66.15% and 76.15% respectively, P &lt; 0.001). In addition, 21.99% of patients whose tumors were triple-negative had four or more axillary nodes involved compared with 27.37% of patients with Her-2+ tumors and 22.78% with HR+/Her-2- tumors (P = 0.004). There were statistical differences in the distribution of TP53 mutation and Cathepsin-D status (P &lt; 0.001 for both). In the univariate analysis, we found a statistical significance for recurrence-free survival (RFS) among the three subgroups (P = 0.0036), with the rate of 72.89% for Her-2+ tumors, 78.26% for HR+/Her-2- tumors and 75.61% for triple-negative tumors at the 11th year respectively. When it came to the time of hazard peaks, discrepancies existed in different subgroups. Triple-negative patients showed an early major recurrence surge peaking at the 2.5th year after surgery, followed by a gradual decline until year 6.5 and then a modest increase. As to HR+/Her-2- patients, the hazard plot exhibited a wide initial plateau-like wave covering at least 4 years and a subsequent rise. The hazard rate for Her-2+ patients displayed a tapering sharp at the 1st year and a second rise. Furthermore, the first peak of triple-negative tumors was higher than that of HR+/Her-2- patients, but lower than that of Her-2+ ones.&#x2028; Conclusions: The recurrence pattern for triple-negative tumors was intermediate between Her-2+ and HR+/Her-2- counterparts.Our findings suggested that biological characteristics and prognosis of Chinese triple-negative breast cancer might be more favorable and somewhat different from those in Western populations.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6080.