bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-04-16: Molecular Profiling of Stage II and III Breast Cancer in Latin American Women Receiving Standard-of-Care Treatment
Authors: Gomez J 
Published: April 2011

Abstract
Breast cancer, though genetically and clinically heterogeneous, still lacks reliable prognostic and predictive markers. Gene expression profiling studies have correlated with long-term survival and response to therapy. Multiple variables thought to modify gene expression (i.e., ancestry, socio-economical and cultural factors) are not always controlled when correlating molecular markers with clinical outcome. Breast cancer rates are lower in Latin America than in other countries; molecularly, variations in gene expression should reflect different genetic and epigenetic levels there. The United States-Latin America Cancer Research Network (US-LA CRN) launches its first breast cancer pilot study in 2010 in over 20 hospitals and research facilities across Argentina, Brazil, Chile, Mexico, and Uruguay, primarily to characterize molecular profile distribution (luminal A, luminal B, HER2-like, and basal) in Latin American women with non-metastatic stage II or III breast cancer. Molecular profiles determined by microarray will be correlated with epidemiological, histological, and clinical data, including pathologic response to standard neoadjuvant chemotherapy; a molecular signature that predicts response to neoadjuvant therapy in breast cancer will be defined. This prospective cohort study will not dispense investigational drugs. Part A characterizes molecular profiles of breast cancer in Latin America; Part B examines associations between response to neoadjuvant therapy and molecular profiles. Tissue samplesfor gene expression profiling will be collected during routine core biopsies or during surgery. Core biopsies and surgical resection specimens from participants will undergo histopathologic evaluation, tumor ER, PgR, HER2, and Ki67 status assessment. During Part B, patients will be sorted by hormone receptor and HER2 status and receive standard neoadjuvant chemotherapy. Tissue samples will be re-assessed to evaluate residual cancer burden for pathologic response to neoadjuvant treatment and gene expression. Five-year patient follow-up will determine associations between molecular profiles and disease evolution after standard treatment. Besides providing data on the effectiveness of standard chemotherapy in Latin American women, study infrastructure includes establishing biobanks in participating countries to conduct additional clinical trials incorporating complex genomic and pathologic biomarkers, including trials to evaluate investigational therapies.
Studying the molecular profile of breast cancer in Latin America will improve diagnosis and treatment, correlate molecular subtypes with long-term survival and response to therapy, and identify indolent-disease subpopulations of cancer patients, perhaps enabling future personalized cancer management.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-16.
Abstract P6-05-05: Signaling Pathways Activated in Her 2 and ER Negative Breast Cancers
Authors: Song D , Gao L , Cui M , Han B , Zhao G , Fu T , Li P , Ye F , Fan MZ , Pelletier G , Zhang DY. 
Published: April 2011

Abstract
Introduction: Breast cancer is the most common cancer in women (192,370 new cases in 2009) and the second leading cause of cancer death (40,000) among women in USA. Current multimodality treatment of breast cancer is based on the level of ER expression and Her 2 gene amplification. However, no effective treatment is currently available for breast cancers with low level expression of ER and no amplification of Her 2 gene. The aim of this study is to identify protein pathways activated in the breast cancer with negative expression of ER and Her 2. Method: Protein Pathway Array was used to assess the level of protein expression and phosphorylation in 71 paired fresh frozen breast samples (tumor and adjacent benign tissue). A total 159 antibodies were evaluated which represent most important signal transduction pathways involved in proliferation, apoptosis, angiogenesis, invasion and metastasis. Several potential therapeutic kinase proteins were also assessed. Results: A total 20 proteins (PCNA, phospho-PTEN, cyclin B1 cyclin E1, CDK6, E-cadherin, NFkB, ect) were differentially expressed between normal and tumor tissues based on the statistical analysis. In Her 2 negative tumors (n=37), 3 proteins were differentially expressed and among them, 2 were up-regulated (CDK6 and HSD1) and 1 was down-regulated (IGF). In ER negative tumors (n=18), 4 proteins (HSD, SK, TDP and Slug) was up-regulated and 1 proteins were down-regulated (E-cadherin). In triple negative tumors (n=13), one protein (E-cadherin) down-regulated and 2 proteins (TDP and HSD) were up-regulated. Furthermore, based on the expression pattern of these proteins, tumors negative for both ER and Her 2 (n=15) can be clustered into 3 groups
Figure 1: Subclassification of breast cancers negative for ER and Her-2 based protein pattern.
Hierarchical clustering analysis of 20 differentially expressed proteins in
15 ER/Her-2 negative breast cancers. The cancers can be separated into 3 subtypes. Red indicates overexpression, green underexpression, black no change, and gray no expression. Each column represents a protein. Each row represents a sample.
Conclusion: Our study showed that distinct sets of signaling pathways activated in ER and Her 2 negative breast cancers. The increased expression of cell cycle progression proteins in Her 2 negative tumors suggests activation of cell proliferation via different growth promotion pathway. Similarly, different cell proliferation pathways are also activated in ER negative tumors. This finding may be used to design future clinical trial based on the activation of different signaling pathways.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-05-05.
Abstract P6-07-02: A Systems Analysis of Oscillations in the MAPK Pathway Reveals New Mechanisms of Feed-Forward and Feedback Signaling Control
Authors: Hu H , Faratian D , Goltsov A , Bown J , Langdon SP , Harrison DJ. 
Published: April 2011

Abstract
Oscillations occur in diverse areas of cellular biology, from mechanotransduction to circadian control. Their physiological, pathological, and therapeutic significance in breast cancer remains undetermined, and their existence has yet to be described in the key oncogenic signaling pathways. Mathematical modeling lends itself to detailed study of these complex dynamic phenomena. We observed damped oscillations in pERK with approximately 20 minute periodicity in MCF7 breast carcinoma cell lines after stimulation with heregulin or epidermal growth factor (EGF). In order to establish mechanisms by which these oscillations might occur, we used an ordinary differential equation-based mathematical model of MAPK/PI3K signaling to simulate oscillatory behaviour in MAPK signaling. Both modification of feed-forward (HER2 overexpression) and feedback (abrogation of early gene transcription, EGFR phosphorylation by pERK, crosstalk between pAKT and RAF, and binding of pERK with SOS) loops resulted in the emergence of sustained oscillations in phospho-ERK. When these simulations were tested experimentally, MCF7 cells stably transfected with HER2 (MCF7/HER2-18) showed sustained oscillations in pERK when stimulated with heregulin, which were abrogated by inhibition of HER2 heterodimerisation with pertuzumab. Likewise, suppression of transcriptional feedback with cycloheximide resulted in sustained oscillations in pERK of increased amplitude. We have therefore described oscillations in MAPK signalling for the first time in breast cancer cell lines. Since the duration and amplitude of these oscillations is altered both by addition of the HER2 oncogene, and by inhibition of feedback control, the functional consequences of changes in oscillations may have fundamental consequences both in oncogenesis and therapeutic efficacy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-07-02.
Abstract P6-08-02: Comparative Analysis between Primary and Secondary in Breast Tumors by Polymorphysim of Androgen Receptor Gene and Mitochondria D-Loop Somatic Mutation
Authors: Umemura SM , Kadowaki T , Kumaki N , Tang X , Takekoshi S , Yoshimura S , Suzuki Y , Tokuda Y , Osamura RY. 
Published: April 2011

Abstract
Background: It has not been fully understood how we can differentiate a new primary breast cancer from a recurrent tumor, when second tumor arises in ipsilateral breast after the surgery for primary breast cancer. To address this research question, we estimate the usefulness of a method analyzing polymorphism of androgen receptor gene and mitochondrial D-loop somatic mutation.
Materials and methods: 1) Select patients: Among the 558 patients who received the breast conservative surgery in Tokai University Hospital (1991∼2004), 9 ipsilateral breast tumors and 11 contralateral breast tumors were submitted for the analysis. 2) Formalin-fixed paraffin-embedded (FFPE) sections of non-neoplastic lymph node were examined whether polymorphism of AR gene present or not. 3) When polymorphism of AR gene in non-neoplastic lymphoid tissue were demonstrated, ipsilateral and contralateral breast cancers were further examined. 4) When AR gene in breast cancers on same allele in primary and secondary tumors, FFPE sections were further analyzed by mutaion analysis of mitochondrial D-loop region.
Results: 1) Polymorphism of AR was demonstrated in 8/9 (88.9%) and 9/11 (81.8%) non-neoplastic lymph nodes obtained from the patients who had ipsilateral and contralateral breast tumor, respectively. 2) Only 2 of 8 ipsilateral breast cancers demonstrated AR polymorphism different from primary cancer. In contrast, 6 of 9 contralateral breast cancers had different polymorphism for AR from primary breast cancers. 3) Analysis of mitochondrial D-loop mutation showed that 8 seconary ipsilateral cancers had different mutation in 3/8 (37.5%), identical mutation in 3/8 (37.5%), and no mutation in 2/8 (25.0%).
Results of analysis for ipsilateral secondary breast cancers
Conclusion: Half of the ipsilateral in breast secondary tumors were estimated as new primary lesions by molecular estimation. Combination analyses of AR gene polymorphism and mitochondrial D-loop somatic mutation unable us to distinguish between true recurrent or new primary cancers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-02.
Abstract P6-08-03: MYC Amplification and Overexpression Discriminate Secondary from Primary Angiosarcoma of the Breast
Authors: Hadj-Hamou NS , Kirova YM , Laé M , Sastre-Garau X , Malfoy B. 
Published: April 2011

Abstract
Background: Secondary angiosarcoma of the breast is defined as a sarcoma developed in the irradiated field in patients previously treated for breast carcinoma. These tumors represent 25% to 50% of sarcomas developed after irradiation for breast cancer and are of poor outcome. Up to now, there are no criteria to distinguish primary from secondary angiosarcomas. The aim of this work was to identify molecular features able to discriminate these two types of tumors.
Material and Methods: Our study was mainly based on the use of whole genome (SNP array) and whole transcriptome (mRNA and miRNA microarray) approaches. Others methods included quantitative PCR, reverse transcription quantitative PCR, fluorescence in situ hybridization and immunohistochemistry.
All patients’ records were reviewed and the clinical information about the primary and secondary sarcomas was recorded. For all radiation-induced sarcomas, the patients’ radiotherapy plans were reviewed and it was confirmed that the tumors respected the classic Cahan's criteria to confirm their secondary nature.
Results: Amplification (5 to 50 fold) of the MYC oncogene was found in all breast secondary angiosarcomas (19 cases) but in none of primary angiosarcomas (6 cases) (p-value = 2.353e-05). MYC amplification was associated with mRNA and protein overexpression of this gene. In tumors with a MYC amplification, numerous genes corresponding to MYC targets and coding for mRNA or miRNAs were found to be deregulated as compared with expression levels observed in tumors without amplifications. These data point to the pathways preferentially involved in the pathogenesis of secondary angiosarcomas of the breast. The relationships between clinical, pathological and biological features are studied.
Conclusions: MYC is amplified and overexpressed in secondary angiosarcomas of the breast. We suggest to exploit these characteristic features as a diagnostic criteria to distinguish primary from secondary angiosarcomas of the breast. Furthermore, those newly identified characteristics of secondary angiosarcomas could serve as a basis for tailored therapeutic approaches.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-03.
Abstract P6-08-14: TRPS-1, a New GATA Family Transcription Factor, Regulates Epithelial-Mesenchymal Transition and Maintains an Estrogen Responsive, Claudin-Positive Phenotype in Breast Cancer Cells
Authors: Bao Y , Chen JQ , Wu Y , Leng X-H , Wang E , Marincola F , Radvanyi LG. 
Published: April 2011

Abstract
We recently reported that TRPS-1 (Trichorhinophalangeal Syndrome-1), a new GATA family transcription factor, is a ductal epithelial cell-specific gene expressed in normal breast and over-expressed in the majority of human breast cancer (BC), especially in ER+ BC. We also found that TRPS-1 is a marker for better prognosis when expressed over a critical threshold level using a new quantitative IHC method applied to over 150 primary BC cases of all subtypes. Here, we studied the molecular function of TRPS-1 using a lentiviral shRNA knockdown approach in an ER+ ductal epithelial BC cell line (T47D; luminal B type) normally expressing high levels of TRPS-1. Strikingly, knockdown of TRPS-1 in T47D cells resulted in a complete loss of epithelial markers, including E-cadherin and CK8/18 protein together with the loss of ER and a host of ER-associated genes, such as GATA-3 and FOXA1. In contrast, N-cadherin, vimentin, slug, and other genes associated with a mesenchymal phenotype were induced. Gene expression profiling using microarray found a number of additional differentially expressed genes following TRPS-1 knockdown, including a large decrease in the Prolactin receptor (PRLR), Claudin-1 and 6, EpCAM, PGR, and CD24, while AKT3 and MET (HGF-R) were increased. The Claudin-1 and PRLR gene were down-modulated 149-fold and 167-fold, respectively. This was verified at the protein level, with a total loss of cell surface Claudin-1 and PRLR expression in the TRPS-1 knockdown cells. Overall, the gene expression profile of TRPS-1 knockdown T47D cells resembled the recently described “Claudin-low” BC subset. TRPS-1 knockdown also had dramatic functional consequences, with the cells acquiring a mesenchymal, spindle-like morphology and high resistance to growth arrest and apoptosis under conditions of serum and estrogen deprivation. Moreover, these cells formed aggressive tumors in nude mice in an estrogen-independent manner after orthotopic injection into mammary fat pads, while control cells produced only small non-palpable tumors. In addition, transient induction of TRPS-1 expression in ER/TRPS-1-negative MDA-MB-231 cells led to a significant expression of ER together with other ER-associated genes. Our data suggests that TRPS-1 is a critical new GATA family transcription factor in the mammary gland that is at the hub of a cell lineage-determination pathway regulating epithelial-mesenchymal transition. In BC it may function in maintaining a more highly differentiated and less aggressive Claudin-positive ductal epithelial phenotype.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-14.
Abstract P6-09-05: Insulin Resistance, Diabetes Mellitus and Breast Cancer Risk in Pre-and Postmenopausal Women: Modification Effect by Moderate Physical Activity
Authors: Torres-Mejía G , Ángeles-Llerenas A , Ortega-Olvera C , Lazcano-Ponce E , Romieu I. 
Published: April 2011

Abstract
Background
It has been hypothesized that diabetes may influence the risk of breast cancer (BC) by impaired regulation of the insulin and insulin-like growth factors (IGF) pathways. Current evidence supports a reduction in BC risk by doing regular physical activity due, in part, by reducing insulin resistance and improving glucose control. Material and Methods
A population based case control study was conducted to evaluate the association between insulin resistance and diabetes mellitus on the risk of BC in Mexican women. A total of 1000 incident cases and 1074 matched controls to cases by five years of age, site and health institution were analyzed. Women provided information on health, diet and physical activity by means of a face to face interview; information about the family history of diabetes mellitus and whether or not women were diagnosed with this disease. Anthropometric measurements and blood samples were obtained from all women. A conditional logistic regression model was used to assess this association. Results
In postmenopausal women, there was an interaction between physical activity and diabetes mellitus on the risk of BC. The effect of diabetes mellitus type 2 decreased with increasing moderate physical activity (OR = 3.67, 95% CI 1.78 — 7.58; OR = 2.86, 95% CI 1.37 — 5.96; OR = 0.82, 95% CI 0.19 — 3.59, by increasing tertiles of daily hours of moderate physical activity respectively); in premenopausal women, this association was not statistically significant (OR = 1.55, 95% CI 0.86-2.79), however in a subsample of premenopausal women, an increase was observed in the risk of BC per unit change in the increase of C-peptide, an indirect marker of insulin resistance (OR = 1.98, 95% CI 1.41 - 2.76). Discussion
The results of this study are consistent with numerous mechanisms linking physical activity directly to reduce BC risk probably, in part, through reducing insulin resistance and improving glucose control.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-05.
Abstract P6-12-01: A Meta Analysis of Risk of Cardiovascular Events in Patients with Metastatic Breast Cancer (MBC) Treated with Anti Vascular Endothelial Growth Factor (VEGF) Therapy — Bevacizumab
Authors: Nasim S , Sousa BA , Dent RA , Pritchard KI. 
Published: April 2011

Abstract
Background and objectives: Bevacizumab, used in combination with chemotherapy has demonstrated efficacy in randomized trials in MBC. Hypertension, congestive heart failure and cardiomyopathy have been reported in trials of bevacizumab in breast cancer. The aim of this systematic review and meta analysis is to determine the overall risk of grade 3-4 hypertension (HTN), left ventricular dysfunction (LVD) and venous (VT) and arterial thromboembolic events (ATE) related to Bevacizumab in patients with MBC.
Methods: We selected randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC as first or second line therapy. Data extraction was carried out from results published in the literature or from conference proceedings of the selected studies. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. We collected all grade 3-4 events reported in these trials in relation to cardiovascular events: HTN, LVD, congestive heart failure, cardiomyopathy, VT and ATE.
Results: Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2 and Miller et al study (capecitabine alone or plus bevacizumab in previously treated MBC). In total 2126 patients received chemotherapy in combination with bevacizumab and 1444 chemotherapy alone. When there was tendency for heterogeneity, random-effects models were used. Thromboembolic events were pooled together as VT and ATE as information was not clear in some of the reported studies. CHF and cardiomyopathy were considered for LVD events in the Miller study as LVD was not reported. Patients treated with bevacizumab-containing regimens had a RR for HTN of 10.32 (95% CI, 4.23- 24.79; p&lt;.0001), RR for LVD 2.58 (95% CI, 1.06 - 6.32; p=0.04) and RR for VT and ATE of 1.71 (95% CI, 0.81- 3.60; p=0.16) as shown in figure 1.
Conclusion: HTN is a recognized side effect of bevacizumab therapy. The risk of LVD is also significantly higher with bevacizumab therapy (RR 2.58) as shown in this pooled analysis, but the risk of thrombotic events is not increased.
Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-01.
Abstract P6-13-01: Impact of the Number of Prior Chemotherapy Regimens on Overall Survival (OS) among Subjects with Locally Recurrent or Metastatic Breast Cancer Treated with Eribulin Mesylate: Results from the Phase III EMBRACE Study
Authors: Blum JL , Twelves CJ , Akerele C , Seegobin S , Wanders J , Cortes J. 
Published: April 2011

Abstract
Background: The randomized, controlled, open-label, phase III EMBRACE study compared the efficacy and safety of eribulin mesylate (E7389) vs. treatment of the physician's choice (TPC) in heavily pretreated subjects with late-stage breast cancer. The study met its primary endpoint by showing that eribulin significantly prolonged OS vs. TPC (HR: 0.809; 95% CI: 0.660-0.991; p=0.041). This exploratory subgroup analysis aimed to determine the influence of the number of prior regimens on OS among eribulin-treated subjects.
Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects had to show progression on or within 6 months of the last chemotherapy regimen. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment and then randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC.
Results: A total of 762 subjects in 135 centers worldwide were randomized to receive either eribulin (n=508) or TPC (n=254). Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81 % had taxane-refractory disease. Overall, 47% and 53% of subjects had received ≥3 and &gt;3 prior chemotherapy regimens in total, respectively. Seventy-five percent and 25% of subjects received ≥3 and &gt;3 prior chemotherapy regimens in total for locally recurrent or metastatic disease, respectively. Subgroup analysis identified consistently longer median OS with eribulin vs. TPC in subjects who received ≥3 prior chemotherapy regimens, both in total and specifically for locally recurrent or metastatic disease (Table). Lesser improvements in OS with eribulin vs. TPC were observed in subjects who received &gt;3 prior chemotherapy regimens. The study was not powered to show statistical significance for this subgroup analysis. Conclusion: In this retrospective subgroup analysis, the OS benefit with eribulin appears greater for subjects with locally recurrent or metastatic breast cancer who received fewer previous therapies. Additional studies are underway to confirm these findings in less heavily pretreated patients.
Table. Overall survival by treatment history vs. TPC

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-01.