bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-01-14: Gene Expression of Immune Mediators within Nipple Aspirate Fluid and Ductal Lavage from Normal and Cancerous Breasts.
Authors: Love SM , Ruffell B , Nguyen T , Mills D , Coussens LM 
Published: June 2012

Abstract
The majority of breast cancers are thought to initiate in the lining of the 6 to 8 ducts that exit the nipple. Evidence suggests that the presence of nipple aspirate fluid (NAF), and in particular NAF containing atypical epithelial cells, in the ducts is predictive of future breast cancer risk. Although NAF fluid and cells may be representative of a preneoplastic state, use of NAF has not proven to represent a robust indicator for future malignancy. Chronic infiltration of tissues by immune cells predisposes them to future malignancy. Since macrophages can represent up to half of the total cells recovered from NAF, and their presence within malignant breast tumors has predictive value in terms of survival, we hypothesized that changes in the inflammatory microenvironment of breast ducts may foster future malignancy and/or provide an early indicator of future neoplasia. To test this hypothesis, we conducted an exploratory study to investigate gene expression in NAF and ductal lavage fluid. We first used real-time PCR to quantitatively measure mRNA expression of select genes within the cellular milieu of NAF to determine if that microenvironment correlated with a tumor-promoting state. Expression of multiple genes was observed in 15 samples collected from healthy volunteers, with robust expression of myeloid-associated genes including CD14, CD68, CCL3, CSF1 and IL1B observed in the majority of samples. To determine whether similar inflammatory microenvironments were found within each duct, and whether they were comparable to those in NAF-containing ducts, ductal lavage (DL) samples were obtained from 4 different ducts at the same time as NAF collection. Out of 7 volunteers, 4 provided samples allowing comparison between NAF and DL, and between multiple ducts. Analysis of gene expression from these healthy volunteers indicated that gene expression differed between NAF samples and each DL sample. More importantly, unique gene expression was found for each duct sampled, indicating that the immune microenvironment within each duct is distinct from other ducts within the same breast. In order to identify a potential inflammatory gene signature, we then obtained NAF samples from patients with breast cancer that had not received neoadjuvant chemotherapy prior to surgery, from both the cancerous and contralateral breasts. With 4 patients analyzed, no consistent expression difference has thus far been observed, indicating either that the relevant genes have not been identified, or that analysis of inflammatory genes within NAF may not be a predictive method with which to evaluate risk of future malignancy in women that produce NAF. A larger study is warranted to further investigate the significance of inflammatory gene expression in breast ductal fluid.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-14.
P1-01-15: Do Serum Cytokines Predict Breast Cancer Behavior?
Authors: Lush E , Dedert E , Daup M , Dhabhar F , Spiegel D , Tillie J , McMasters K , Sephton SE , Chagpar A 
Published: June 2012

Abstract
Introduction: The role of inflammation in breast cancer development and progression is poorly understood. The potential for serum cytokines to predict breast cancer behavior is an intriguing hypothesis, and data to date, has been conflicting. We sought to determine if serum inflammatory cytokines could predict clinicopathologic factors in breast cancer patients.
Methods: Fifty-seven women with newly diagnosed breast cancer (stage 0–4) were accrued to this IRB-approved study. Serum cytokine levels were obtained in 50 of these women; this was the cohort of interest. All patients underwent surgical therapy, and log serum cytokine levels were correlated to final pathologic results. Results: The median patient age was 51 (range; 21–79) with a median tumor size was 19.5 mm (range; 2.3−95.0 mm). A variety of cytokines were evaluated. None were found to correlate with tumor size, lymph node status, presence of metastases, tumor grade, or lymphovascular invasion (all p's &gt; .05). While most of the cytokines evaluated did not correlate with hormone receptor status, a significant correlation was seen between serum IFN-gamma and estrogen receptor (p = .011) and progesterone receptor (p = .013) status. No correlation was seen with her-2-neu status (p &gt; .05).
Conclusions: Serum cytokine levels do not seem to correlate with tumor size, lymph node status or grade. However, the strong correlation between IFN-gamma serum levels and hormone receptor status is hypothesis-generating and requires further study.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-15.
P1-02-09: Epigenetics-Regulated microRNAs Related with Epithelial-Mesenchymal Transition of Breast Cancer Cells.
Authors: Sato F , Ito T , Tsuchiya S , Kawaguchi-Sakita N , Shimizu K , Tsujimoto G , Toi M 
Published: June 2012

Abstract
Background: Epithelial-mesenchymal transition (EMT) is a program in which biological cells change morphologically and functionally from an epithelial phenotype to a mesenchymal phenotype. The EMT is involved in the process of cancer metastasis. On the other hand, accumulated evidence showed epigenetics and microRNA plays important roles in breast cancer. However, to date, biological networks between epigenetics and microRNAs regarding EMT remains largely unclear. Thus, the aim of this study is to identify epigenetics-regulated microRNAs related with EMT of breast cancer.
Materials / Methods and Results: MicroRNA expression profiles of 11 breast cancer cell lines (8 epithelial-phenotype (E-type) cells and 3 mesenchymal-phenotype (M-type) cells) were obtained by microarray method. Unsupervised clustering analysis showed that E- and M-type breast cancer cells had different microRNA expression profiles. On the other hand, we obtained a genomewide methylation status of these breast cancer cell lines by a MeDIP-seq method. An integrated in silico analysis identified microRNAs which microRNA and DNA methylation were inversely correlated. All of miR-200b/a/429 cluster members were listed in top5 differentially expressed miRs between E-and M-type cells, and also in top 5 epigenetics-regulated microRNAs. In the further study, we focused upon the miR-200b/a/429 cluster. A COBRA assay revealed that promoter regions of miR-200b/a/429 cluster in M-type breast cancer cells were more frequently methylated than that in E-type cells (65.1% vs 6.8%, p&lt;0.0001, respectively). The methylation levels were inversely associated with miR-200b/a/429 cluster expression (Taqman assay, p&lt;0.01). In addition, demethylating treatment using 5-aza-dC unmasked miR-200b/a/429 expression in M-typed breast cancer cell lines. Taken together, the finding indicated that the expression of miR-200b/a/429 cluster is epigenetically regulated. Next, we investigated an effect of the miR-200b/a/429 cluster upon cell motility as a function of the EMT. A transfection of exogenous miR-200b/429 inhibited 24% of cell migration ability (Transwell assay). Utilizing microRNA target prediction algorithm, we identified fibronectin as a target gene of miR-200b/429. Utilizing several prediction algorithms for microRNA target genes, we identified fibronectin as a target gene of miR-200b/429. A luciferase-based reporter assay demonstrated that miR-200b/429 were directly associated with fibronectin-3'UTR and repressed 21% (p&lt;0.0001) of the reporter gene expression post-transcriptionally. Conclusion: The promoter hypermethylation of miR-200b cluster is associated with epithelial-mesenchymal transition, and stimulates cell motility by upregulating fibronectin expression in mesenchymal-phenotype breast cancer cells.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-09.
P1-03-07: Subtype-Specific Gene Expression Signatures in Peritumoral Non-Neoplastic Breast Tissue.
Authors: Williams T , Roman-Perez E , Rein JL , Amos KD , Troester MA 
Published: June 2012

Abstract
Tumors and histologically normal-tissue adjacent to cancer share many biological features with healing wounds. We previously described that the majority of cancer-adjacent normal (CN) tissues show activation of wound response gene expression signatures. However, CN tissue also shows considerable heterogeneity across patients. Therefore, to characterize interindividual variation in CN tissues, we performed unsupervised clustering on gene expression data from women with invasive breast cancer or ductal carcinoma in situ of the breast. Two distinct classes of CN tissue were identified, one of which showed gene expression consistent with epithelial-to-mesenchymal transition (EMT), a process that is well known to be activated in healing wounds. Activation of this signature was present in ∼40% of cancer-adjacent normal specimens and it was also correlated with poor outcome among ER-positive patients. We next hypothesized that gene expression changes in cancer-adjacent normal tissue would be associated with breast cancer subtype and/or estrogen receptor status. To test this, we performed supervised analysis to identify subtype-associated gene expression profiles in CN. We observed that more aggressive tumor subtypes had distinct gene expression profiles in the adjacent normal tissue in supervised analysis. Specifically, Basal-like and luminal B tumors were characterized by reduced expression of claudins and cell adhesion genes, while also exhibiting higher expression of transcription factors associated with migration. These characteristic changes were validated in independent datasets by evaluating the ability of these signatures to predict subtype. It is possible to predict tumor subtype using just adjacent normal gene expression. Thus, our findings show that cancer-adjacent tissue may have value in identifying tumor subtype for cases where tumors are too small to allow genomic analyses. Furthermore, genomic field effects may have clinical implications if, as our data suggests, subtypes with higher local recurrence rates (e.g. basal-like and luminal B breast cancers) have widespread genomic alterations, even in non-neoplastic tissue. Widespread genomic changes may indicate a need for mastectomy rather than breast conserving therapy. Ongoing work is (1) assessing these signatures in association with relapse outcomes in the Polish Women's Breast Cancer Study, where more than 10 years of follow up data have been accrued on more than 200 patients, and (2) using co-culture models systems to study paracrine communication between breast cancer cells and stroma according to breast cancer subtypes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-07.
P1-06-06: The Importance of CXCL10 and CXCR3-A in Breast Cancer.
Authors: Hilborn E , Sivik T , Kot A , Fornander T , Skoog L , Nordenskjöld B , Stål O , Jansson A 
Published: June 2012

Abstract
Background: CXCL10 is a chemokine with chemo attractant properties which signals through G protein-coupled receptor CXCR3. At least two reported isoforms exists; CXCR3-A and CXCR3-B. CXCL10 is involved in the recruitment of leucocytes, immune modulation and angiogenesis. In animal models CXCL10 inhibits tumour growth, metastase formation and inhibits angiogenesis. The receptors have opposite features; CXCR3-A mediates proliferative or anti-apoptotic response and CXCR3-B mediates growth inhibition and apoptosis in response to ligand binding. The aim of this study was to investigate the role of CXCL10 and CXCR3-A as prognostic or tamoxifen treatment predictive factors in breast cancer.
Material and Methods: A randomized tamoxifen trial comprising 1,780 breast cancer patients was conducted in Stockholm, Sweden, 1976–1990. All patients had lymph node negative primary breast cancer and were postmenopausal at the time of diagnosis. The patients were randomized to tamoxifen or no endocrine treatment. We analyzed the protein expression of CXCL10 and the receptor CXCR3A with immunohistochemistry using tissue microarrays, which were constructed from paraffin blocks originating from 912 patients. CXCL10 and CXCR3A could be scored in 793 (87%) and 735 (81%), respectively.
Results: High expression of CXCL10 was associated with significant benefit of tamoxifen treatment concerning local recurrence and breast cancer survival (P=0.02 and P=0.008). For patients with high CXCL10 expression, tamoxifen decreased the risk concerning local recurrence (rate ratio (RR) = 0.56, 95% C.I. 0.33−0.97, P=0.0029) and breast cancer survival (RR 0.6 95% C.I. 0.39−0.97, P=0.023). High expression of CXCR3-A was associated with significant benefit of tamoxifen treatment concerning total recurrence and breast cancer survival (P=0.00001 and P=0.004, respectively). For patients with high CXCR3-A expression, tamoxifen decreased the risk of total recurrence (RR 0.54 95% C.I. 0.35−0.83, P=0.005) and breast cancer survival (RR 0.49 95% C.I. 0.35−0.69, P=0.00003). On the opposite, in the cohort of patients with no endocrine treatment and high CXCR3-A expression, there was an increased risk of total recurrence (P=0.003). (RR 2.07 95% C.I. 1.18−3.61, P=0.011).
Conclusions: This study indicates that high expression of CXCL10 can be used as predictive markers for tamoxifen treatment. Further, high expression of CXCR3-A is related to bad prognosis and predicts tamoxifen treatment in breast cancer patients. This needs to be further evaluated.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-06.
P1-06-07: TIMP-1 in Combination with HER2 and TOP2A for Prediction of Benefit from Adjuvant Anthracyclines in High Risk Breast Cancer Patients.
Authors: Hertel PB , Tu D , Ejlertsen B , Jensen M-B , Balslev E , Jiang S , O'Malley FP , Pritchard KI , Shepherd LE , Bartels A , Brünner N , Nielsen TO 
Published: June 2012

Abstract
Purpose: HER2 amplification, TOP2A aberrations and absence of TIMP-1 (Tissue Inhibitor of Metalloproteinase-1) expression in breast carcinomas have been associated with incremental benefit from anthracycline-containing adjuvant chemotherapy in several reports. In the DBCG 89D trial, we demonstrated that the predictive value of these markers improved when they were combined in a profile and the present study was undertaken to validate these findings in NCIC CTG MA.5, a similar but independent clinical trial.
Design: TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to CEF or CMF in the MA.5 trial. Patients were classified according to 2 predefined marker profiles — the HT profile (HER2, TIMP-1) and the 2T profile (TOP2A, TIMP-1) and the statistical analyses were performed as closely as possible to the analytical approach used previously in the MA.5 trial and when analysing the biomarker profiles in the DBCG 89D trial.
Results: 98 (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. 44% of patients were classified as HT responsive (HER2-positive and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT responsive patients, CEF was superior to CMF with improved RFS (adjusted HR, 0.64; 95% CI, 0.42 to 0.98) and a borderline-significant improvement in OS (adjusted HR, 0.66; 95% CI, 0.42 to 1.04). A significant HT profile versus treatment interaction was detected for OS (P=0.03). In 2T responsive patients, CEF was superior to CMF with borderline significant improvement in RFS (adjusted HR, 0.67; 95% CI, 0.43 to 1.03), and with improvement in OS (adjusted HR, 0.58; 95% CI, 0.36 to 0.93). A significant 2T profile versus treatment interaction was detected for OS (P=0.01).
Conclusion: In the MA.5 trial, we have validated the HT and 2T profiles as predictors of incremental benefit from anthracycline-containing chemotherapy. The proportion of patients categorized as anthracycline responsive increases from 18–27% using individual markers to 37–44% when combining TIMP-1 with either HER2 or TOP2A. Patients with responsive profiles had a 34–42% relative reduction in mortality when treated with CEF. In contrast, patients with non-responsive profiles (56-63% of patients) had no incremental benefit from CEF compared with CMF. All 3 biomarkers are easily applied in the pathology lab and as such could be used in daily clinical practice to select patients for anthracycline or non-anthracycline containing adjuvant chemotherapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-07.
P1-06-26: The EndoPredict Score Is a Response Predictor for Neoadjuvant Chemotherapy in ER-Positive, HER2−Negative Breast Cancer.
Authors: Brase JC , Gehrmann MC , Petry C , Weber KE , Schmidt M , Kölbl H , Brauch H , Schwab M , Müller V , Jänicke F , Rody A , Kaufmann M , Filipits M , Gnant M , Denkert C , Loibl S , von Minckwitz G , Kronenwett R 
Published: June 2012

Abstract
Background:
The EndoPredict (EP) score is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2−negative breast cancer patients treated with adjuvant endocrine therapy. Two large randomized phase III trials involving endocrine therapy only (n &gt; 1700) demonstrated additional prognostic information of the EP score independent from clinicopathological parameters by classifying 49% as low risk. However, the predictive role of the EP is not clear. Therefore, we examined whether the EP Score also predicts sensitivity towards neoadjuvant chemotherapy in ER-positive, HER2−negative breast cancer patients.
Methods: Four publicly available gene expression data sets (Affymetrix HG-U133A) were retrieved from the gene expression omnibus (GEO) data repository. All analyzed breast cancer patients were treated with anthracycline or taxane/anthracycline-based neoadjuvant chemotherapy. Microarray cel files were MAS5 normalized with a global scaling procedure and a target intensity of 500. The analysis was restricted to ER-positive, HER2−negative breast cancer patients according to pre-specified cut-off levels for the respective ESR1/ERBB2 Affymetrix probesets. The EP score was calculated and patients were classified as having low or high risk according to the pre-specified validated cut-off value. Pathological complete response (pCR) — defined as no residual invasive cancer in the breast or lymph nodes — was used as the primary endpoint for the assessment of treatment response.
Results: The EP Score was examined in 221 ER-positive, HER2−negative breast cancer patients treated with neoadjuvant therapy. Among the 221 patients, 61 tumors (27.6%) were classified as EP-low-risk, whereas 160 tumors (72.4%) were EP-high-risk. Only one of the EP-low-risk tumors achieved a pCR after neoadjuvant therapy, whereas 24 of the 25 pCR events were classified as EP high risk. The sensitivity of the EP score was 96% and the negative predictive value 98% with an area under the receiver operating characteristic curve of 0.73.
Conclusions: The EP Score is a predictor of chemosensitivity in the neoadjuvant setting. The test correctly identified all but one of the patients achieving a pCR suggesting that the benefit of cytotoxic chemotherapy is limited to the EP high risk group.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-26.
P1-07-09: Estrogen Receptor (ER) mRNA and ER-Related Gene Expression in Breast Cancers That Are 1%-10% ER-Positive by Immunohistochemistry.
Authors: Iwamoto T , Booser D , Valero V , Murray JL , Koenig K , Esteva FJ , Ueno NT , Zhang J , Shi W , Qi Y , Matsuoka J , Hortobagyi GN , Hatzis C , Symmans WF , Pusztai L 
Published: June 2012

Abstract
Purpose: Our goal was to examine whether borderline estrogen receptor (ER)-positive cancers, defined as 1–10% positivity by immunohistochemistry (IHC), show the same global gene expression pattern and high ESR1 mRNA expression as ER-positive cancers or are more similar to ER-negative cancers.
Patients and methods: ER status was determined by IHC in 465 primary breast cancers and with Affymetrix U133A gene chip (ESR1 mRNA gene expression: Probe set = 205225_at). We compared expressions of ESR1 mRNA and a 106-probe set ER-associated gene signature score between ER-negative (n=183), 1–9% (n=25), exactly 10% (n=6), and &gt; 10% ER-positive (n=251) cancers. We also assessed the molecular class of the borderline ER-positive cases using the PAM-50 classifier.
Results: Among the 1–9%, 10% and &gt; 10% IHC positive cases, 24%, 67% and 92% were also ER-positive by ESR1 mRNA expression. The average ESR1 expression was significantly higher in the &gt; 10% IHC-positive cohorts compared to the 1–9% or completely negative cases but in these latter two cohorts ER expression was similarly low. The average ER gene signature scores were similar for the ER-negative and 1–9% IHC-positive cases, but significantly lower than in &gt; 10% ER-positive cases. None of the 1–9% ER-positive cases were classified as Luminal A, 2 were Luminal B and 12 were Basal-like. Among the 10% ER-positive cases, 2 were Luminal A and 1 was Luminal B. Conclusion: Overall, 24% of the 1–9% and 67% of the 10% ER-positive cancers show ESR1 mRNA levels and gene signatures that are consistent with ER-positive, potentially endocrine sensitive tumors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-09.
P1-07-17: Multiplex Plasma Biomarkers Associated with Bone Metastasis from Breast Cancer.
Authors: Leitzel K , Ali S , Bisen A , Lomakin A , Simonyan V , Lipton A 
Published: June 2012

Abstract
Background: Over two-thirds of breast cancer patients who relapse will develop bone metastasis, and there are currently no effective biomarkers to predict for this event. Multiplex immunoassay technology for 60 bone metastasis-associated biomarkers was conducted on pretreatment plasma from 40 patients enrolled in a 2nd-line phase III hormone therapy trial of metastatic breast cancer, to discover effective circulating biomarkers predictive of bone metastasis.
Methods: Pretreatment EDTA plasma from 20 patients with bone metastasis, and 20 patients with non-bone metastasis from the letrozole-megace 2nd-line phase III hormone therapy trial of metastatic breast cancer was evaluated using Searchlight multiplex immunoassay technology (Aushon Biosciences, Billerica, MA) on 60 biomarkers custom-selected for known association with bone metastasis. Multiplex data analysis for maximal discrimination of bone metastasis vs. no bone metastasis cohorts was performed by two independent statisticians: one evaluated the predictive capacity of individual biomarkers as well as two-marker combinations constructed by Monte Carlo optimization using Metropolis algorithm (MMC), and the other used a machine learning technique called hybrid bootstrapped RLDA +PCA (regularized linear discriminant analysis with principal component analysis, with dimensionality reduction used in the bootstrapping procedure).
Results: One of the 60 analytes (IL-17) was undetectable at the 1.6 pg/ml lower limit of detection, and was not included in the multiplex statistical analyses. Of the remaining 59 analytes, MMC multiplex analysis yielded 9 biomarkers that predicted for bone metastasis, whereas RLDA + PCA multiplex analysis yielded 20 predictive biomarkers. Common to both analyses, which were limited in this small 40 patient study, were 5 biomarkers, with varying functions including growth factors, cytokines, inflammatory factors, protease inhibitors, and cell adhesion molecules.
Conclusions: Multiplex analysis of 60 biomarkers custom-selected for known association with breast cancer metastasis to bone yielded 5 pretreatment plasma biomarkers classified as predictive of bone metastasis by 2 different multiplex statistical analysis methods. Evaluation of these biomarkers is now warranted in a larger validation cohort of breast cancer patients with and without bone metastasis.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-17.