bluuebunny/crossref_metadata_2025_split huggingface dataset:
YB-1 Mediates a Crosstalk between ERα and TGFβ Signaling in Breast Cancer Cells.
Authors: Popp S. , Stope M. , Buck M. , Joffroy C. , Fritz P. , Knabbe C. 
Published: December 2010

Abstract
The multifunctional Y-box binding protein-1 (YB-1) belongs to the highly conserved family of cold shock proteins being involved in transcriptional/translational regulation, DNA repair as well as stress response. Additionally, it is highly expressed in many malignant tissues which seems to correlate with a high proliferation level, drug resistance and a poor prognosis in a variety of tumors including breast cancer.Using quantitative immunohistochemistry we now confirm the previously described negative prognostic impact of YB-1 on survival in a clinical study with tumor samples from 199 breast cancer patients (p=0.0146; median follow up 79 months).Treatment of the estrogen receptor α (ERα) positive human breast cancer cell line MCF-7 with antiestrogens (4-hydroxytamoxifen, faslodex) resulted in a time and dose dependent decrease of YB-1 expression on the RNA- as well as on the protein level. In contrast, antiestrogen treatment of the ERα negative cell line MDA-MB-231 does not have any effect indicating that the antiestrogen effect on YB-1 is mediated by ERα. We have already demonstrated that the action of all antiestrogens is at least partially mediated by transforming growth factor β (TGFβ) (e.g. Breast Cancer Res. Treat. 107: 15-24, 2008). Using TGFβ-responsive reporter gene assays we now show that overexpression of YB-1 in MCF-7 cells enhances the induction of p3TPlux activity by TGFβ suggesting a crosstalk between YB-1 and TGFβ signaling pathways. Moreover, YB-1 also increases the antiestrogen induction of the TGFβ2-mRNA level coming along with a YB-1 regulated enhancement of the antiestrogen effect on cell growth.Very recent findings of our group point towards a ligand-independent influence of ERα on TGFβ signaling (Breast Cancer Res. Treat., in press). Due to the antiestrogen regulation of YB-1 via ERα and its crosstalk with the TGFβ pathway, the potential role of YB-1 as a mediator of the interaction between ERα and TGFβ signaling was analyzed. Performing pull-down assays with recombinant GST-ERα and whole cell lysates of MCF-7 cells confirms a protein-protein interaction between YB-1 and ERα. The physiological relevance of this interaction could be demonstrated, as the TGFβ-induced p3TPlux activity is clearly modulated by both, YB-1 and ERα.In conclusion, we present evidence that YB-1 and TGFβ signaling are functionally linked in MCF-7 cells. Combined with the detection of a physical interaction between YB-1 and ERα, our findings shed new light on a potential role of YB-1 as a part of the mechanism responsible for switching TGFβ from its anti-proliferative role in early tumor stages to tumor promoting effects in late-stage disease, most likely via a YB-1 regulated shift of TGFβ-signaling to pro-invasive pathways. This would also explain why high levels of YB-1 correlate with a poor prognosis in breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4172.
RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab In Combination with Chemotherapy for Second-Line Treatment of HER2-Negative Metastatic Breast Cancer.
Authors: Brufsky A. , Bondarenko I. , Smirnov V. , Hurvitz S. , Perez E. , Ponomarova O. , Vynnychenko I. , Swamy R. , Mu H. , Rivera R. 
Published: December 2010

Abstract
Background: Three prior Phase III trials (E2100, AVADO, and RIBBON-1) established the clinical benefit of adding bevacizumab (BV) to various chemotherapies (chemos) as first-line treatment for metastatic breast cancer (MBC). A previous Phase III study (AVF2119g) in patients with predominantly heavily pre-treated MBC, in which BV was added to capecitabine (Cape), resulted in a significant increase in objective response rate (ORR), but did not meet the primary endpoint for progression-free survival (PFS). The current study, RIBBON-2, was designed to evaluate the efficacy and safety of the addition of BV to chemotherapies used as second-line treatment for MBC.Methods: Patients were randomized in a 2:1 ratio to chemo+BV or chemo+placebo (PL). Key eligibility criteria included one prior cytotoxic treatment for MBC, ECOG performance status of 0 to 1, and HER2-negative or unknown status. Prior to randomization, investigators chose one of the following chemo agents: taxane (T; paclitaxel 90 mg/m2/wk for 3 of the 4 weeks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, docetaxel 75–100 mg/m2, all given q3wk), gemcitabine (G; 1250 mg/m2 on Days 1 and 8 q3wk), Cape (2000 mg/m2 Days 1–14 q3wk), or vinorelbine (V; 30 mg/m2/wk). BV or PL was administered at 10 mg/kg q2wk or 15 mg/kg q3wk, depending on the chemo regimen. The primary endpoint of the study was investigator-assessed PFS pooled across the chemo cohorts. Key secondary endpoints included overall survival (OS), PFS within individual chemo cohorts, ORR, and safety.Results: 684 patients (T, 304; G, 160; Cape, 144; and V, 76) at 211 sites in 19 countries were randomized between February 2006 and June 2008. Overall, the two study arms were balanced for patient characteristics at baseline. The study met its primary endpoint of PFS pooled across chemo cohorts and also demonstrated a 10% increase in ORR when BV was added to chemo. At the interim analysis for OS, the median durations were 18 mo for chemo+BV and 16.4 mo for chemo+PL (see table).Across all chemo cohorts the incidence of BV-related AEs was consistent with data from previous studies. Hypertension was the only BV-related AE consistently increased in the chemo+BV arm across all chemo cohorts.Conclusions: The addition of BV to chemotherapies used for second-line treatment of MBC led to a significant improvement in PFS. The AE profile of BV in the overall study population and across the chemotherapy cohorts was consistent with that previously observed. Additional analyses, including PFS for the individual chemo cohorts, will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 42.
Phase III Randomized Trial of Sunitinib (SU) vs. Capecitabine (C) in Patients (Pts) with Previously Treated HER2-Negative Advanced Breast Cancer (ABC).
Authors: Barrios C. , Liu M. , Lee S. , Vanlemmens L. , Ferrero J. , Tabei T. , Pivot X. , Iwata H. , Aogi K. , Brickman M. , Zhang K. , Kern K. , Martin M. 
Published: December 2010

Abstract
BackgroundC monotherapy is approved for pts with ABC who progress after anthracycline (A) and taxane (T) therapies. SU is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated a single-agent response rate of 11% in heavily pretreated ABC.MethodsTo test the hypothesis that SU is superior to C, we compared the 2 agents in a multicenter, randomized, open-label, phase III trial of 700 pts. Eligible pts (≥18 yrs, ECOG PS ≤2) had HER2-negative ABC that recurred after A and T therapy in the (neo)adjuvant, metastatic, or locally advanced disease settings. Pts were randomized (1:1) to continuous daily dosing of SU 37.5 mg or to C 1,250 mg/m2 (1,000 mg/m2 in pts &gt;65 yrs) twice daily on days 1–14 q3wk. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), patient-reported outcomes, and safety.ResultsAfter a pre-planned interim analysis showed that the primary endpoint would not be reached, the Independent Data Monitoring Committee recommended stopping trial enrollment for futility. Pts randomized to SU were offered alternative treatment (tx). As of March 2009, 464 pts were randomized to SU (n=231; mean age 52.7 yrs; 29 pts ≥65 yrs) or C (n=233; mean age 52.4 yrs; 44 pts ≥65 yrs). 22.9% vs. 35.6% of pts continued to receive SU and C, respectively. Tx was discontinued due to adverse events (AEs) in 10.8% of pts in the SU arm vs. 7.7% of pts in the C arm. Most common AEs leading to discontinuation of SU were neutropenia (3 pts) and hand–foot syndrome, congestive cardiac failure, epistaxis, and thrombocytopenia (2 pts each). C was discontinued due to neutropenia in 3 pts. Median PFS was 2.8 mos (95% CI: 2.4–3.9; 162 PFS events) vs. 4.2 mos (95% CI: 3.4–5.0; 135 PFS events) for SU vs. C, respectively (HR 1.473; 95% CI: 1.167–1.858; P&lt;0.001). ORR for SU was 9.1% (95% CI: 5.7–13.6) vs. 12.9% (95% CI: 8.9–17.9) for C. CBR was 14.3% (95% CI: 10.0–19.5) for SU vs. 21.9% (95% CI: 16.8–27.8) for C. Other secondary endpoint analyses are ongoing.ConclusionsAlthough some pts continue to benefit from SU, these data suggest that SU is not superior to C given as monotherapy. The observed AE profiles were similar to those previously reported for SU and C. C was better tolerated than SU. SU cannot be recommended as monotherapy on this dosing schedule. Phase III studies with SU in combination with chemotherapy and other agents are ongoing in ABC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 46.
CIRG/TORI 010: 10-Month Analysis of a Randomized Phase II Trial of Motesanib Plus Weekly Paclitaxel as First Line Therapy in HER2-Negative Metastatic Breast Cancer (MBC).
Authors: Mackey J. , Hurvitz S. , Crown J. , Forbes J. , Roché H. , Pinter T. , Eiermann W. , Kennedy M. , Priou F. , Provencher L. , Adrover E. , Pienkowski T. , Houé V. , Rupin M. , Martin M. 
Published: December 2010

Abstract
Background: We assessed, in a double-blinded placebo-controlled trial, the effect of adding motesanib (M), a small molecule antagonist of VEGF, PDGF and Kit receptors, to paclitaxel (P) as first line treatment of subjects with MBC. A P plus bevacizumab (B) open-label arm was included. The study was supported by Amgen Inc.Methods: 282 subjects with HER2-negative and measurable MBC were randomly assigned treatment with P 90mg/m2 on days 1, 8 and 15 in combination with blinded placebo (Arm A), blinded M 125mg once daily (Arm B) or open-label B 10mg/kg on days 1 and 15 (Arm C). Treatment was administered in 28-day cycles until disease progression, toxicity or consent withdrawal. The primary objective was to compare objective response rate (ORR: CR or PR) between Arm A and B. Treatment efficacy was assessed every 8 weeks according to RECIST version 1.0 and scans were centrally reviewed.Results: 277 subjects received study treatment. Subject characteristics at entry were balanced: median age was 55, 80% had hormone receptor positive tumors and 66% had received adjuvant chemotherapy. At this analysis, 10 months after last enrolled subject, 235 subjects had completed treatment (median duration: 6 cycles). The median cumulative dose of P was similar across the arms: 1530, 1455 and 1652 mg/m2 in Arms A, B and C, respectively. Subjects received a median cumulative dose of 179 mg/kg of B (Arm C) and a median daily dose of 111 mg of M (Arm B). The table displays the efficacy results and relevant differences in toxicity incidences:More adverse events were reported in Arm B compared to the other arms, mainly grade 3 and 4 gastrointestinal toxicities, hepatobiliary toxicities and hypertension. Infections and stomatitis were more frequently reported in Arm C. Venous thrombo-embolic events were similar across all three arms. Among serious hepatobiliary disorders, 5 subjects experienced serious cholecystitis or gallbladder enlargement: 4 of them were managed by surgery and 4 subjects could resume study treatment.The ORR favored Arms B and C as compared to Arm A, with 49%, 52% and 41% respectively but the difference between Arm A and B was not statistically significant (p=.31, adjusting for stratification factors). Stable disease lasting at least 24 weeks was reported for 34%, 36% and 33% of subject in Arms A, B and C respectively. The Progression-Free Survival (PFS) did not significantly differ between the three arms.Conclusion: The antitumor effect of P and M is comparable to P and B as treatment of subjects with HER2-negative MBC but P and M increases toxicities compared to the other arms.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 47.
Changes in [18F]Fluorothymidine Pharmacokinetics Following Capecitabine Treatment in Human Breast Cancer Detected by Positron Emission Tomography.
Authors: Kenny L. , Contractor K. , Stebbing J. , Al-Nahhas A. , Palmieri C. , Shousha S. , Aboagye E. , Coombes R. 
Published: December 2010

Abstract
Background: Pre-clinical models used by our group have demonstrated that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases the tissue uptake of [18F]fluorothymidine (FLT).Methods: In this study we assessed, for the first time, the altered pharmacokinetics of FLT in patients following TS inhibition. We analyzed 10 lesions from 6 breast cancer patients by positron emission tomography (PET) before and after treatment with capecitabine.Results: Whereas drug treatment did not alter tumor delivery pharmacokinetic variables or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient. The baseline average standardized uptake value (SUV) at 60 min, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki) and unit impulse response function (IRF) at 60 min were 11.11 x 10-5 m2/ml, 4.38 x 10-2 ml plasma/min/ml tissue and 4.93 x 10-2 /min, respectively. At 1 h after capecitabine, the SUV was 13.55 x 10-5 m2/ml (p=0.004), Ki 7.40 x 10-2 ml plasma/min/ml tissue (p=0.004) and IRF 7.40 x 10-2 /min (p= 0.002).Conclusion: FLT pharmacokinetics did not change in normal tissues suggesting that the effect was largely restricted to tumor (p=0.55). In summary, we have identified FLT-PET retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5003.
Molecular Alterations in Pleomorphic Lobular Carcinoma In Situ (PLCIS) of the Breast.
Authors: Chivukula M. , Brufsky A. , Carter G. , Chandran U. , Lyons-Weiler M. , Dabbs D. 
Published: December 2010

Abstract
Introduction: Pleomorphic lobular carcinoma in situ (PLCIS) is a rare distinct variant of lobular carcinoma in situ (LCIS) which is morphologically difficult to distinguish from high-grade ductal carcinoma in situ (DCIS). We performed microarray DNA analysis to characterize the genetic changes of this entity in order to determine if such changes were unique to PLCIS.Materials and Methods: 5 Pleomorphic (4 in situ and 1 invasive) and 4 normal non-paired breast tissues were analyzed for copy number changes using the Affymetrix 250K Sty array. Copy Number (CN) changes were detected by the Partek (Partek Inc, St Louis, MI) software. Data processing steps included GC content correction and segmentation to determine regions of amplifications and deletions.Results: Each sample demonstrated a unique pattern of CN changes with amplifications being more frequent than deletions, and between 25 and 66 changes per sample. Chromosomes 1, 11, 14, 16 and 8 exhibit the most frequent changes. Large deletions in chromosome 16q were seen in 4 out of 5 samples and amplification of regions of 1q in 4 out of 5 samples. Focal common amplifications, defined as less than 100kb in length, CN&gt;5 and present in at least 3 samples, were seen in a number of regions including 8q23.1 containing the NUDCD1 gene (5/5 samples), 14q23.3 containing the GPHN (3/5 samples) gene, 12p12.2 containing the gene SLCO1B3 (3/5 samples), and 4p16.1.Discussion: Our results indicate that changes on chromosomes 1, 11, 14, 16 and 8 are frequently observed in pleomorphic lobular carcinoma (PLC) as well as PLCIS. Deletions in chromosome 16q and amplification of regions of 1q seen in our cases are associated with loss of e-cadherin and β-catenin expression and are the characteristic genetic abnormalities seen in classic lobular carcinoma. In addition, the characteristic 8q23.1, 14q23.3 and 12p12.2 reported in high grade DCIS were seen in our cases as well. PLCIS exhibits overlapping features with both classical lobular neoplasa and high grade DCIS.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5004.
Correlation between 18F Fluorodeoxyglucose (FDG) Uptake and Tumor Characteristics in Locally Advanced Breast Cancers.
Authors: Giacchetti S. , Groheux D. , Hamy A. , Hindie E. , Cuvier C. , Lehmann-Che J. , Lehmann-Che J. , de Roquancourt A. , Albiter M. , Marty M. , Moretti J. , Espie M. 
Published: December 2010

Abstract
Background: This study analysed the correlation between [18F]fluorodeoxyglucose (FDG) uptake, assessed by positron emission tomography (PET), and prognostic factors in locally advanced breast cancersMaterial and Methods: All locally advanced breast cancers seen at Saint Louis hospital and treated with neo-adjuvant chemotherapy (NAC) have a FDG PET after core needle biopsy and before chemotherapy. We correlated the tumor characteristics: T-stage, histological grade, estrogen and progesterone receptors, c-erbB2 over-expression (immuno-histochemistry determination) and P53 (determinate on frozen biopsies by the FASAYmethod) to FDG standardized uptake value (SUV max). The statistics tests used are student test (comparison of 2 means) and kendall correlation.Results: From June 2006 to April 2009, 91 patients with locally advanced breast tumors have both PET scan and frozen tissue before NAC. Median age at diagnosis is 48 (26-81) and 45 % are post menopausal.Conclusion: This study indicates that FDG-PET uptake is correlated with the phenotype of breast tumours. Over-expression of c-erbB2 does not influence FDG uptake. Triple negative tumours and p53 mutated tumors have a high initial SUV which can reflect their aggressiveness and their chemotherapy sensitivity. The knowledge of SUV uptake according to tumor characteristics allows a better understanding of the role of FDG-PET in the prediction of neoadjuvant chemotherapy response.Patients characteristicsPtes characteristicsNumber of patients (%)Tumor size: T2/T3/T438 (41)/32 (35)/21(23)Lymph nodes N0/N1/N232 (35)/46 (50.5)/13 (14 )Invasive ductal carcinoma/invasive lobular carcinoma/miscellaneous82 (90 )/5 (5 )/3 (3)Histological grade/ 1/2/37 (7 )/49 (54)/35 (38)ER + / ER-58 (64 )/33 (36)PR+ /PR-35 (38) /56 (61)C-erbB2 +++15 (16 )Triple negative22 (24 )P53 ( 64 ptes) mutated/wild type32 (50)/32 (50)
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5010.
Comparison of Synchrotron Images of DCIS of the Breast with Their Pathologic Findings.
Authors: Park S. , Bong J. , Hong J. , Wang H. , Kim H. , Kim J. , Oh H. , Jheon S. , Huang J. 
Published: December 2010

Abstract
Background: Synchrotron radiation x-ray imaging have opened a new door to explore breast tissue below the micron scale providing detailed internal structures of the samples with a great magnification and an excellent resolution. Using phase contrast technique, we got monochromated synchrotron images of DCIS (Ductal Carcinoma In Situ) of the breast tissue section. To figure out relation with their optical microscopic features, we compared the synchrotron images of the DCIS with their histopathologic findings of the same stained section.Material and Methods: A x-ray microscope was installed on 1B2 beamline of Pohang Light Source, a third generation synchrotron radiation facility with operating energy of 2.5 GeV in Pohang, Korea. The x-ray energy was set at 11.1 keV, and the x-ray beam was monochromatized by a W/B4C monochromator. Zernike phase-shifter was adapted for phase contrast x-ray microscopy. Formalin-fixed 5µm-thick breast tissue sample was attached onto the Kapton film, and positioned 25 m away from the beam source. The synchrotron image of sample was converted into a visual image on the CsI(TI) scintillation crystal, and this visual image was captured by a full frame CCD camera. After scanning, we patched these images one and another to show the large area of the tissue section. For the comparative analysis with their synchrotron image, synchrotron-scanned breast tissue sections were stained, and the histopathologic findings of the samples were captured by image analyzer. The magnifying power of this microscope was 100x.Results: The monochromated x-ray microscopic images of DCIS of the breast tissue were obtained with a good resolution. These images revealed various structures of DCIS lesion with a good contrast and high visibility by phase contrast technique. They include prominent and intact periductal basement membrane - a hallmark of DCIS lesion, and stippled fine microcalcifications which were indistinct in the histologic section, and a shadow of intense peritumoral inflammatory cell infiltration. But the minute changes of each cancer cell showing the features of cancer tissue such as, cellular differentiation and nuclear grade, were not identified well.Discussion: The x-ray microscopic imaging of DCIS of the breast tissue section with synchrotron radiation showed a good correspondence with the histopathologic findings of their stained tissue sections. And the synchrotron image of DCIS had some unique radiologic features differentiating from histopathogic findings. Therefore the synchrotron images of the DCIS lesion appear to have a new possibility of use for the clinical and research purposes in near future.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5015.
The Optical Characteristic of Breast Cancer.
Authors: Ogura H. , Ohmae E. , Nasu H. , Teruya C. , Yamashita D. , Ueda Y. , Oda M. , Yamashita Y. , Sakahara H. 
Published: December 2010

Abstract
Objectives: The optical parameters of breast were measured by time-resolved spectroscopy additionally to optical mammography (O-MMG), which utilizes near-infrared light for the detection of abnormal breast tissue as a non-invasive and painless new breast imaging technique. Here we report the spectroscopic feature of the breast cancer tissue clarified by comparing the optical characteristic of cancer tissue with contra-lateral normal area.Materials and Methods: Absorption coefficient (μa), and reduced scattering coefficient (μs')of the breast tissue were measured using Time-Resolved Spectroscopy method, and analyzed by photon diffusion equation. We irradiated a pulsed laser of 760, 800,and 830 nm wave-length at multiple sites including a site just above the cancer by TRS-20SH (Hamamatsu Photonics K.K.). The clinical trial started in January 2007. A total of sixty breast cancer patients participated in the trial and written informed consent were obtained from all of the patients.Results: In 800nm wave-length, absorption coefficient (μa) of breast cancer tissue was significantly high, compared with contra-lateral normal breast area (cancer: 0.0759±0.052, normal: 0.0572± 0.034, p=0.02). The result was also the same in 760,and 830 nm. There was no difference in reduced scattering coefficient (μs') of breast cancer tissue compared with contra-lateral normal area (cancer: 9.049±01.345, normal: 9.521±1.492, p=0.07).Conclusion: Absorption coefficient (μa) of breast cancer tissue was significantly high compared with contra-lateral normal area.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5019.