bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-03-06: Initial ex-vivo study of the ability of an in situ fluorescence spectroscopy probe to distinguish benign from malignant breast tissues
Authors: Mathieu M-C , Moniz-Koum H , Vincent Y , Toullec A , Balleyguier C , Eyrignoux T , Vielh P , Chatellier F , Al Chab L , Fontaine-Aupart M-P , Farcy R , Delaloge S 
Published: August 2014

Abstract
Background:
The native fluorescence spectra of human cancerous and normal breast tissues under the selected excitation of a 405 nm light should differ according to their different content of NAD(P)H, FAD, collagen or retinol and derived fluorophores. Nodea Medical has developed an in situ probe, Probea®, installed in a 25-Gauge needle, which is able to measure endogenous tissue fluorescence under 405 nm specific wavelength. Tissues are excited by this blue light; their back-production of fluorescence (around 480 nm) is caught and immediately analyzed.
The objectives of the present preclinical study are to evaluate the ability of the Probea® probe to distinguish benign versus malignant breast lesions among freshly harvested ex-vivo surgical samples, and to evaluate the fluorescence behaviour of adjacent and remote normal tissues among cancer specimens.
Methods:
Fresh breast samples coming out of the operating room were harvested and analyzed prior to pathological fixation. Surgical specimens included mastectomies, lumpectomies, and plastic surgeries in different malignant or non-malignant situations. For each of them, the probe was placed within the main target surgical lesion, as well as within surrounding normal epithelial and fat tissues, and remote normal tissues where available (mastectomies or reduction mammoplasties).
We aimed at measuring different parameters of the endogenous fluorescence at each measurement point: maximum intensity, peak wavelength, level of signal stability, growth or spontaneous decay in a fixed position. Fluorescence signals harvested were compared to the detailed pathological analyses of each area explored within the surgical samples.
Results :
49 fresh breast samples were harvested and analyzed, of which 40 were from patients with cancer and 9 from patients without cancer.
The presence of a fluorescence signal within the main lesion was overall strongly associated with a cancer diagnosis (N = 40/49 malignant lesions versus 0/9 benign lesions, p = 0.001). The positive predictive value of the test in this preliminary series is 98%, whereas the negative predictive value is 100% analyzing the maximum fluorescence intensity with a cut-off of 1000. Interestingly, normal adjacent fat tissues surrounding and remote from breast cancer lesions also produced fluorescence which could also be considered as criteria to define malignancy. Complete analyses of multiple parameters are ongoing.
Conclusion:
In this initial preclinical study, the Probea® probe has shown an elective ability to distinguish benign and malignant lesions. Particularly, its negative predictive value appears very promising. A clinical study to confirm these findings is planned.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-03-06.
Abstract P4-04-01: Understanding estrogen receptor transcription in breast cancer
Authors: Carroll JS 
Published: August 2014

Abstract
Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FOXA1 (HNF3a) was subsequently shown to bind to half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to explore ER and FoxA1 functional interactions in breast cancer, with a specific focus on changes in binding dynamics that occur during endocrine resistance. To this end, we have established transcription factor mapping approaches (ChIP-seq) in primary tumor material, to investigate differential ER/FoxA1 binding that occurs during tumor progression. We have functionally explored underlying factors that contribute to altered transcription factor binding and activity. In addition, we have recently established a method for rapid unbiased discovery of protein interactomes, which we have applied to discover ER and FoxA1 associated proteins. We find unexpected interactions between ER and additional nuclear receptors in ER+ breast cancer, which appear to be important modulators of cellular growth and endocrine response. These findings help delineate the complexes that influence ER transcriptional activity and ultimately impinge on tumor progression and drug sensitivity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-01.
Abstract P4-04-06: Systematic analysis of molecular subgroups and age in patients with breast cancer
Authors: Liedtke C , Karn T , Gluz O , Becker S , Pusztai L , Holtrich U , Rody A 
Published: August 2014

Abstract
Background: Breast cancer (BC) molecular subgroups show significant differences with regard to prognosis. Similarly, young age at diagnosis is significantly associated with an unfavorable prognosis.
Methods: Our aim was to analyze the association between BC molecular subtypes and age at diagnosis. Publically available gene expression data (Affymetrix U133A) of 3488 BC patients was analyzed using MAS5.0 and pooled into a single database. Age information was available for 2604 of the patients (74.7%). Of a total of 579 cases with TNBC, 394 samples with most comparable array data were selected to avoid batch effects as previosly described. Age information was available for 309 of these 394 patients (78.4%). Significance Analysis of Microarrays (SAM) was performed to identify genes with differential expression according to age at diagnosis in these 309 patients with TNBC.
Results: Patients &lt;40 years significantly more often presented with triple negative BC compared to patients 40-50 and &gt;50 (34.8 vs. 25.4 vs. 17.3%, respectively). In contrast, a luminal A subtype was diagnosed less often in patients &lt; 40 yrs (20.6 vs. 31.9 vs. 41.1%, respectively). Although we observed significant differences for EFS according to i) age at diagnosis and ii) molecular subtype, EFS differences between patients of distinct age were only modest after stratification for molecular subtype. Among patients with TNBC, 134 genes were upregulated and 627 genes were downregulated in patients &lt; 40 yrs compared to patients ≥ 40 yrs (median FDR &lt; 4%). Several of the downregulated genes in young TNBC patients belong to a metagene for the molecular-apocrine subtype of TNBC and several upregulated genes represent cell cycle genes. However, the effects for individual genes were rather small. Conclusion: The frequency of molecular subgroups differs with age at diagnosis. Young age at diagnosis is significantly associated with adverse prognosis. Within the group of TNBC patients young age is associated with high proliferation and a basal-like phenotype and inversely correlated with the molecular-apocrine subtype of TNBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-06.
Abstract P4-04-11: Correlation study of gene polymorphisms on 19p13.1 with triple negative breast cancer
Authors: Xu Z , Xing H , Wang L , Zhou H , Gu Y 
Published: August 2014

Abstract
Objective:The aim of this study was to investigate the association between triple negative breast cancer (TNBC) susceptibility and single nucleotide polymorphisms (SNPs) of MERIT40(c19orf62)and ANKLE1 genes located in 19p13.1, so as to find the clinical helpful molecular markers and therapeutic targets to the early detection and to guide individualized treatment.
Materials and Methods:Totally 252 patients with breast cancer diagnosed and treated in Breast Surgery Department of China-Japan Union Hospital affiliated to Jilin University were taken into the study, Among them,there were 124 cases identified as TNBC by using IHC technique, and others there were 128 cases as non-TNBC. Using common PCR assay and DNA sequencing to detect the SNPs of candidate genes. Finally, the association was analyzed between triple negative breast cancer group and non-triple negative breast cancer group with incidence and impact factors.
Results:Three genotypes were detected in rs8170,a SNP of MERIT40 gene located in 19p13.1.The frequencies of CC, CT and TT genotype in the triple negative breast cancer group and non-triple negative breast cancer group were 52.9% vs 93.5%, 41.2% vs 6.5% and 5.9% vs 0.0%.The difference of the distribution of genotypes between two groups was statistically significant (P = 0.004).Three genotypes were detected in rs2363956,a SNP of ANKLE1 gene also located in 19p13.1. The frequencies of TT, GT and GG genotype in the triple negative breast cancer group and non-triple negative breast cancer group were 35.7% vs 38.5%, 42.9% vs 53.8%and 21.4%vs7.7%.The difference of the distribution of genotypes between tow groups was no significant correlation (P = 0.464).Rs2363956 genotypes had obvious correlation with clinical stage (P = 0.005) and lymph node metastasis (P = 0.029) in non-triple negative breast cancer group, but not in triple negative breast cancer group(P = 0.323, P = 0.510).Neither rs8170 nor rs2363956 genotypes had obvious correlation with breast cancer-related immune group, such as EGFR,P53(P&gt;0.05). Logistic regression analysis showed that TT genotype of rs8170 would increase the risk of in TNBC patients (OR = 1.426,95% CI = 1.266-2.872 P = 0.024).There was no significant association between the risk of incidence and the SNPs of ANKLE1 genes. Multivariate Logistic regression analysis showed that the polymorphism of ANKLE1 rs2363956 was an independent prognostic factor with lymph node metastasis and high clinical installments in for non-triple negative breast cancer (OR = 1.228, 95%CI = 1. 104-1.908 P = 0.045), but not for triple negative breast cancer.
Conclusions :The rate of incidence is comparatively higher in TNBC patients with TT genotype of MERIT40 rs8170, which may be an important molecular markers to predict the incidence of triple negative breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-11.
Abstract P4-05-03: Unique genetic, epigenetic, and transcriptomic changes in premenopausal breast cancer suggest novel strategies for therapy
Authors: Liao G , Hartmaier RJ , Luthra S , Chandran U , McGuire KP , Puhalla SL , Lee AV , Tseng GC , Oesterreich S 
Published: August 2014

Abstract
Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM) even when controlling for prognostic variables. In particular, preM ER+ tumors have a poor prognosis on endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for finding personalized therapies for this group of women.
We analyzed gene expression, CNV, methylation, and somatic mutations in tumors from preM (≤45; ER+ n = 110, and ER- n = 39) and postM (≥55, ER+ n = 392, and ER- n = 102) women in The Cancer Genome Atlas (TCGA). Unbiased hierarchical clustering of 2,900 most variably expressed genes (using both RNA-seq and Agilent expression array data) in the whole dataset (n = 643) identified four major subtypes which correlated highly with the PAM50 defined subtypes LumA, LumB, Basal and HER2; however, there wasn't any separation between preM and postM samples. Similarly, principal component analysis using 10,000 genes with the highest inter-quartile range (IQR) demonstrated high similarity across preM and postM samples. Direct examination of gene expression differences between PreM and PostM ER+ tumors using unpaired t-test (5% FDR) identified 3,044 differentially expressed genes. The genes most upregulated in premenopausal tumors included AREG, TFPI2, MSMB, TCN1, and GLRA3. Ingenuity Pathway Analysis revealed a highly significant enrichment for TGFb (p&lt;1.9E-16) pathway activity in preM tumors. Intriguingly, no significant gene expression differences between preM and postM ER- tumors were identified. We thus then focused on genetic and epigenetic alterations that may underlie these transcriptomic changes in ER+ preM tumors.
Comparison of methylation (450K Illumina array) between preM and postM ER+ tumors showed a difference in 1% (n = 1,738) of the probes. Genes with the largest difference included ESR1, SIM2, and KLF6. Significant differences in DNA copy number variation (Affymetrix SNP 6.0 array) were also identified in ER+ preM tumors. A number of somatic mutations were significantly enriched in preM ER+ tumors including DSPP and GATA3. Integrated analysis also showed that approximately half of the observed differences in gene expression are driven by CNVs.
Conclusion: Our in silico study has identified a number of genes and pathways which are significantly altered between preM and postM ER+ breast cancer. Distinct genetic and epigenetic differences suggest unique etiology for some preM tumors. Currently ongoing Paradigm analysis, and confirmatory studies using METABRIC data are expected to further identify pathways that could specifically be targeted in premenopausal breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-03.
Abstract P4-05-05: Molecular effects of initial core biopsies in neoadjuvant window studies
Authors: Arthur LM , Turnbull AK , Renshaw L , Sabine VS , Bartlett JM , Sims AH , Dixon JM 
Published: August 2014

Abstract
Background
A growing number of studies are assessing the effects of drugs on breast cancers by investigating the molecular changes in tumours between the initial core biopsy taken at diagnosis and the excision specimen removed at surgery 2-3 weeks later. It is imperative to know if molecular profiles of tumours change over time without treatment and to assess whether the core biopsy itself influences the molecular profile. This study aimed to investigate changes in molecular profiles of breast cancer between the initial core biopsy and the excision specimen in patients who had no intervening treatment.
Methods
83 patients with paired fresh frozen tissue specimens from an initial diagnostic core biopsy and the later surgical excision biopsy have been studied. Following RNA extraction and processing, Illumina HT-12 BeadArrays were used for gene expression profiling. Samples were analysed for significant changes in gene expression and compared with a large dataset of patients treated with neoadjuvant letrozole.
Results
Analysis is on-going and results from all patients will be available by December 2013. Pairwise Rank Product analysis (false discovery rate 0.01) of the first 12 patients representing all subtypes of breast cancer (6 ER+, 4 HER2+, 2 triple negative) with a mean interval of 22.9 days (range 15 - 33 days) between specimens, identified 346 down regulated genes. Functional processes represented by these genes were; ribosomes, regulation of cell death and apoptosis, and protein complex biogenesis. Up-regulated processes (236 genes) included functions relating to regulation of transcription, mRNA processing/splicing and ECM remodelling.
No consistent changes in a 60 gene immune signature were seen across these 12 patients. Integration of this dataset with a large letrozole-treated dataset, demonstrated that less than 1% of genes that changed on-treatment with letrozole, changed without treatment.
Conclusions
This is the largest study investigating molecular profiles of the same breast cancer sampled at different times. It has shown:
· No consistent changes in expression of genes associated with wound healing and immune response 15-33 days after core biopsy
· Stability of the genetic profile of individual tumours despite multiple biopsies
· Stability in the genes that are changed by two weeks of treatment with daily letrozole.
This study provides definitive evidence of the validity of preoperative or window of opportunity molecular studies and has major implications for investigating the effects of new therapeutic drugs.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-05.
Abstract P4-05-06: Host inflammation and breast cancer molecular subtypes: Updated results from a TCGA sub-analysis
Authors: Allison KH , Chen Y-Y , Jensen KC , Sanders ME , Reis-Filho J , Lester SC , Johnson NB , Factor RE , Tse GMK , Shin SJ , Eberhard DA , Tan PH , Collins LC , Korski K , Waldman FM , Perou CM , Beck AH 
Published: August 2014

Abstract
Background: There is increasing evidence that the presence of a host inflammatory response to breast cancer may influence outcomes. Utilizing inflammation scores on the histology of breast cancer samples submitted for comprehensive molecular analyses for The Cancer Genome Atlas (TCGA), we provide an updated look at associations between the presence of host inflammation and breast cancer molecular and pathologic features.
Design: Experts in breast pathology reviewed the digital slides of breast cancer samples submitted for comprehensive molecular profiling to the TCGA and scored each case for the level of inflammation present (high/moderate vs mild/minimal). We tested pairwise associations between host inflammation and molecular subtypes (DNA copy-number, RNA expression, RPPA defined subtypes, miRNA subtypes, methylation subtypes) and pathological features by performing Chi-Square analyses. Multiple hypothesis testing correction was performed using the Bonferroni method.
Results: 598 breast cancer cases with TCGA molecular profiling data were scored by the expert breast pathologists for morphological features (including inflammation). 195 (33%) of these were scored as high/moderate inflammation. Cases with inflammation had a significantly higher rate of TP53 mutations (p = 9.0e-8) with 64 of 118 (54.2%) p53 mutant cases with inflammation. Inflammation was also significantly associated with PAM50 molecular subtypes (p = 2.2e-11), with the greatest enrichment among basal-like (64.5% of 70 basal-like cases had inflammation) and the greatest depletion among Luminal A (18.1% of 166 Luminal A cases had inflammation). Cases with inflammation were significantly less likely to be lobular (p = 1.5e-7), had less tubule formation (p = 0.0006), increased mitoses (p &lt;2.2 e-16), increased nuclear pleomorphism (p = 2.9e-15), and increased necrosis (p = 2.9e-14).
Conclusions: There are strong associations between breast cancer molecular and pathological features and the host inflammatory response.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-06.
Abstract P4-07-13: High microRNA-621 level predicts a better response to neoadjuvant chemotherapy in breast cancer patients
Authors: Xue J , Chen Y , Chi Y , Ye X , Wu Z , Wu J 
Published: August 2014

Abstract
Purpose: Weekly paclitaxel plus carboplatin (PCb) regimen is an effective neoadjuvant chemotherapy for breast cancer. However, some patients respond to this regimen poorly and suffer from side effects. In this study, we aimed to define the microRNA (miRNA) biomarker for predicting sensitivity to PCb chemotherapy in breast cancer patients, and to explore the potential molecular mechanisms.
Experimental Design: 81 patients with stages II and III breast cancer, who received four cycles of weekly PCb regimen preoperative chemotherapy, were included. Gene expression profiles from 31 patients was used as training set to determine differentially expressed genes (DEGs) and to predict miRNAs that may be associated with chemotherapeutic sensitivity. The other 50 patients were analyzed as validation set to test the accuracy of DEG identification and miRNAs prediction by quantitative real-time PCR. In parallel, in vitro and in vivo analyses were carried out to determine the potential mechanisms of miRNA-dependent drug sensitivity.
Results: Gene profiling analyses in the training set revealed significant correlation between high expression level of miR-345 and miR-621 and pathologic complete response (pCR) in breast cancer patients. We further validated that the expression level of miR-621 was significantly higher in tumor tissues of pCR patients than that in non-pCR patients (P = 0.01). In breast cancer cell lines, ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to paclitaxel and carboplatin both in vitro and in vivo. The potential miR-621-target genes were determined by TargetScan and miRNA CLIP-seq database, which were further confirmed as DEGs reversely-correlated to miR-621 in breast cancer patient samples. Among those, FBXO11 was verified as one of the direct targets of miR-621 in breast cancer cells, whose expression level negatively associated with chemosensitivity in breast cancer patients. The molecular mechanisms by which miR-621/FBXO11 axis regulates chemosensitivity may involve regulation of p53 transcriptional activity and epithelial-mesenchymal transition (EMT) in breast cancer cells.
Conclusions: Our study revealed a strong correlation between miR-621 expression and chemosensitivity in breast cancers. High level of miR-621 predicts sensitivity to PCb regimen neoadjuvant chemotherapy in breast cancer patients who tend to achieve pCR. The increased chemosensitivity may be mediated by down-regulation of FBXO11 gene, which leads to enhanced p53 transactivity and reduced EMT in breast cancer cells. Therefore, miR-621 may be used as predictive biomarker and the potential therapeutic target in breast cancer treatment.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-13.
Abstract P4-07-18: PDGFRbeta-induced miR-9 is up-regulated in triple negative breast cancer
Authors: Plantamura I , D'Ippolito E , Tessari A , Cresta S , Orlandi R , Moliterni A , Carcangiu ML , De Braud F , Tagliabue E , Iorio MV 
Published: August 2014

Abstract
miR-9 has been described as an oncogenic microRNA associated to a metastatic phenotype and able to induce EMT (epithelial-to-mesenchymal transition) through direct targeting of E-cadherin. However, data available concerning the expression and the role of this microRNA in different subgroups of breast cancer are still not exhaustive.
Evaluating miR-9 expression by Real-Time PCR in a series of 92 breast cancer specimens (35 luminal, 36 HER2, 21 triple negative), we found that this microRNA is increasingly higher in HER2 and Triple Negative versus ER positive patients (fold change 3 and 8 respectively).
Moreover, preliminary analysis of miR-9 expression in correlation with bio-pathological features and clinical data also indicates a trend in association with disease progression.
Triple Negative Breast Cancers represent a very aggressive breast cancer subgroup, still lacking specific markers for an effective targeted therapy; we investigated whether miR-9 might play a role in the biology of this tumor subtype. Preliminary data indicate that miR-9 is activated downstream PDGFRbeta, which represents a crucial player in the aggressive phenotype of Triple Negative Breast Cancer.
In summary, here we show that miR-9 is significantly upregulated in triple negative breast cancer in comparison with other breast cancer subgroups and is activated downstream PDGFRbeta.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-18.