bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-01-03: The Predictive Value of Serum Serum Her-2/neu for Response to Anthracycline-Based and Trastuzumab-Based Neoadjuvant Chemotherapy of Advanced Primary Breast Cancer
Authors: Jeon C , Lee JS , Min W 
Published: April 2011

Abstract
Background:There excists little information about a possible influence of serum Her-2/neu on response to chemotherapy. We aimed that the assessment of serum Her-2/neu in pretreatment serum sample can be useful in predicting response to neoadjuvant chemotherapy. Methods: All breast cancers were tested by immunohistochemical stain and FISH for Her-2/neu before treatment. Serum Her-2/neu was twice measured by Chemiluminescence immunoassay (ADVIA centaur®TMsystem) before neoadjuvant chemotherapy and before operation. The cutoff value was 10.2 mg/ml according to previous study. Pathologic complete response (pCR) was considered as no residual tumor or remnant ductal carcinoma in situ, partial response (PR) was less than 50% decrease in maximal diameter in pathologic tumor size.The measurements for the change of serum Her-2/neu were defined as pretreatment Her-2/neu — preoperation Her-2/neu. We compared the change of serum Her-2/neu between 1) before prechemotherapy and after chemotherapy 2) pathologic complete response and partial response 3) trastuzumab (H) group and anthracyline (A) group. Results: Serum Her-2/neu was decreased after neoadjuvant chemotherapy. Mean of serum Her-2/neu in prechemotherapy was 15.4±9.0 ng/mL, that of postchemotherapy was 10.5± 2.0 ng/mL (p= 0.04). Pathologic response was correlated with the change of serum Her-2/neu (PR: 6.1 ng/ml vs. pCR: 42.0 ng/ml, p= 0.014). Serum Her-2/neu of trastuzumab group was more decreased than of anthracyline group (H=12.9 ± 14.5 ng/mL ; A= 2.2 ± 1.2 ng/mL; p=0.024). In trastuzumab group, pCR was boreline significantly correlated with change of serum Her-2/neu (PR: 0.8 ± 0.84 ng/ml vs. pCR: 21.1 ± 13.2 ng/ml, p= 0.08). Conclusions: Prechemotherapy serum Her-2/neu was to be a significant predictor of pathologic response to neoadjuvant chemotherapy. Serum Her-2/neu levels during treatment were associated with pathologic response in patients receiving neoadjuvant chemotherapy, particularly, in trastuzumab-based regimen. Serum Her-2/neu levels may serve to monitoring neoadjuvant therapy in Her-2/neu overexpressed breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-01-03.
Abstract P3-02-03: Prognostic Value of Circulating Tumor Cells (CTC) in HER-2 Positive Metastatic Breast Cancer (MBC) Patients (pts) Treated with Anti-HER2-Based Therapy
Authors: Giuliano M , Giordano A , Handy BC , Ueno NT , Alvarez RH , Hortobagyi GN , Reuben JM , Valero V , Cristofanilli M. 
Published: April 2011

Abstract
Background. Detection of ≥5 CTC per 7.5 mL of blood before starting systemic treatment is a strong and independent predictor of worse progression-free survival (PFS) and overall survival (OS) in MBC. Trastuzumab (Herceptin®) was shown to be highly effective in reducing CTC number in all HER-2 amplified MBC cases after the first dose (De Giorgi et al., SABCS 2009). Furthermore, trastuzumab can target chemotherapy-resistant CTC in pts with breast cancer (Bozionellou et al. 2004). To date no significant analysis exploring the effect of another anti-HER2 therapy, lapatinib (Tykerb®) on CTC has been published.We hypothesized that anti-HER2-based therapy may modify the detection rate and prognostic value of CTC in pts with HER-2 amplified MBC. Patients and Methods. We retrospectively evaluated 91 HER-2 positive MBC pts, treated at the M. D. Anderson Cancer Center with trastuzumab-based (n=59), or lapatinib-based therapy (n=32). In all pts, CTC were enumerated before starting systemic treatments, using CellSearch™. Follow-up CTC counts were available for 41 (69%) pts treated with trastuzumab and 25 (78%) pts treated with lapatinib. PFS and OS were estimated by Kaplan-Meier product limit, and compared between groups according to baseline CTC count (&lt;5 vs ≥5) by log-rank test. Results. Median follow-up was 27 months (range, 8-65) and 16 months (range, 3-33) for pts receiving trastuzumab and lapatinib, respectively. Treatments administered and CTC counts are reported in table 1. Two (5%) pts receiving trastuzumab and 4 (16%) pts treated with lapatinib had CTC ≥5 at the follow-up assessment. Estimated median PFS and OS according to baseline CTC value, for both treatments are shown in table 2. An elevated CTC count was associated with poor prognosis in pts treated with lapatinib (median OS: 25.8 vs 13.6 months in pts with CTC &lt;5 and ≥5, respectively, P=.072). Surprisingly, in the trastuzumab group, PFS showed a non-statistically significant trend in favor of pts with CTC ≥5 compared to those with &lt;5.
Conclusions. According to previously published data, our study confirms that trastuzumab-based therapies can drastically reduce the number of CTC and neutralize their negative prognostic value. Furthermore, we found that lapatinib had a limited effect on the detection rate and prognostic value of CTC, although the low number of pts and the high percentage of pre-treated women do not allow us to draw definitive conclusions.
Table 1
Table 2

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-03.
Abstract P3-02-04: Dendritic Cells from Breast Cancer Patients with ≥5 CTCs Are Functionally Impaired
Authors: Lee B-N , Gao H , Cohen EN , Tin S , Jackson SA , Valero V , Alvarez R , Cristofanilli M , Reuben JM. 
Published: April 2011

Abstract
Background: Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer patients and patients with ≥5 CTC per 7.5 mL of whole blood (WB) have a poor prognosis and overall survival than patients with fewer than 5 CTC. Dendritic cells (DCs), the most efficient antigen presenting cells (APC), are essential for a robust host immune response. Therefore, we investigated the relationship between CTCs and the immunophenotype and function of DCs in breast cancer (BC) patients.
Methods: This ongoing prospective study consists of 47 patients, 26 with metastatic breast cancer, 19 with inflammatory breast cancer; and 2 with locally advanced breast cancer, with a median age of 52 years (range: 34-71 years). Primary tumor characteristics of patients included 28 hormone receptor positive, 18 HER2 amplified, and 12 triple receptor negative. Fluorescence-activated cell sorting analysis was used to enumerate circulating DC subsets, myeloid (mDC) and plasmacytoid (pDC), that express costimulatory molecules (CD40, CD80, and CD86). Additionally, we assessed the ability of DCs to synthesize interleukin (IL)-10, IL-12, interferon-alpha (IFN-a) and tumor necrosis factor (TNF)-a constitutively and following activation with toll-like receptor (TLR) agonists. CTCs were enumerated in 7.5 mL of WB using CellSearch (Raritan, NJ). Results: CTCs were detected in 26 patients (range from 1 to 1009) including 12 patients with ≥5 CTCs. Compared with patients with &lt; 5 CTCs, those with ≥5 CTCs have a significantly higher median number of mDC (P = 0.007) and higher median percentages (%) of TLR-activated mDC that expressed CD80 (P = 0.047) and CD86 (P = 0.063). Additionally, compared with patients who had &lt; 5 CTCs, patients with ≥5 CTCs had a lower median % of TLR-activated mDC that synthesized IL-12 (P=0.028), TNF-α (P=0.006), or IL-10 (P = 0.031); and there was a higher median % of TLR-activated pDC that synthesized IL-10 (P = 0.000). Conclusions: Even though BC patients with ≥5 CTCs have more mDC, activated mDCs are less capable of synthesizing inflammatory factors (TNF-a and IL-12) responsible for adaptive immunity. Moreover, there was increased % of activated pDC that synthesized IL-10, a cytokine responsible for downregulating adaptive immune responses. These preliminary data suggest that activated DCs from BC patients with ≥5 CTCs are likely to have a suboptimal ability to sustain an efficient adaptive immune response compared with activated DCs of BC patients with &lt; 5 CTCs. This is the first report linking CTCs, a proven poor prognostic indicator, with potential dysfunctional APC in BC patients.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-04.
Abstract P3-04-03: Combined Epigenetic Targeting Reverses Epithelial-Mesencymal Transition (EMT) and Reduces Invasiveness of Human Breast Cancer Cells
Authors: Joshi AD , Rao R , Fiskus W , Buckley KM , Nalluri S , Balusu R , Atadja P , Bhalla KN. 
Published: April 2011

Abstract
Background: Epithelial-Mesenchymal-transition (EMT) is a highly conserved biologic process that is involved in organ development, tissue regeneration, tumor invasion and metastasis. EMT is phenotypically associated with the loss E-cadherin and a gain of mesenchymal markers (e.g., vimentin). Both promoter methylation by DNMT1 and histone H3- K27 trimethylation by the histone methyl transferase EZH2 have been shown to cause E-cadherin expression. Several transcription factors, including ZEB1, Snail, Slug and Twist, directly bind to E-cadherin promoter, recruit histone deacetylase (HDAC) activity and repress E-cadherin. We have previously shown that the pan-HDAC inhibitor panobinostat (PS, Novartis Pharmaceuticals) depletes EZH2 and DNMT1 levels, and co-treatment with PS and DNMT1 inhibitor decitabine (DAC) synergistically depletes EZH2 and DNMT1.
Methods: Here, we determined the effects of PS (20 to 100 nM) and/or DAC (0.5 to 5.0 uM) on E-cadherin levels and other EMT-associated markers, as well as on invasiveness of human breast cancer MB-231 and SUM159PT cells, which have undetectable levels of E-cadherin. Results: Treatment with PS dose dependently inhibited the migration and invasion of the breast cancer cells (by Boyden chamber assay). This was associated with induction of mRNA and protein levels of E-cadherin and decline in vimentin levels. PS treatment inhibited HDAC activity and reduced DNMT1 and EZH2 levels. Additionally PS repressed ZEB1 mRNA and protein levels. Co-treatment with bortezomib partially restored ZEB1 levels, indicating that PS treatment promotes proteasomal degradation of ZEB1. Chromatin immunoprecipitation (ChIP) analyses demonstrated that PS treatment inhibited H3K27 chromatin repressive and increased H3K4 chromatin permissive mark associated with the E-cadherin promoter. PS treatment also diminished ZEB1 occupancy on the E-cadherin promoter. Pre-treatment of MB-231 and SUM 159PT cells with DAC or 5-azacytidine (AC, also a DNMT1 inhibitor) (0.5 to 5.0 uM) further enhanced PS-mediated induction of E-cadherin, which was associated with further decline in ZEB1 levels. Additionally, co-treatment with PS and DAC caused greater inhibition of in vitro invasion by the breast cancer cells. Discussion: Collectively, these findings indicate that combined epigenetic targeting with PS and DAC depletes ZEB1, induces E-cadherin and reverses EMT, thereby, attenuating invasiveness of human breast cancer cells.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-03.
Abstract P3-04-04: Novel Genome-Wide DNA Methylation Signatures of Primary Breast Tumor Subtypes
Authors: Lee MP , Kadota M , Yang HH , Clifford RJ , Dunn BK. 
Published: April 2011

Abstract
Background: Gene expression signatures can be used to classify breast tumor tissues into distinct categories: luminal, “basal”, and HER2 subtypes, which have distinct clinical prognoses. Since gene expression is largely determined at the level of epigenetic modification, we hypothesize that DNA methylation signatures may also be used to classify breast tumor subtypes and possibly to define new cancer subtypes; thus, such epigenetic signatures can complement gene expression signatures for a better understanding of breast tumorigenesis and in turn, may lead to improvement in clinical diagnosis.
Material and Methods: We used antibodies to 5-methylcytosine to immunoprecipitate DNA enriched for methylation by means of the MeDIP method on 66 breast primary tumors. Then we analyzed the MeDIP-derived DNA by means of the Affymetrix 500K SNP array. We normalized DNA methylation data from the 66 tumors using a modified quantile normalization procedure. The data were generated in two phases, phase 1 consisting of 42 tumors and phase 2 containing 24 tumors, data from the latter being reserved for validation purposes. We concentrated DNA methylation analysis on the SNPs that are located within promoter regions, defined here as +/− 2 kb flanking the transcription start site (TSS), and within CpG islands, since methylation in these regions is especially relevant for gene expression regulation. We searched for DNA methylation signatures that show distinct patterns among tumors with different clinical phenotypes such as histological grade and lymph node involvement. Results: We identified one DNA methylation signature consists of 78 genes that separated the tumors with high grade from those with low-mid grade; we found another DNA methylation signature consists of 42 genes that separated the tumors with lymph node positive status from those with lymph node negative status. We were able to validate these signatures using methylation data obtained from an independent set of 24 tumors. The performance of the signature for predicting lymph node status in the testing samples showed accuracy of 83%, sensitivity of 70%, and specificity of 90%.
Discussion: We have identified DNA methylation signatures that could classify breast tumor subtypes and correlate with clinical phenotypes. We are investigating whether such epigenetic signatures can complement gene expression signatures for a better understanding of breast tumorigenesis and for application in clinical diagnosis and treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-04.
Abstract P3-04-07: Loss of Expression of the 14-3-3 Sigma by CpG Island Methylation and Relations with Prognostic Factor in Breast Cancer
Authors: Martínez-Galán J , Torres-Torres B , Ríos S , Del Moral R , Nuñez MI , González-Flores E , Conde V , Peñalver J , Delgado JR , Ruiz Almodóvar M. 
Published: April 2011

Abstract
Background: Expression of 14-3-3 σ is a tumor suppressor gene induced in response to DNA damage, and has been implicated in G2/M cell cycle arrest by p53. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. Objetive: To correlation methylation levels of promoter 14-3-3σ with association prognostic factors in breast cancer.Material and Methods:This is a prospective study we quantified methylation levels of promoter 14-3-3 σ gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer. Results: Median age was 58 years (32-88); 69% were postmenopausal women.Nodal involvement N0; 63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%,G2;37%,G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047).The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (P&lt;0.05),nodal positive status (P&lt;0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (P&gt;0.05).Conclusions:Hypermethylation of the 14-3-3σ a promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3σ may be an important event in tumor progression and particularly in breast carcinogenesis.Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-07.
Abstract P3-04-08: Epigenetic Changes Due to DNA Methylation in CpG Islands during Breast Cancer Progression
Authors: Dimitrova N , Gorthi A , Prasada SK , Chakrabarty S , Keswarpu P , Banerjee N , Janevski A , Kiradi PH , Khandige S , Satyamoorthy K. 
Published: April 2011

Abstract
DNA methylation has been associated with several key events of gene regulation and to human cancer. It is not yet known how the epigenome of various populations is associated with clinical manifestations during the course of the disease. In this poster we describe a method for stratifying breast cancer patients from Indian origin using CpG island microarray from the University Healthcare Network (UHN) Toronto (human CpG island 12k microarray chip, HCGI12K). DNA samples were obtained from a prospective study cohort which consisted of 51 female primary breast cancers. All patients had been undergoing treatment in a tertiary care hospital and its associated centers in the southern part of India between 2007 and 2009. We have identified and classified the DNA methylation in CpG islands of patient samples using various clinical parameters such as age of disease onset, menopausal status, hormone receptor status and Her2 status. We present the methods to analyze the data from UHN CpG island arrays used in a high throughput methylation study in order to derive decision rules of stratifying the data into basic classes such as normal and benign conditions, and infiltrating ductal carcinoma. Results will be presented pertaining to differential methylation status of patients in different categories such as age of disease onset, menopausal status, hormone receptor status and Her2 status.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-08.
Abstract P3-06-02: Prevalence of TP53 p.R337H Mutation in Cases of Breast Phyllodes Tumours in Southern Brazil
Authors: Giacomazzi J , Koehler-Santos P , Alemar BB , Ashton-Prolla P , Graudenz MS. 
Published: April 2011

Abstract
Background: Previous studies in Brazilian patients diagnosed with the core-cancers of Li-Fraumeni syndrome (LFS) and its variants (LFL) indicate that a particular germline mutation, TP53 p.R337H, may be highly prevalent and strongly associated with pediatric adrenocortical tumors in Southern Brazil. However, other tumours types, including breast cancer, have been observed in carriers, raising the possibility that the TP53 p.R337H mutation may also contribute to breast tumorigenesis. Breast phyllodes tumour, a very rare and aggressive breast neoplasia that accounts for less than 1% of all breast cancer cases, may be associated with LFS, and has suggested by some to be particularly frequent in TP53 mutation carriers. Methods: Formalin fixed paraffin-embedded (FFPE) tissue from disease-free lymph nodes of an unselected consecutive series of women diagnosed with benign and malignant phyllodes tumours between 2000 and 2010, was obtained from 7 Pathology Laboratories in Southern Brazil. Genomic DNA was isolated from FFPE with the QIAamp DNA Tissue Kit. Genotyping was performed by qPCR using TaqMan technology and direct bi-directional sequencing for confirmation in mutation-positive cases. Results: Analysis of the first 48 cases included in the study (9 malignant, 3 borderline and 36 benign phyllodes tumors) resulted in identification of the TP53 p.R337H mutation in the germline of a 61 year-old patient with malignant phyllodes and a 38 year-old patient with a benign phyllodes tumor of the breast.
Conclusion: Preliminary analysis of a case series of breast phyllodes tumors indicates that germline the founder mutation TP53 p.R337H may be particularly common in women with these tumors in Southern Brazil. Further analysis of the entire TP53 coding region and evaluation of the founder haplotype in the mutation-positive cases is ongoing. The identification of germline TP53 mutations in patients diagnosed with phyllodes tumors of the breast has important implications for disease management and in cancer risk counseling for these patients and families.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-06-02.
Abstract P3-08-03: Defects in BRCA1 Contribute to Global Differential Allele-Specific Expression
Authors: Chen X , Schaeffer A , Devarajan K , Liao C , Zhou Y , Slater CM , Vanderveer L , Conroy J , Godwin AK. 
Published: April 2011

Abstract
Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variability in humans and more recently to the pathogenesis of cancer. DASE is associated with X-chromosome inactivation and genomic imprinting and is relatively common among non-imprinted autosomal genes. The DASE phenotype can also be transmitted by Mendelian inheritance. We have previously reported that nonsense-mediated mRNA decay (NMD) of mutant BRCA1 as well as other epigenetic mechanisms can lead to DASE of BRCA1 and enhanced susceptibility to breast cancer. BRCA1 has been implicated in many cellular processes including DNA repair, cell-cycle-checkpoint control, protein ubiquitination, and chromatin remodeling. Importantly, cells carrying a deleterious BRCA1 mutation exhibit increased genome instability, therefore, we hypothesize that defects in BRCA1 lead not only to DASE of itself, but increase genome-wide DASE and thus contribute to increased breast cancer susceptibility. To test this hypothesis, we employed a genome-wide ASE assay (Illumina Human Omni1-Quad BeadChip) using primary mammary epithelial cells [3 BRCA1 wild-type vs. 3 BRCA1 mutant carrying (2800delAA, 4154delA and R1751X)]. As shown in Table 1, cells carrying a BRCA1 mutation had significantly more DASE events as compared to wild-type cell (P&lt;10-7). In addition, we identified 351 genes demonstrating DASE that were unique to the BRCA1 mutant cells. The cellular functions of these genes are wideranging, including DNA repair, cell cycle control, lipid metabolism and protein degradation. In summary, this study provides the first evidence that mutant BRCA1 can lead to global DASE, which in turn may contribute to the development of breast cancer in mutation carriers. This work was supported in part by the Eileen Stein-Jacoby Fund and a grant from the Congressionally Directed Medical Research Programs, Department of Defense, W81XWH-08-1-0361 (XC).
Table 1. BRCA1 mutations increase the global DASE in PMECs
t; A DASE event is defined as that the Log-ratio of allele-specific expression level of one gene is more than 1 or less than -1, i.e. the expression level from one allele is at least 50% less than the level of another allele

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-08-03.