bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients.
Authors: Solomayer E , Gebauer G , Hirnle P , Janni W , Lück H , Becker S , Huober J , Kraemer B , Wackwitz B , Fehm T 
Published: December 2010

Abstract
Abstract #2048
Background: The presence of disseminated tumor cells (DTC) in the bone marrow is associated with an increased risk for subsequent bone metastases. Bisphosphonates reduce the occurence of bone metastases in patients (pts) with primary breast cancer (BC) with DTC. The aim of this trial was to evaluate the effect of adjuvant zoledronic acid (ZOL) on DTC in the bone marrow and the Patients and methods: Eligibilty criteria for this prospective, randomized multicenter trial were primary BC pts (pT1-4, N1-2, M0) with positive bone marrow status as determined by a standardized immunocytochemistry staining procedure. Ninety-eight pts were enrolled between April 2002 and January 2006. Randomization and medication had to be started within 28 days of primary surgery. Consenting pts were randomized to the treatment arm (ZOL 4mg i.v. q 4 weekly) or control arm. During the study, all pts received adjuvant treatment in the form of chemotherapy ± hormonal therapy or hormonal therapy alone. Bone marrow aspirations were performed to analyze the presence of DTC at surgery (baseline) and 12 months later. Efficacy and tolerability of intravenous ZOL in pts with primary Result: Bone marrow status was available for 76 patients both at baseline and 12 months after surgery. At baseline a median of 2.0 / range 1-6 (mean 2.1±1.1) DTC were detected in the ZOL group and a median of 2.0 / range 1-35 (mean 2.9±5.5) DTC in the control group. In both groups the number of detected tumor cells decreased during the 12 months follow-up with 0.5±0.8 (median 0.0; 0-2) DTC in the ZOL group and 0.9±0.8 (median 1.0; 0-2) DTC in the control group. By ANCOVA analysis a trend was seen towards a reduction of the number of DTC in the ZOL group compared with the control group (p=0.066). In addition, bone marrow-positive pts treated with ZOL were more likely to become bone marrow negative after 12 months (66.7% versus 35.1%, (p=0.009) compared to the control group. Most frequently reported AEs were musculoskeletal,arthralgia and myalgia in Conclusions: In this first prospective, randomized, multicenter trial we were able to show, that both treatment groups have a reduction in the number of DTC after 12 months as compared to baseline. There is a tendency to more reduction of DTC in the ZOL group. More pts under ZOL achieved a change from positive to negative bone marrow status than controls (p=0.009). Treatment with ZOL was safe and well tolerated.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2048.
Identification of breast cancer metastasis initiation and virulence genes.
Authors: Ellsworth RE , Heckman C , Love B , Shriver CD 
Published: December 2010

Abstract
Abstract #2049
Background: Metastasis involves processes such as invasion, angiogenesis, intravasation, extravasation and eventual proliferation in the target organ. Metastasis initiation genes are those involved in dissemination of cells from the primary tumor while metastasis virulence genes contribute to metastatic colonization, specifically at the secondary site. Identification of metastasis initiation and virulence genes is critical to improve our understanding of and the ability to effectively treat metastatic breast cancer.&#x2028; Methods: A 51-gene signature was previously identified using RNA from 20 primary breast and matched metastatic lymph node tumors using the U133 2.0 microarrays (Affymetrix). Real-time PCR was performed for each assay using TaqMan assays (Applied Biosystems) using RNA from 25 pairs of primary breast and matched metastatic lymph node tumors. Data was evaluated using Mann-Whitney testing.&#x2028; Results: Gene expression levels were significantly different for 40 genes including 25 with P&lt;0.001 and 15 with P&lt;0.05. Thirteen of these genes had significantly higher levels and 27 had lower levels of expression in metastatic tumors. Ten genes had &gt;50-fold difference in expression including WNT2, KRT14, TAC1, COL11A1, MMP13, GRP, and KERA with higher expression in primary tumors and EPHA3, PAX5 and NTS with higher expression in the metastasis.&#x2028; Discussion: A breast cancer metastasis signature involving 40 genes has been identified and validated. Genes expressed at higher levels in primary breast tumors are largely involved in degradation of the extracellular matrix (ECM), likely enabling cells with metastatic potential to disseminate. Decreased expression of these genes in the metastatic tumors suggests that once tumor cells have disseminated, invasion into foreign tissues does not require active tissue remodeling. Rather, cells that have successfully metastasized are characterized by the expression of genes involved in transcription, metabolism and immune response, potentially blocking cellular differentiation and providing cells with proliferation and survival advantages. These data not only improve our understanding of the biological processes involved in successful metastatic but provide new targets to arrest tumor cells dissemination and metastatic colonization.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2049.
Knockdown of Abl interactor 1 expression impairs invadopodia formation, tumor angiogenesis, and markedly slows tumor growth of breast cancer cells.
Authors: Li C , Sun X , Gilmore WC , Cobos E , Tao Y , Dai Z 
Published: December 2010

Abstract
Abstract #2054
Background: Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. Previous studies have revealed that Abi1 interacts with Wiskott–Aldrich syndrome protein (Wasp) family proteins, and regulates the nucleation promoting activity of Wasp proteins. In addition to Wasp family proteins, Abi1 also binds to a variety of other signaling molecules, including those involved in the signal transductions of small GTP-binding protein Rac and PI3 kinase. The ability to interact with diverse signaling pathways places Abi1 at a central position in the signaling network that regulates cell motility and proliferation. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo.&#x2028; Material and Methods: The short hairpin RNA (shRNA)-mediated gene silencing was used, in conjunction with murine tumor xenograft models, to examine the effects of Abi1 knockdown on cytoskeleton remodeling, cell migration, invasion, as well as tumor growth and angiogenesis of MDA-MB231 breast cancer cells.&#x2028; Results: We report here a novel function for Abi1 in the regulation of invadopodia formation as well as in the tumor angiogenesis and invasion of breast cancer cells, possibly through the modulation of Src and matrix metalloproteinase 9 (MMP-9) activities. Abi1 co-localizes with invadopodia, the specialized adhesive/invasive structures believed to control the invasion of tumor cells, in MDA-MB231 breast cancer cells. Epigenetic silencing of the Abi1 gene by shRNA in MDA-MB231 cells impaired the formation of invadopodia and decreased the activity of c-Src and MMP-9. The decreased invadopodia formation and MMP-9 activity correlated with a reduction in the ability of these cells to degrade extracellular matrix (ECM). Remarkably, the knockdown of Abi1 expression inhibited tumor invasion and angiogenesis and markedly slowed tumor growth in xenograft mouse models. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2054.
Alternative suppression strategy for human breast cancer invasion and metastasis: a potential for a new differentiation therapy.
Authors: Sultan AS , Sherif ZA 
Published: December 2010

Abstract
Abstract #2059
Poor prognosis of human breast cancer is associated with a high potential of cancer cells invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. We have recently uncovered novel evidence that signal transducers and activators of transcription 5a (Stat5a) and its Janus tyrosine kinase, (Jak2), suppress invasion and promote human breast cancer cells differentiation through inhibition of epithelial-to-mesenchymal dedifferentiation.&#x2028; However, the precise mechanism of Jak2/Stat5a role in human breast cancer is still under investigation.&#x2028; In this study, we have further critically taken advantage of the combination of Jak2/Stat5a genes expression, HDAC inhibitors, and Mistletoe (Viscum album) plant extracts as an alternative way to suppress breast cancer progression by reversing the mesenchymal phenotype, and restoring homotypic adhesion, and in turn induce tumor differentiation in vitro and in vivo. We have expanded our investigation to involve a highly invasive breast cancer cell line, MDA-231, in addition to BT-20 and T-47D human breast cancer cells that display different phenotypic and differentiation patterns ranging from poor to high differentiation. Cells were pretreated with or without different HDAC inhibitors, and/or Mistletoe (Viscum album) plant extracts, and then either mock infected or infected with adenovirus carrying Wild type (Wt-Jak2), Wt-Stat5a, Dominant negative (Dn-Stat5), or a combination of Wt-Jak2 and Wt-Stat5a.&#x2028; Using three-dimensional (3D) Matrigel model system in vitro, the pretreatment with HDAC inhibitors and/or Mistletoe (Viscum album) plant extracts synergized with co-expression of Wt-Jak2/Stat5a genes to promote epithelial differentiation by reversing the mesenchymal phenotype morphology, inducing homotypic adhesion, and inhibiting cell motility and invasiveness.&#x2028; We have also established a xenograft tumor model of MDA-231 cells in nude mice for in vivo studies. After 4 week, the growth of MDA-231 tumors that co-expressing Wt-Jak2/Stat5a was inhibited by 47.90% compared to the mock group (t=2.821, P&lt;0.05) and by 52.86% compared to the tumors expressing Dn-Stat5 group (t=2.394, P&lt;0.05). Furthermore, the pretreatment with HDAC inhibitors and/or Mistletoe (Viscum album) plant extracts enhanced significantly the growth inhibition of MDA-231 xenografted tumors expressing Wt-Jak2/Stat5a compared to the tumors expressing Wt-Stat5a or Wt-Jak2 alone.&#x2028; Collectively, the observations support a novel role of Jak2/Stat5a genes as a new tool to restore lost differentiation of human breast cancer through inhibiting EMT that could lead to new therapeutic strategies to reverse cancer progression-related changes and introduce alternative cancer treatments in addition to standard chemotherapy and radiation treatment.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2059.
Anoikis-resistant MDA-MB-231 cells: characteristics and pathway analysis.
Authors: Yu J , Han W , Kim J , Lee J , Ko E , Kim E , Moon H , Noh D 
Published: December 2010

Abstract
Abstract #2062
Background : Apoptosis in response to inappropriate adhesion or lack of adhesion has been termed anoikis. Resistance to anoikis is regarded as a prerequisite for invasion and metastasis in cancer cells. Recently many studies were performed to understand mechanism of anoikis resistance. However, there have been few studies on the role and mechanism of anoikis resistance in cancer cells.&#x2028; Materials and Methods : Anoikis-resistant MDA-MB-231 cells were induced and selected through culture on polyhydroxyethylmethacrylate (Poly-HEMA) substratum and invasiveness by matrigel invasion assay and drug-resistance to doxorubicin were checked. At the same time, expression of genes were evaluated in anoikis-resistant and adherent MDA-MB-231 cells by cDNA microarray. Pathway analysis on high-expressed genes in anoikis-resistant cells was performed by software(Ingenuity Pathway Analysis)&#x2028; Results : Invasion assays revealed that anoikis-resistant cells were more invasive than adherent cells. Anoikis-resistant cells were also more resistant to doxorubicin than adherent cells. Genes related to NF-kB pathway were highly expressed in anoikis-resistant cells. Therefore, the effect of Bay11-7085, inhibitor of NF-kB, on the growth of anoikis-resistant MDA-MB-231 cells was tested. The blockage of NF-kB pathway inhibited the growth of anoikis-resistant MDA-MB-231 cells.&#x2028; Conclusion : These results demonstrated that anoikis resistance was associated with increased invasiveness and resistance to chemotherapeutic agents and that NF-kB pathway involved in anoikis resistance.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2062.
Role of Src family members in breast cancer-dependent on site of phosphorylation.
Authors: Elsberger B , Tovey SM , Tan BA , Brown SB , Brunton VG , Mallon EA , Cooke TG , Edwards J 
Published: December 2010

Abstract
Abstract #2074
Background: In vitro work implicates c-Src in breast cancer. However there is little evidence to support this in clinical specimens. Activation of Src family members are associated with phosphorylation at two different tyrosine sites Y419: the classical activation site and Y215, known to induce a 50-fold increase in activation.&#x2028; We have analysed a cohort of human breast cancers to establish if expression levels of 2 Src family members (c-Src and Lyn) are associated with survival and whether this is dependent on site of activation.&#x2028; Methods: Tissue microarrays were constructed from 895 breast cancer tumors. Median follow up was 6 years with 229 breast cancer specific deaths. Immunohistochemistry was performed using antibodies to c-Src, Lyn, pSrc419 and pSrc215 (antibodies to Y419 and Y215 will detect phosphorylation of either c-Src and Lyn). Expression was assessed by two independent scorers. All statistical calculations were performed using SPSS 15.&#x2028; Results: Membrane expression of c-Src and Lyn was rarely observed. However, cytoplasmic expression of c-Src and Lyn was frequently observed and further results presented relate to this site. High expression levels of c-Src but not Lyn were associated with HER2 positivity (p=0.001) and ER negativity (p&lt;0.001).&#x2028; High c-Src expression was associated with a poor outcome. In direct contrast pSrc215 was associated with improved outcome on univariate and multivariate analysis.&#x2028; Antibodies to phosphorylation sites will detect both activated c-Src and Lyn (and other family members). The individual impact of phosphorylation on clinical outcome was determined by categorising expression based on overexpression of c-Src or Lyn in combination with activation at each site.&#x2028; &#x2028; Discussion: Our findings demonstrate that phosphorylation of c-Src at Y419 is associated with poor prognosis in breast cancer. In contrast phosphorylation at Y215 was independently associated with better outcome.&#x2028; Further work is ongoing to explore our hypothesis that:&#x2028; 1. phosphorylation at 215 'deactivates' c-Src or desensitizes downstream pathways or,&#x2028; 2. that activation of Lyn or other Src family members at 215 is responsible for good outcome.&#x2028; If confirmed, these results strongly suggest that commercial development of highly specific Src inhibitors is necessary and that these will require appropriate patient selection.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2074.
Analysis of the rate of missing data, the rate of discordance between readers, and the rate of site versus central discordance in clinical studies of recently approved breast cancer agents that have used blinded independent central review.
Authors: Borradaile K , Cadogan K , Somers S , Ford R 
Published: December 2010

Abstract
Abstract #2081
Background: The United States Food and Drug Administration (USFDA) recommends blinded independent central review (BICR) for oncology registration studies when the primary study endpoint is based on tumor measurements, such as progression-free survival (PFS) or objective response rate (ORR). However, there is no published guidance regarding acceptable metrics during the BICR.&#x2028; Method: The USFDA Summary Basis of Approvals and Oncologic Drugs Advisory Committee (ODAC) transcripts for the following recently approved breast cancer therapies: Gemzar, Abraxane, Tykerb, Ixempra, and Avastin, were reviewed with attention to metrics referable to the BICR. The findings are summarized.&#x2028; Results: Up to 13% of subjects were reported as unevaluable at the BICR based on missing data, with missing data defined as missing radiographic evaluations. The rates of discordance between two readers during the BICR were reportedly between 34-51% depending on the number of adjudication variables. The rates of discordance between the site and BICR were reportedly between 34-49% for the date of progression and 24-29% for the progression status. Up to 9% of subjects enrolled with measurable disease at baseline did not have this confirmed by the BICR. The causes of discordance were reportedly related to differences in the methodologies used to perform the reviews, and clinical or image data that was missing at the time of the BICR. Additional reported causes included imaging requirements not detailed in the protocol, the BICR charter containing more stringent requirements for determining response and progression than was indicated in the protocol, protocol amendments issued midway through the study which changed the imaging eligibility criteria for the sites while the BICR used the same requirements throughout the study, differences in the choice and classification of lesions, radiographic exams only repeated at subsequent time points if deemed positive by the investigator resulting in missing data and unevaluable assessments at the BICR, variability in measurement of small lesions, and discordance in the determination of new lesions. Inter- and intra-reader variability was reported in a small population of subjects; 8% resulted in 1-step response discrepancies for inter-reader variability and 31% for intra-reader variability.&#x2028; Conclusion: Based on FDA approvals, metrics as described above may prove to be valuable benchmarks when using BICR data to determine endpoints in future breast cancer studies.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2081.
Admixture mapping to identify breast cancer susceptibility loci in African American women.
Authors: Croft DT , Mao X , Hooke JA , Shriver CD , Shriver MD , Ellsworth RE 
Published: December 2010

Abstract
Abstract #2090
Background: The incidence of breast cancer in young women is higher in African American (AAW) compared to Caucasian (CW) and is associated with an aggressive phenotype, including high-grade, ER/PR and HER2 negative status and p53 positive characteristics. The aggressive tumor behavior and pathological features of AAW are also seen in women from the Bite of Biafra, an area of Western Africa that was the predominant source of the American slave trade. Similar tumor characteristics and shared ancestry suggest that population-specific molecular factors contribute to the aggressive tumor phenotypes associated with AAW. Therefore, a method of admixture mapping is proposed for this study. Admixture mapping is also known as mapping by admixture linkage disequilibrium. It assumes in a recent admixed population, if certain phenotype or the prevalence of a disease is mainly caused by one of the ancestral groups, the genetic variant can be located by the elevated ancestry from that group.&#x2028; Methods: Pathological characterization was performed histology specimens from 91 self-described AAW diagnosed with invasive breast cancer enrolled in the Clinical Breast Care Project. Genomic DNA was isolated and SNP data generated using the Affymetrix Mapping 100K arrays. African ancestry was determined using maximum likelihood estimator and chromosomal regions associated with disease identified using AncestryMap and AdmixMap.&#x2028; Results: The average age of diagnosis was 51 years. 25% of patients had poorly-differentiated, triple negative tumors. All 91 patients had significant African ancestry, with a mean level of Nigerian ancestry of 0.3857. Results from both AncestryMap and AdmixMap suggest loci on chromosomal regions 5q32.2, 9q13.1 and 17p13.3 are associated with the development of breast cancer.&#x2028; Discussion: Recently, admixture mapping was used to successfully identify a prostate cancer gene to chromosome 8q24 in African American men. Using a similar approach, we identified three chromosomal regions associated with the presence of invasive breast cancer in AAW with significant Western African ancestry. Of note, loss of 9q13 has been associated with poor survival, and allelic imbalance of 17p13.3 has been associated with loss of hormone receptor expression and poor prognosis. Thus, the use of admixture mapping may aid in the identification of genes involved in the development of the aggressive form of breast cancer associated with AAW.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2090.
Triple negative status as a risk factor for the development of brain metastases in African American breast cancer patients.
Authors: Khan AM , Sabnani I , Rogers-Phillips E , Tsang P , Voora R , Pinera E , Cohen AJ 
Published: December 2010

Abstract
Abstract #2093
Background: Previous studies have described triple negative (TN) breast cancer (ER/PR/ HER2/neu negative) as an aggressive and poor prognostic phenotype with higher relapse rate (RR), distant RR, and shorter survival. The incidence of TN breast cancer has reportedly been higher (30-35%) in African American (AA) women compared to the general population (15%) but the clinical outcomes of TN patients (pts) who develop brain metastases compared to the non-triple negative (NTN) group has not been well described.&#x2028; Methods: We retrospectively reviewed tumor registry data from a large academic medical center serving an inner city population. A total of 282 AA women with invasive breast cancer were identified from 1994-2006 and 248 were determined to be in stages I-III. Characteristics evaluated include age, TNM stage at diagnosis, ER, PR, Her2/neu status, and grade. The RR, distant RR, rate of brain metastases, time from diagnosis to brain metastases, and overall survival were determined.&#x2028; Results: The incidence of TN disease in AA women was 30% (82/282). Median age (57 yrs) was similar in both TN and NTN groups. With a median follow-up of 5.5 years, the RR (30% vs. 14%; p=0.02) and distant RR (22% vs. 10%; p=0.02) were higher for the TN vs. NTN group. Six of 72 (9%) TN pts developed brain metastases compare to 6/178 (3%) in NTN group. There was a shorter time to development of brain metastases (1.7 vs. 6.1; p=0.01) and a lower survival time after brain metastases (0.6 yrs vs. 1.6 yrs) in the TN vs. NTN group.&#x2028; &#x2028; Conclusion: This study represents one of the largest reported series of AA women with breast cancer. TN pts are at higher risk of developing brain metastases. Not only the time to develop brain metastases was shorter but overall survival after development of brain metastases remained poor in TN group compared to NTN group. TN status should be considered as an independent risk factor for the development of brain metastases.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2093.