bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug efflux by breast cancer resistance protein (BCRP) is a mechanism of resistance to the insulin-like growth factor receptor/insulin receptor inhibitor, BMS-536924.
Authors: Haluska P , Carboni JM , Asmann YW , Ten Eyck C , Attar RM , Tibodeau JD , Hou X , Nakanishi T , Ross DD , Kaufmann SH , Gottardis MM , Erlichman C 
Published: December 2010

Abstract
Abstract #2149
Background: Inhibitors of the insulin-like growth factor 1 receptor (IGF-1R) are currently undergoing clinical testing. Preclinical investigations have identified IGF-1 signaling as a key mechanism for breast cancer growth and resistance to clinically useful therapies, including tamoxifen and trastuzumab. Thus, agents targeting IGF-1R have promise in the treatment of breast cancer. Determining mechanisms that can confer resistance to these agents may aid their clinical development.&#x2028; Methods: To understand factors may be important in predicting sensitivity to targeting the IGF-1 signaling pathway, we developed a cell line (MCF-7R4) that is resistant to BMS-554417, a small molecule, dual-kinase inhibitor of IGF-1R and insulin receptor (InsR). Compared with the parental MCF-7 cells, MCF-7R4 cells are 40- to 50-fold resistant to BMS-554417 and cross-resistant to the similar compound BMS-536924. The expression profiles of MCF-7R4 and that of MCF-7 were compared using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Intracellular concentrations of BMS-536924 were examined by reverse phase high performance liquid chromatography. BMS-536924 cellular accumulation in vitro was visualized by fluorescence microscopy using a DAPI filter set. MCF-7 cells stably transfected with either the empty mammalian expression vector pcDNA (MCF-EV) or full length BCRP (MCF-BCRP) were examined for sensitivity to BMS 536924 by MTS assays.&#x2028; Results: Compared to MCF-7 cells, BCRP expression was increased 9-fold in MCF-7R4, which was highly statistically significant by t-test (p= 7.13E-09). Little change was observed in other ABC transporter proteins, including ABCB1. No change was observed in IGF-1R or InsR expression. BCRP overexpression in MCF-7R4 cells was confirmed by western blotting. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared to MCF-7 cells. Confirming these results, MCF-BCRP cells were significantly less sensitive to the cytoxic effects of BMS-536924 cells than MCF-EV cells.&#x2028; Conclusions: BCRP expression was stimulated by prolonged exposure of MCF-7 cells to BMS-554417. Upregulation of BCRP is one of the most significant changes observed in MCF-7R4 cells in comparison to parental cells. BCRP expression decreased cellular exposure to BMS-536924 and was sufficient to confer resistance. These data suggest that BSM-536924 is a substrate for BCRP-mediated efflux. Expression of BCRP may be important in de novo and acquired resistance to benzimidazole –based inhibitors of IGF-1R/InsR. Supported in part by the Mayo Clinic Breast SPORE (CA116201-03), NIH K12 (CA090628-05) and the Mayo Clinic Cancer Center (CA15083).
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2149.
Immunotherapy following high-dose chemotherapy (HDCT) and peripheral blood progenitor cell transplantation (PBPCT) in the treatment of high-risk early breast cancer (HREBC) and metastatic breast cancer (MBC).
Authors: Recchia F , Candeloro G , Necozione S , Sureda M , Brugarolas A , Rea S 
Published: December 2010

Abstract
Abstract #2159
Background: Meta-analyses have shown that HDCT with PBPCT is not superior to standard dose chemotherapy in the treatment of high risk early breast cancer (HREBC) and metastatic breast cancer (MBC). The reason for the limited efficacy is due to failure to eradicate all cancer stem cells, resistant to chemotherapy, and capable to reproduce the tumor in immunodeficient mice. Lymphopenia has been described after HDCT. We have previously shown that low dose inteterleukin 2 (IL-2) and oral 13-cis- retinoic acid (RA) improved lymphocyte (L) count, and decreased vascular endothelial growth factor (VEGF), of patients with advanced tumors having a clinical benefit from chemotherapy. Primary endpoint of this study was to verify if IL-2 and RA, improving L count, and decreasing VEGF after HDCT with PBPCT of patients with advanced breast cancer, reduced angiogenic switch. Secondary endpoints were the evaluation of progression-free survival (PFS) and overall survival (OS).&#x2028; Methods: From 02-1998 to 02-2003, 30 patients with HREBC and 18 with MBC were entered into the study. One month after HDCT, patients received, for 1 year, 5 days/week, 3 weeks/month, subcutaneous IL-2 (1.8 x 106 IU daily) plus RA (0.5 mg/kg body weight). Immunotherapy was continued, with intermittent schedules, up to 5 years. Patients with estrogen receptor positive (ER+) tumors received hormonal therapy, while those in premenopause received also a LHRH analogue for 5 years.&#x2028; Results: Characteristics of HREBC patients: median age, 48 years (range 34-60); median number of positive axillary nodes, 13 (range-11-27); ER+/ER-: 20/10; characteristics of MBC patients: median age, 46 years (range 28-60); median number of disease sites 1.5, (range-1-4); ER+/ER-: 5/13; Major adverse effects from IL-2 were fever, rash and autoimmune reactions; no treatment-related mortality was seen. After a median follow-up of 61 months, a statistically significant improvement of L and decrease of VEGF were observed for both HREBC and MBC. 5 years PFS and OS rate were, for HREBC 76% and 85%, respectively, for MBC, 22% and 35%, respectively.&#x2028; Conclusions: These data show that IL-2 administration after HDCT and PBPCT is feasible, has a moderate toxicity, gives a statistically significant improvement of L a decrease of VEGF, and seems to give an improvement of expected PFS and OS, both in HREBC and MBC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2159.
Identification of high-risk lesions through automated natural language processing (NLP) of pathology reports.
Authors: Ozanne EM , Sharko J , Drohan B , Grinstein G , Hughes KS 
Published: December 2010

Abstract
Abstract #3001
Purpose&#x2028; Pathology reports contain extensive research information that is inaccessible except through costly and time consuming chart reviews. This is due to the fact that pathology reports are recorded as semi-structured prose with critically important descriptive text intended for human interpretation. Key challenges for processing this data include interpreting multiple methods of describing the same finding, and subsequently aggregating the findings of multiple reports into episodes of care. Investigators tested NLP techniques in the processing of pathology reports into structured data and episodes of care, allowing for the rapid identification and epidemiologic modeling of high-risk breast lesions.&#x2028; Methods&#x2028; Using state-of-the-art NLP software (ClearForest, A Thomson Reuters Company, Waltham, MA), breast pathology reports stored as text files were processed into a structured electronic database using these steps: 1) identification of diagnosis of interest (i.e. high risk lesions, cancer), 2) use of NLP to identify all terms and phrases used to report each finding (e.g. atypical hyperplasia, hyperplasia with atypia), 3) grouping of relevant terms into categories, 4) identification of categories occurring in each patient report, and 5) grouping of patient reports into episodes of care (defined as all reports within 6 months of an initial diagnosis).&#x2028; Results&#x2028; Under IRB approval, 27,931 breast pathology reports from Massachusetts General Hospital in 16,208 patients seen between 1990-2007 were analyzed. The results were compared against manually reviewed pathology reports for quality control. For DCIS diagnoses, the initial error rate for both the NLP process and the manual process was 2%. The NLP process was then re-tuned using the identified discrepancies which reduced the error rate to zero. Using the refined model, we identified 1) patients with atypical lesions (atypical ductal hyperplasia (ADH), severe ADH, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS)) without prior or concurrent cancer, and 2) patients who developed cancer greater than 6 months post diagnosis.&#x2028; &#x2028; Conclusion&#x2028; This process successfully identified high-risk diagnoses that were otherwise relatively inaccessible, and appears to match the accuracy of a human research associate. The results of this first implementation are promising and will be further validated over time. In the future, this approach can be applied to other medical reports and diseases. NLP has significant potential to decrease the cost of research and for improving patient care.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3001.
Usefulness of intraoperative touch smear cytology in breast-conserving surgery.
Authors: Sumiyoshi K , Nohara T , Iwamoto M , Tanaka S , Kimura K , Takahashi Y , Tsuji M , Kurisu Y , Tanigawa N 
Published: December 2010

Abstract
Abstract #3011
[Objective] In the treatment of breast-conserving surgery, positive margins are closely related to intramammary recurrence, but methods of assessing resection stumps during breast-conserving surgery have not been standardized. The present study investigated the usefulness of intraoperative touch smear cytology at our department.&#x2028; [Subjects and Methods] From 2005 to 2007, a total of 308 patients underwent breast cancer surgery. Subjects comprised 160 patients who underwent breast-conserving surgery and touch smear cytology. Results of touch smear cytology were compared to those of histological tissue analysis.&#x2028; [Results] Touch smear cytology displayed 70% sensitivity (14/20), 97.1% specificity (136/140) and a diagnostic accuracy of 93.8% (150/160). Six false-negative cases and 4 false-positive cases were identified. Of the 6 false-negatives, cancer cells were seen in the mammary duct in 5 cases, and the degree of cancer cell atypia in the stump was low. Residual cancer cells were seen in the stump in 18 cases, and additional resection was performed on 16 cases. Cancer cells were identified histologically in the additionally resected tissue in 8 of these 16 cases (50.0%). The direction of positive cytology was towards the mammary papilla in 16 cases, lateral tissue in 5 cases and contralateral mammary papilla in 2 cases. The tendency was that that the greater the cancer cell volume as assessed by touch smear cytology, the higher the frequency of positive margins as assessed by histological tissue analysis.&#x2028; [Discussion] Histological tissue analysis and touch smear cytology can be performed to assess resection stumps during breast-conserving surgery. Histological tissue analysis is accurate, but: 1) analyzing all areas of a large resection stump is difficult; 2) preparing high-quality frozen sections is difficult due to the high adipose content of breast tissue; 3) assessing the malignancy of intraductal proliferating lesions is difficult; and 4) part of the tissue sample is damaged. Touch smear cytology is easy to perform, offering a very useful technique yielding comparable results to histological tissue analysis.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3011.
Simultaneous quantitative assessment of tumor cells in blood and bone marrow in primary breast cancer patients.
Authors: Moore AP , Magbanua MM , Scott J , Moore D , Alvarado MD , Esserman LJ , Park JW 
Published: December 2010

Abstract
Abstract #302
Background: Both circulating tumor cells (CTCs) in peripheral blood and disseminated tumor cells (DTCs) in bone marrow have been detected in primary breast cancer, but typically not quantitatively, simultaneously and using the same methodology. Here, we simultaneously assessed CTC and DTC levels in 390 primary breast cancer patients (Stages I-III), including treatment-naïve and post-neoadjuvant patients.&#x2028; Materials and Methods: CTCs/DTCs were enumerated via a novel two-step assay (IE/FC) consisting of immunomagnetic enrichment (IE) and flow cytometry. First, samples were enriched for epithelial cells using magnetic beads coated with anti-EpCAM monoclonal antibody (mAb). Next, fluorescently labeled mAb specific for an alternate EpCAM epitope was combined with a mAb against CD45 and a nucleic acid stain in multiparameter flow cytometry. Tumor cells were also isolated by IE followed by FACS sorting.&#x2028; Results: The assay quantitatively detected tumor cells in either blood or bone marrow obtained at time of breast surgery. Tumor cells were detected with greater frequency and at generally higher levels in bone marrow than in blood. In blood, CTCs ranged from 0 to 33.7 cells/mL (mean = 0.9 ± 2.4 cells/mL) and in bone marrow DTCs ranged from 0 to 501.8 cells/mL (mean = 16.8 ± 38.7 cells/mL). Direct comparisons in each patient revealed complex but significant correlation (Spearman's rank correlation = 0.12, p = 0.02) between CTC and DTC levels. In the subgroup of patients receiving neoadjuvant therapy (N=84), 51/79 (64%) were considered positive for DTC (&gt;5.5 cells/mL, with range 0.3-262.2, mean 34±17.1) while 15/79 (19%) were considered positive for CTC (&gt;0.8 cells/mL, with range 0-38.7, mean 1.4±5.7.) Treatment-naïve patients were more likely to be considered positive in the blood (29% vs 19%, p=0.03.) than neoadjuvant patients, possibly reflecting treatment effect. CTCs or DTCs were isolated from selected patients with high cell burden and subjected to expression or genomic analyses, which confirmed the malignant nature of the cells and indicated the feasibility of molecular profiling of isolated CTCs/DTCs.&#x2028; Discussion: This approach provides quantitative detection and isolation of CTCs/DTCs in blood and bone marrow, and may be useful for analysis of early events in cancer progression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 302.
Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer.
Authors: Gokmen-Polar Y , Toroni RA , Badve S , Bruckheimer E , Kinch MS , Miller KD 
Published: December 2010

Abstract
Abstract #3020
Background: Overexpression and altered function of EphA2 receptor tyrosine kinase are critical in the progression of breast cancer and provide a novel target for breast cancer therapy. We have previously demonstrated that EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity both in vitro and in vivo. EA5, a novel monoclonal antibody that mimicks the binding of ephrin A to EphA2, reverses the effect of EphA2 overexpression and restores tamoxifen sensitivity in EphA2-transfected MCF-7 cells (MCF-7EphA2) in vitro. Here we report the impact of EA5 on in vivo tumor growth and its ability to overcome in vivo tamoxifen resistance in MCF-7EphA2 xenografts. Furthermore, we investigated the mechanisms by which EphA2 overexpression decreases the estrogen dependence and contributes to tamoxifen resistance in ER+ breast cancer models.&#x2028; Material and Methods: MCF-7 cells transfected with vector (MCF-7neo) or EphA2 (MCF-7EphA2) were implanted in the right and left mammary fat pads of athymic mice. Treatment with EA5 (5 mg/kg/i.p./5 days/week), vehicle, tamoxifen (1 mg/oral gavage/5 days/week), or EA5 and tamoxifen in combination was initiated once tumors were established. To explore the role of EphA2 overexpression on ER-dependent mechanisms, we used two different ER+/EphA2-transfected cell line models (MCF-7neo/ MCF-7EphA2 and T47Dneo/ T47DEphA2). We measured ER activity and expression of ER-dependent proteins in response to 17β-estradiol (E2;10-10 M), 4-hydroxy-tamoxifen (10-6 M, and EA5 antibody (3μg/mL). Interaction of ER and EphA2 was investigated using GST-pulldown and co-immunoprecipitation approaches. Gene array studies suggested that EphA2 may impact ER via noncanonical pathways, leading to an investigation of focal adhesion kinase (FAK) signaling.&#x2028; Results: EA5 inhibits primary tumor growth and restores tamoxifen sensitivity in the MCF-7EphA2 in vivo model;EA5 had no impact on in vivo tumor growth in MCF-7neo xenografts. Using T47DEphA2 in vitro model, we verified that EphA2 decreases ER activation in response to E2 stimulation consistent with our earlier results in MCF-7EphA2 model. We found no direct interaction between ER and EphA2 and no difference in expression of canonical ER-dependent proteins, ER coactivators or corepressors. However, E2 stimulation phosphorylates FAKTyr925 in ER+/EphA2+ cell lines but not in ER+/EphA2- cell lines. Treatment of T47DEphA2 cells with EA5 and tamoxifen leads to dephosphorylation of FAKTyr925 in the presence of E2 stimulation.&#x2028; Conclusion: Our data demonstrate that dual targeting of EphA2 and ER is a promising approach for delaying resistance to tamoxifen. The data support our hypothesis that EphA2 impacts ER function via a FAK dependent pathway.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3020.
Proteomics analysis of tissue samples obtained before and during letrozole treatment in postmenopausal patients with locally advanced breast cancer.
Authors: Hans V , Evans DB , Lonning PE , Geisler J 
Published: December 2010

Abstract
Abstract #3030
Introduction&#x2028; We report on the analysis of protein expression in the tumor tissue of postmenopausal patients before and after 4 months of letrozole treatment in the neoadjuvant setting. All patients had ER and/or PGR positive breast cancer and were enrolled in the “FAST-study”. Letrozole was given orally as 2.5 mg once daily. Tumor tissue was obtained by large, open biopsies prior to treatment and during final surgery (in general: mastectomy).&#x2028; Methods&#x2028; We used paired samples from 13 postmenopausal breast cancer patients. Breast cancer tissue and plasma samples were obtained prior to treatment and after 4 months of therapy with letrozole in the neoadjuvant setting. Thus, all in all 26 tumor samples were used from 13 individual patients. Proteins were extracted from 20-50 mg of breast cancer tissue, labeled with fluorescent dyes and separated using 2-dimensional difference gel electrophoresis (2-D DIGE). After image analysis, differentially expressed proteins (p&lt;0.01, paired T- and Wilcoxon tests) were identified using MALDI tandem mass spectrometry.&#x2028; Results and discussion&#x2028; The 2-D DIGE based method allowed monitoring of 2000-2500 protein species in each sample. After alignment of all these patterns, around 25 cellular proteins were found to be differentially expressed in the pairwise pre-/post-treatment comparison, along with several plasma proteins. Among these cellular proteins were several reported tumor markers such as stathmin and NDPKA, chaperones such as HSP-60, and members of the annexin family. We are currently investigating the correlation between these proteins and the clinical parameters.&#x2028; To our knowledge this is the first report on proteomics analysis comparing samples obtained before and during treatment with a third-generation aromatase inhibitor. The study demonstrates the feasibility of performing a high-resolution proteomics analysis on tumor material derived from needle biopsies and yielded a number of potential markers, which will require further confirmation in a larger population. The results might be useful to elucidate adaptive mechanisms to estrogen suppression in vivo.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3030.
Coassociation of ERα and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.
Authors: Redmond AM , Bane FT , Stafford AT , McIlroy M , Dillon MF , Hill AD , Young LS 
Published: December 2010

Abstract
Abstract #3032
The p160 coactivators AIB1 and SRC-1 are known to play a critical role in modulating transcription in breast cancer cells in conjunction with ligand-bound estrogen receptor. The interactions of the p160 proteins with this nuclear receptor are also important in the development of resistance to endocrine treatments. Using quantitative coassociation immunofluorescent microscopy, the colocalisation of the p160s and ERα was increased in the LY2 endocrine resistant cell line following treatment with the anti-estrogen tamoxifen in comparison to the endocrine sensitive MCF-7 cell line. In cell cultures derived from patient tumours at the time of primary surgery prior to treatment, there was an increase in association of the coactivators with ERα following treatment with estrogen but dissociation was evident in the presence of tamoxifen. Immunohistochemical staining of a tissue microarray, constructed from 560 breast cancer patients, revealed that SRC-1 was a strong predictor of reduced disease-free survival, both in patients receiving adjuvant tamoxifen treatment and untreated patients (p&lt;0.0001 and p=0.0111 respectively). AIB1 was not a significant independent predictor of disease recurrence. SRC-1 was assigned a hazard ratio of 2.12 when survival analysis using a Cox proportional hazards model was applied. Quantitative coassociation analysis of the p160 coactivators with ERα in the patient TMA revealed significantly stronger colocalisation of SRC-1 and ERα in patients who are known to have relapsed than those patients who did not recur (p=0.00001). This data suggests SRC-1 is pivotal in tumour aggressiveness and is a powerful predictor of progression of disease in breast cancer patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3032.
Amphiregulin is an estrogen-responsive gene which predicts recurrence-free survival in patients with estrogen receptor positive breast tumors.
Authors: Kenny PA 
Published: December 2010

Abstract
Abstract #3039
Estradiol is a potent growth factor in estrogen receptor positive breast disease. Activated estrogen receptors have been reported to activate many hundreds of genes, yet the key effector genes for breast cancer cell proliferation remain poorly understood. Here, we have focused on one such target gene, Amphiregulin, which encodes a ligand for the Epidermal Growth Factor Receptor. We report that Amphiregulin is induced by estrogens and repressed by estrogen receptor antagonists in several breast cancer cell lines (MCF7, ZR75B and T47D), and that it promotes breast epithelial cell proliferation. Using microarray analysis of primary tumors, we find that Amphiregulin and ER-alpha expression are highly positively correlated in human breast cancer cases (n = 295). Additionally, in a cohort of women with ER+ breast tumors (n = 60), high levels of Amphiregulin predicted response to tamoxifen. We further demonstrate that Amphiregulin production can be blocked by inhibiting TACE/ADAM17, a metalloproteinase which regulates the shedding of Amphiregulin from the cell surface.&#x2028; Collectively, these data suggest that Amphiregulin may be a key transcriptional target of estrogen receptor signaling and a marker for Estrogen Receptor positive tumors that are especially dependent on estrogen and, therefore, particularly sensitive to tamoxifen.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3039.