bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose Dependent Effects of G-CSF on Ca27.29 in Early Stage Breast Cancer Patients.
Authors: Hepp P. , Rack B. , Schneeweiss A. , Schrader I. , Lorenz R. , Tesch H. , Soeling U. , Rezai M. , Gerber B. , Lichtenegger W. , Beckmann M. , Janni W. 
Published: December 2010

Abstract
Background:13% of 2556 patients (pts) examined in the SUCCESS trial showed elevated levels of Ca27.29 only after chemotherapy (SABCS2008). Early data indicate a possible relationship between the administration of G-CSF and a rise in the tumor marker. This analysis focuses on the dose dependency of this effect.Methods:The SUCCESS Trial is a phase III trial comparing FEC-Docetaxel vs. FEC-Doc-Gemcitabine regime and 2 vs. 5 years of treatment with zoledronate in patients with primary breast cancer in 3754 pts (BC) (N+ or high risk). Blood samples for this analysis are drawn before and after chemotherapy (CHT). Ca27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for Ca27.29 is &gt;=32 U/ml. For chi² analysis patients were grouped to increasing or not increasing values of Ca27.29 and 1 to 6 cycles with G-CSF or no G-CSF at all. The absolute difference of Ca27.29 values before and after CHT was correlated with the number of G-CSF cycles administered.Results:The analysis of Ca27.29 is based on the data of 2556 pts. 1252 pts (49%) received at least one course of G-CSF. 338 pts (13%) exceeded the threshold for CA27.29 only after CHT. In this group 209 pts (62%) received G-CSF and 129 (38%) did not. 1043 pts with stable or decreased CA27.29 received G-CSF (47%) and 1175 did not (53%). This difference was highly significant (p&lt;0.0001). Correlating the number of G-CSF cycles received during CHT with the absolute difference in Ca27.29 levels showed a highly significant positive correlation of 0.13 (Spearman-Rho; p&lt;0.0001[two-sided]).Discussion and Conclusion:This analysis gives strong evidence that there is a dose dependent correlation between elevated levels of CA27.29 post CHT and the application of G-CSF. This might be attributed to an illegitimate expression of MUC-1 in leucocytes during leucopoiesis. Whether this effect is also related to the destruction of remaining disseminated tumor cells needs to be further evaluated.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6030.
No Clinical Evidence for Increase in Tumour Malignant Potential in Patients (Pts) with Metastatic Breast Cancer (mBC) Treated with Bevacizumab (BV) and Docetaxel (D) in the Phase III AVADO Study.
Authors: Harbeck N. , Chan A. , ten Bokkel Huinink D. , Chollet P. , Gimenes D. , Fabiani C. , Salvagni S. , Pérez-Michel L. , Schneeweiss A. , Chlistalla A. , Miles D. 
Published: December 2010

Abstract
Background: The monoclonal antibody BV is directed against soluble VEGF and has shown significant clinical benefit when combined with chemotherapy in a range of tumour types, including in three phase III trials in mBC. Recent preclinical reports suggest that some anti-angiogenic agents (VEGFR tyrosine kinase inhibitors [TKIs] or VEGFR antibodies) increase the malignant potential of tumours (Pàez-Ribes; Ebos: Cancer Cell 2009:15). Although BV has a distinctly different mechanism of action, exploratory analyses to investigate those preclinical findings were performed on data from AVADO, a placebo (PL)-controlled study in first-line mBC.Methods: Pts received D (100mg/m2) q3w for up to 9 cycles, plus PL or BV (7.5 or 15mg/kg) q3w until disease progression (PD) or unacceptable toxicity. Mortality rates were calculated at 30-day intervals up to day 210 after discontinuation of PL or BV for any reason. For pts discontinuing PL or BV for toxicity, PFS was analysed using Kaplan-Meier methods. In the overall population, the proportion of pts with new metastatic lesions was analysed at PD.Results: As of 30 April 2009, 91 pts had discontinued PL or BV for toxicity; median PFS from discontinuation was longer in the BV arms than the PL arm. Mortality rates in pts stopping BV or PL for any reason (n=339) were similar or lower in the BV arms than the PL arm at all 30-day intervals for the first 210 days after discontinuation, the timeframe over which the analyses were performed. At PD, fewer BV than PL pts had developed new lesions. PL + DBV 7.5mg + DBV 15mg + DITT population, n241248247 Pts with PD, n (%)208 (86)212 (85)210 (85) Pts with PD & new lesion, n (%)160 (77)*154 (73)*138 (66)*All pts discontinuing BV or PL, n108118113 Mortality, n (%) Day 9028 (12)26 (11)15 (7) Day 15041 (18)38 (16)32 (15) Day 21053 (23)52 (23)45 (22)Pts discontinuing BV or PL for toxicity, n292735 PFS from discontinuation of BV or PL Median, months3.36.46.8 HR vs PL 0.710.73 [95% CI] [0.40–1.27][0.42–1.24]*% of pts with PDDiscussion: Although recent preclinical studies, carried out using agents targeting VEGF receptors, suggest that anti-angiogenic therapy increases tumour malignant potential, exploratory data from a large clinical trial of BV do not support this theory. PFS in AVADO was longer after discontinuation of BV than after discontinuation of PL. Mortality rates up to day 210 after PL/BV discontinuation were similar. The proportion of BV pts with new metastatic lesions at PD was lower than that of PL pts, suggesting that metastatic spread was not increased.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6086.
Different Biological Processes Are Associated with Prognosis and Chemotherapy Sensitivity in the Different Molecular Subtypes of Breast Cancer.
Authors: Iwamoto T. , Iwamoto T. , Bianchini G. , Coutant C. , Shiang C. , Matsuoka J. , Symmans W. , Hortobagyi G. , Simon R. , Pusztai L. 
Published: December 2010

Abstract
Background: Breast cancer includes multiple different molecular subtypes. We hypothesized that different biological processes and molecular markers may be associated with prognosis and chemotherapy sensitivity in the different subtypes.Methods: We performed gene set analysis in ER-positive/HER-2-normal (ER+) and ER-negative/HER-2-normal (ER-) cancers separately to identify gene sets that are associated with prognosis and chemotherapy sensitivity. We tested 5295 different, functionally annotated gene sets (GS) that collectively represent almost all known biological and metabolic pathways in human cells. Significance was estimated with permutation test. Three separate cohorts on untreated HER2-normal patients (n=234, n=175, n=170) and 3 cohorts of patients with neoadjuvant therapy (n=198, n=85, n=61) were included in this analysis. We performed analysis of each data set separately and also as pooled data.Results: When data sets were analyzed individually, 753 to 938 GS were associated with prognosis (P≤0.05) in ER+ cancers including 186 common to all, and 408 to 579 GS were associated with prognosis in ER- cancers including 1 common to all and 141 common to at least two data sets. Within each data set, the number of overlapping GS between the ER+ and ER- prognostic lists ranged from 33 to 112. In the neoadjuvant data sets, 555 to 674 GS were associated with response in ER+ cancers (195 common to at least two, 4 common to all) and 543 to 730 in ER- cancers (268 common to two, 22 common to all). When the predictive GS for ER+ cancers were compared to those for ER- cancers, there were only 10 GS in common. A meta analyses of the combined prognostic data sets yielded 384 GS with p≤0.0001 in ER+ cancers and 47 in ER- cancers, respectively, with 12 GS common to both. A meta analyses of the combined neoadjuvant data sets yielded 92 GS associated with pCR in ER+ cancers and 110 GS in the ER- cancers. Only 2 GS were common to both. Functional analysis indicated that DNA replication, mitotic spindle checkpoint and plasma cell function were the most common prognostic pathways in ER+ cancer. T cell differentiation, glycolipid metabolism and immune functions were the most commonly prognostic pathways in ER- cancer with a notable absence of proliferation related gene sets. DNA replication, spindle and microtubule activity and cell cycle regulation were associated with chemotherapy response in ER+ cancers; oxidative stress, blood vessel formation in ER- cancers.Conclusion: These data indicate that prognosis and chemotherapy response are associated with different gene sets in ER+ and ER- cancers.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6124.
Instability in Chromosomes 9, 7, and 5 Correlate with Lymph Node Metastasis at Presentation in Basal Phenotype Carcinoma.
Authors: Oakley III G. , Brufsky A. , Chivukula M. 
Published: December 2010

Abstract
Introduction: Basal phenotype breast carcinoma has been described as an aggressive variant with comparatively poor prognosis; however, increasing experience suggests that only a subset show increased mortality. We performed microarray analysis of DNA from 11 basal phenotype carcinomas (from 10 patients) and paired normal breast tissue with copy number and loss of heterozygosity analysis with hierarchical clustering to see if characteristic genetic changes were present that correlated to lymph node metastasis at presentation.Materials and Methods: Electronic search of the medical records from 2006-2008 of our institution by an honest broker for all cases of basal phenotype carcinoma (based on medullary-like histology and immunohistochemistry positive for at least two of CK14, CK17, CK5/6 and EGFR) with known lymph node status at presentation and archived snap frozen fresh and tumor samples returned 10 cases (one with bilateral basal phenotype carcinoma), which were de-identified. 5 of these cases had lymph node metastasis at presentation. DNA isolation by column extraction was performed on 0.25 g of paired tumor and normal samples (confirmed by pathologist review before extraction). An Affymetrix 5.0 mapping microarray was performed on isolated DNA per manufacturer's protocols, and analyzed with Partek Genomics Suite software using copy number/LOH workflows using hidden Markov model and genomic segmentation in separate analyses with unsupervised hierarchical clustering.Results: Copy number and LOH analysis using hidden Markov model and genomic segmentation methods gave equivalent hierarchical clustering for our data set. Adjusting the obtained cluster analysis for known lymph node metastasis showed that changes in chromosomes 9, 7, and 5 that differentially clustered 4 of 5 cases which presented with lymph node metastasis (and 2 closely related initially lymph node negative cases).Discussion: Our results suggest that changes on chromosomes 9, 7 and 5 may correlate with the most important prognostic indicator in breast cancer, lymph node status, in basal phenotype carcinomas. Globally suboptimal amplification prevented accurate quantitation of copy number changes or precise loss of heterozygosity localization on these chromosomes. Additional studies to confirm these results using separate molecular techniques are underway, as well as correlation with 5 year survival when the cohort reaches that milestone.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6133.
HOXB9 Promotes the Acquisition of Tumorigenic Phenotypes in Mammary Epithelial Cells.
Authors: Hayashida T. , Hayashida T. , Takahashi F. , Chiba N. , Brachtel E. , Jinno H. , Kitagawa Y. , Maheswaran S. 
Published: December 2010

Abstract
Background:The class I HOX gene family consists of 39 members with a shared highly conserved 61-amino acid homeodomain motif. HOX genes are important regulators of developmental processes, and their role in neoplastic transformation and tumor progression is increasingly recognized (Abate-Shen et al., Nat Rev Cancer, 2002; Cantile et al., Eur J Cancer, 2003). However, the molecular mechanisms by which HOX proteins promote tumorigenesis is not well understood. We recently, observed that HOXB9, a 9th HOX gene paralogue involved in mouse mammay gland development, is deregulated in breast cancer and enhanced expression correlated with high tumor grade. A role for elevated HoxB9 expression in breast tumor progression is demontrated by its ability to activate the ErbB and TGF-B pathways which influence tumor-associated phenotypes in cells.Methods and results:Overexpression of HOXB9 was found in 43% of primary breast cancer by RT-PCR and in situ hybridization (Figure 1A) and correlated with high tumor grade. Ectopic expression of HOXB9 in MCF10A mammary epithelial cells induced EMT, cell migration, invasion (Figure 1B, and 1C). It also increased the expression of angiogenic factors, which enhance the formation of new vessels in mouse dorsal air sac model. Conversely, genetic ablation of endogenous HOXB9 in MDA-MB-231 breast cancer cells suppresses their motility and angiogenic potential. Further, we confirmed that HOXB9-induced tumor phenotypes arise through the activation of both ErbB-AKT and TGFß signaling pathways. Finally, in mouse xenograft model, we observed that HOXB9 cooperates with activated H-Ras to transform mammary epithelial cells leading to large, vascularized and invasive tumors (Figure 2).Discussion:Our findings imply that overexpression of HOXB9 in human breast cancer contributes to tumor progression through activation of signaling pathways that alter both tumor-specific cell fates and tumor-stromal microenvironment, leading to increased invasion and metastasis. It is suggested that combined suppression of ErbB and TGFß signaling pathways to target breast cancers overexpressing HOXB9 may be effective in tumor inhibition.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6145.
Heparanase: A Critical Determinant of Breast Cancer Metastasis to Brain.
Authors: Marchetti D. , Zhang L. 
Published: December 2010

Abstract
Identification of mechanisms responsible for brain-metastatic breast cancer (BMBC) is imperative for the development of novel therapies. Heparanase (HPSE) is the only functional mammalian endoglycosidase degrading heparan sulfate (HS), the main polysaccharide component of growth factor - binding cell surface and extracellular matrix proteoglycans. HPSE relevance in cancer invasion and metastasis has been established. HPSE overexpression correlates with cancer metastasis, tumor vascularity, and the reduced post-operative survival of cancer patients, making it a promising target for anti-cancer therapeutics.Her-2 is a member of the epidermal growth factor receptor (EGFR) family; Her-2 overexpression and EGFR positivity are key characteristics of BMBC. EGFR is important for Her-2 signaling via Her-2/EGFR heterodimer formation. However, mechanisms linking Her-2 function and pathways to precise targets and BMBC onset have not been investigated.We hypothesize that Her-2/EGFR activation augments BMBC by inducing HPSE. We examined HPSE expression, intracellular trafficking, and activity in human Her-2 expressing BMBC models. We demonstrate that: 1) HPSE is expressed in human BMBC cells and expression is augmented according to their metastatic propensities (231parental &gt; 231Br &gt; 231Br2 &gt; 231Br3); 2) EGF induces HPSE expression and nucleolar localization in Her-2 expressing BMBC cells in a dose- and time-dependent fashion; 3) DNA Topoisomerase I (Topo I) is a HPSE target in nucleoli; and 4) HPSE affects Topo I activity and function. Topo I is essential for transcription, and abnormal levels of the enzyme have been observed in a variety of tumors, including brain tumors.These novel findings are relevant to BMBC mechanisms. HPSE – Her-2 interactions will be elucidated to decipher how Her-2 signaling regulates HPSE functionality and mechanistic linkages between these two oncogenic proteins in BMBC cell lines and pre-clinical models.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6156.
Aberrant Expression of ARP2/3 in Breast Cancer and the Association with Disease Progression.
Authors: Moazzam M. , Ye L. , Kynaston H. , Mansel R. , Jiang W. 
Published: December 2010

Abstract
Background: Increased motility is an important characteristics of neoplastic cells, a cell function mediated through actin polymerization. During this process, aside from creation of new branches and lengthening of pre-existing actin molecule, Actin-Related Proteins (ARP)- 2 and ARP-3 work as a complex promotes polymerization through production of new nuclei for actin polymerization. This regulation is orchestrated by other intracellular regulators including and WAVE and WASP proteins, which have been shown to be aberrant in breast cancer (1,2). In this study we determined the differential expression of ARP-2 and ARP-3 and correlated the expression with various prognostic factors.Methods: Expression of ARP-2 and ARP-3 was examined in a cohort of mammary tissues (n=33 normal breast tissue and n=127 primary breast tumor tissue samples). Transcript levels of ARP2 and ARP3 were then determined using quantitative real time PCR (Q-PCR) and protein levels were assessed using immunohistochemical (IHC) staining. Results were analyzed by Mann-Whitney U test.Results: Cytoplasmic staining for both ARP-2 and ARP-3 was noted along with strong epithelial staining as compared to stromal cells. Quantitative real time PCR (Q-PCR) data analysis showed lower expression of both ARP -2 & -3 in tumour tissue as compared to normal but without statistical significance. ARP-2 expression was significantly reduced in tumour samples from patients with poor prognosis (p=0.037) and patients who died of breast cancer (p=0.0265). Primary breast tumor tissue samples from patients classified as TNM stage 3 and 4 showed statistically significant lower expression of ARP-3 as compared to normal tissue (p= 0.019 and 0.020, respectively). ARP-3 expression was also significantly lower in patients who developed local recurrence of breast cancer (p=0.027). Using a Spearman correlation analysis, ARP-3 transcripts were find to be significantly correlated with the WAVE-2 transcript (r=0.42, p&lt;0.01).Conclusions: Breast cancer shows aberrant expression of ARP-2 and ARP-3, a pattern linked to the prognosis of the patients. ARP-3 and WAVE-2 may have an intimate interplay in this association which warrants further investigation.References1. Fernando HS et al. Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer. Oncology. 2007;73:376-3832. Martin TA, et al. N-WASP is a putative tumour suppressor in breast cancer cells, in vitro and in vivo, and is associated with clinical outcome in patients with breast cancer. Clin Exp Metastasis. 2008;25:97-108
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6169.
T47D/PKCα Cells Are Nonmigratory and Noninvasive In Vitro Despite Tamoxifen Resistance In Vivo.
Authors: Perez White B. , Tonetti D. 
Published: December 2010

Abstract
Background: We have previously reported that overexpression of PKCα in T47D (T47D/PKCα) breast cancer cells results in hormone independence, growth inhibition by estradiol, and tamoxifen resistance (Chisamore, 2001). This has clinical relevance because we have shown that PKCα overexpression may predict disease recurrence and tamoxifen treatment failure suggesting consideration of other treatments (Tonetti, 2003). Further characterization reveals that T47D/PKCα cells are noninvasive in vitro compared to T47D/neo control cells in Matrigel invasion assays and that knockdown of PKCα reverses the phenotype (Perez White, AACR 2009). We have further characterized the in vitro phenotype of T47D/PKCα cells using migration assay and profiling of proteins associated with epithelial-mesenchymal transition (EMT). Adherens junctions are made of a complex of proteins including E-cadherin whose dissolution is thought to play a role in EMT. E-cadherin can be transcriptionally repressed by the embryonic transcription factor Snail1. Generally, cells that lose expression of E-cadherin gain expression of N-cadherin and/or vimentin which is correlated to increased migration, invasion, and metastasis.Methods: To determine migration, cells were plated in serum-free media into Boyden chambers for 24 h with media containing 10% fetal bovine serum as chemoattractant. Protein expression levels were determined by western blot of whole cell extracts and transcript levels by RT-qPCR. Statistical analyses were performed by t-test with GraphPad Prism 5.Results: Migration assay results show that T47D/PKCα cells are nonmigratory compared to T47D/neo cells (P &lt; 0.0001). Western blots show that there is significantly lower expression of E-cadherin in T47D/PKCα cells compared to T47D/neo cells (P &lt; 0.005). However, transcripts of E-cadherin are expressed at 3-fold higher levels in T47D/PKCα cells compared to T47D/neo cells. Neither cell line expresses vimentin, N-cadherin, or Snail1 proteins.Conclusions: T47D/PKCα cells have reduced invasive and migratory potential even though they have decreased expression of E-cadherin. Results indicate that regulation of E-cadherin may be due to translational repression or increased degradation due to increased transcripts and absence of a transcriptional repressor. In summary, despite the fact that PKCα overexpression correlates with tamoxifen resistance, these tumors may have a better prognosis due to the less invasive and migratory nature of these cells. Future mechanistic and clinical studies are needed to determine the full prognostic impact of PKCα tumor overexpression in patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6173.