bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-02-02: Prognostic significance of the ratio of absolute neutrophil to lymphocyte counts for breast cancer patients in neoadjuvant setting
Authors: Koh YW , Lee HJ , Ahn J-H , Lee JW , Gong G 
Published: August 2014

Abstract
Background: The baseline absolute neutrophil count/absolute lymphocyte count ratio (NLR) has potential prognostic importance in solid tumors, including breast cancer. However, NLR as a predictive factor of the pathologic complete response (pCR) or as a prognostic factor has not been fully studied in breast cancer patients who have received neoadjuvant chemotherapy.
Materials and Methods: Using receiver operating characteristic curve analyses, we retrospectively examined the predictive and prognostic impact of the NLR at the diagnosis in 401 patients with primary breast cancer who were treated with neoadjuvant chemotherapy, followed by definitive surgical resection. Of the 401 included patients, 72 (18%) received anthracycline-based, 285 (71%) received anthracycline- and taxane-based, 37 (9.2%) received herceptin-based, and 7 (1.7%) received fluorouracil-based regimens. The significance of NLR was analyzed according to clinicopathologic variables and clinical outcomes.
Results: Forty-three (10.7%) patients achieved pCR. On univariate analysis, high NLR (&gt; 2.2) correlated with poor recurrence-free survival (RFS; P = 0.001) and overall survival (OS; P = 0.003). Subgroup analysis of the non-pCR group showed that NLR was significant for RFS and OS (P = 0.002 and P = 0.007, respectively). Multivariate analysis showed NLR to be an independent prognostic factor for RFS and OS (P = 0.002 and P = 0.007, respectively).

Subgroup analysis of the pCR group showed that patients with high NLR have a higher recurrent rate than low NLR (30.8% vs. 13.3%). The NLR was not related to pCR (P = 0.098).
Conclusion: Our results suggest that the NLR is an independent prognostic factor for RFS and OS in breast cancer patients receiving neoadjuvant chemotherapy and may provide additional prognostic information for patients not achieving a pCR to determine who might profit from further therapy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-02-02.
Abstract P2-04-05: Prolonged targeted overexpression of Aurora-A in mammary epithelium promotes mammary adenocarcinoma with genomic instability
Authors: Treekitkarnmongkol W , Katayama H , Sen S 
Published: August 2014

Abstract
Aurora kinase-A (referred to as Aurora-A) identified as a sereine/threonine kinase induces mitotic progression process including centrosome amplification, bipolar spindle formation and chromosome segregation through modulation of activity and localization of its interacting proteins during cell division. Beside its essential roles in mitosis, cancer profiling studies have revealed that Aurora-A function is implicated in tumor relevant signaling pathways and overexpressed in many human tumors. The findings showed highly frequent overexpression of Aurora-A in human breast ductal carcinoma in situ and primary invasive ductal breast carcinoma. Moreover, the Aurora-A overexpression correlates with poor prognosis in breast carcinoma, deregulated overexpression of Aurora-A associates with centrosome anomalies and chromosome instability in rodent models of mammary caricinogenesis.
However, published studies in several transgenic mouse models attempting to address the role of Aurora-A in tumorigenesis and genomic instability have raised conflicting results. In this report we targeted expression of Aurora-A transgene in an inducible mouse model in which expression of Aurora-A was restricted to mammary epithelium during multiple pregnancy and lactation cycles under the activity of β-lactoglobulin promotor. The results demonstrate that overexpression of Aurora-A could induce tumorigenesis in mouse mammary epithelium. The tumor incidence was 70% of Aurora-A transgenic mice at 16 months of age. Of note, overexpression of Aurora-A led to genomic instability. Comparative genomic hybridization (CGH) array analyses revealed loss of Trim12a, Trim12c, Trim30b, Trim30d, Trim30e, Cdkn2d, Pten, Cep55 and gain of Adam6. Notably, Aurora-A overexpression caused nuclear accumulation of cyclin D1, activation of AKT, overexpression of TPX2 and PLK1and loss of ERα expression in tumors. Our findings indicated that prolonged Aurora-A expression in mammary epithelium leads to mammary adenocarcinomas with genomic instability. Aurora-A driven adenocarcinoma reveals deregulation of critical tumor relevant genetic pathways involving both oncogenes and tumor suppressor genes. These transgenic mouse model findings indicate that Aurora-A may be an important therapeutic target for mammary cancer.
Keywords: Aurora-A, carcinogenesis.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-05.
Abstract P2-04-07: Modeling orthotopic and metastatic progression of mammary tumors to evaluate the efficacy of TGF-β inhibitors in a pre-clinical setting
Authors: Biswas T , Yang J , Zhao L , Sun L 
Published: August 2014

Abstract
Preclinical models are elemental in understanding drug efficacy and safety in vivo. Many existing models of breast cancer metastasis use immune compromised animals and do not effectively characterize the differential stages of metastasis. Transforming growth factor-β (TGF-β) has been shown to be a major contributor in epithelial-mesenchymal transition and enhances various steps during metastasis.
The aim of this study is to develop mouse models of tumor metastasis using murine mammary cells in a syngeneic background. This will help illustrate the effect of TGF-β inhibitors on metastasis in an immune competent environment, and also allow determining the optimal time of drug administration. We demonstrate that TGF-β signaling has differential effects on a pair of murine mammary cell lines derived from PyMT tumors in C57Bl/6 mice. These cell lines represent luminal (Py 230) and basal (Py 8119) epithelial cell populations in the tumor. In vitro characterization revealed differences in viability, motility, and transcriptional and translational activation of Smad. Py 230 (clonal luminal) cells are growth inhibited and exhibit epithelial-mesenchymal transition on treatment with TGF-β, whereas Py 8119 (basal cells) are non-responsive to both effects. Furthermore, intra cardiac injections were performed using luciferase-GFP labeled PyMT cells in syngeneic background and animals were treated with either placebo or TβRI-KI (kinase inhibitor for TGF-β receptor I). Results from Py 8119 cell injections showed that TβRI-KI treatment enhanced bone and brain metastases. Further results will shed light on the effect of TβRI-KI during specific stages of metastasis progression.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-07.
Abstract P2-06-05: Single-cell RNA sequencing of paclitaxol-treated breast cancer cell lines to find individual cell response
Authors: Vaske CJ , Lee W , Benz SC , Sanborn JZ , Emerson BM , Pourmand N , Lopez Diaz F 
Published: August 2014

Abstract
Cancer treatments act on a population of cells, each of which may experience different individual responses to treatment. Such differential response will result in resistance to treatment even if a majority of cancerous cells are eliminated. To examine differential cell response, we simultaneously profiled the gene expression and mutation spectrum of individual cells from the MDAMB231 cell line using next generation sequencing of isolated RNA. A total of 23 transcriptomes were characterized from paclitaxel-treated and paclitaxel-surviving cells. We found significant different changes in mutation rates between paclitaxel treated cells, with a dose-dependent increase in single nucleotide changes in RNA in paclitaxel-treated cells. Cells undergoing exposure to paclitaxel also showed higher pathway activity in SRC, as well as an integrin switch from ITGB1 to ITGB3. In contrast, cells that survived a high dose of paclitaxel showed an insignificant number of single nucleotide changes, suggesting that these cells either evaded initial paclitaxel exposure or were better able to repair the effects of paclitaxel exposure. Despite the RNA sequence similarity between surviving and untreated cells, there were changes in gene expression and pathway activities including higher PI3K activity. Paclitaxel-surviving cells also showed activation of pathways associated with higher proliferation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-05.
Abstract P2-06-07: Exome sequencing identifies somatic mutations in basal-like breast cancer before and after neoadjuvant chemotherapy
Authors: Jiang Y-Z , Yu K-D , Shao Z-M 
Published: August 2014

Abstract
Purpose: Among the five breast cancer subtypes, basal-like breast cancers (BLBCs) have drawn much attention, because they are associated with poor clinicopathological features, lack of effective treatment targets, and have poor prognosis. We designed the experiment to test the hypothesis that significant mutational evolution of BLBCs might occur during chemotherapy.
Methods: We performed exome sequencing (100-fold coverage) to examine the exomes of 11 paired BLBC samples (pretreatment tumor biopsies and posttreatment tumors). The molecular subtype of BLBC was proven by gene-expression profile as well as by immunohistochemistry assay. Firstly, we sequenced the tumor genomic DNA obtained before and after neoadjuvant chemotherapy and their matched normal breast tissues. After analyzing and comparing potential somatic single nucleotide variations (SNVs) and insertions & deletions (indels), we focused on the functional mutations in certain genes or pathways. Furthermore, after validation of the mutations by Sanger sequencing, we investigated their biological functions (e.g. drug-resistance, cell proliferation, etc.).
Results: Compared with pretreatment biopsies, analysis of whole-exome sequence data identified and validated TEKT4 (tektin 4) — a constitutive protein of microtubules in cilia, flagella, basal bodies and centrioles — as a significantly mutated gene in posttreatment tumors with a mutation frequency of approximately 17.6% in an independent extension cohort of 84 paired BLBC samples. TEKT4 mutations are biologically relevant, as ectopic expression of mutant TEKT4 increased paclitaxel resistance of BLBC cell lines both in vitro and in vivo. Additionally, compared with the normal breast tissues, 16 significantly mutated genes were identified and validated in the paired cancer samples, including TP53, ARID1A, BEND5, LCT, COL4A4, GAP43, COL6A6, LOC728369, STAP1, KCNK17, LZTS2, TST, IL9R, HDLBP, RASL11A and FAM22D. These genes have functions that could be broadly grouped into five biological classes: (i) MAPK signaling, (ii) PI3K/AKT signaling, (iii) cell cycle, (iv) metabolism and (v) loss of genome stability.
Conclusion: Our data reveal the novel concept that significant evolution might occur during chemotherapy and mutational heterogeneity could be a property of BLBCs. In addition, the identification of somatic mutations as biomarkers for pCR (pathologic complete remission) prediction and prognosis might help us optimize choice for sequential therapy and improve patients' survival. Prospective clinical trials based on these findings might illustrate the drug-resistant mechanism and identify resistance pathways that can be exploited for therapeutic selection.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-07.
Abstract P2-09-04: DNA methylation landscapes in ER-negative breast cancer
Authors: Worsham MJ , Chen KM , Chitale D , Divine G 
Published: August 2014

Abstract
The biological significance of DNA methylation in the regulation of gene expression and its role in cancer is increasingly recognized. The underlying hypothesis of this study is that strategic global approaches will identify aberrantly methylated genes that underlie the pathogenesis of ER-negative (ER−) breast cancer (BC). We used the Infinium HumanMethylation450 BeadChip to profile the methylome of ER− breast cancers. The 450K array includes 485,577 cytosine positions of the human genome. From these cytosine sites, 99.3% are CpG dinucleotides.
Whole genomic DNA from 20 primary ER− and 8 normal breast tissue samples were assayed for genome-wide methylation using the Illumina 450K array. We had 8634 hypermethylated CpGs or 1.8% of the 485,577 sites on the 450K array. The proportion with hypermethylation was higher for promoter regions (2.1% vs 1.5%), and highest for the “FirstExon” promoter subregion. Of the 8634 CpGs, 2980 (adjusted p = 0.05) were differentially methylated between tumor and normal samples. This resulted in 206 genes with significant hypermethylation (all mean breast cancer betas &gt;= −0.2, and ratio of tumor to normal mean beta &gt;= 2.0).
Estrogen receptor-negative BC is a more aggressive form than ER positive BC with approximately double the incidence in African Americans than in Caucasian Americans. The emerging differential methylation pattern within hormone receptor negative breast cancers would further help stratify them into distinct subgroups. Promotor methylation being potentially reversible, methylated genes may serve as future molecular targets for demethylating therapies.
Support: Komen Foundation: KG110218
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-09-04.
Abstract P2-10-02: Clinical validation of the PAM50 risk of recurrence (ROR) score for predicting residual risk of distant-recurrence (DR) after endocrine therapy in postmenopausal women with ER+ early breast cancer (EBC): An ABCSG study
Authors: Gnant M , Filipits M , Mlineritsch B , Dubsky P , Jakesz R , Kwasny W , Fitzal F , Rudas M , Knauer M , Singer C , Greil R , Ferree S , Storhoff J , Cowens JW , Schaper C , Liu S , Nielsen T ,   the ABCSG
Published: August 2014

Abstract
Aim: To assess the performance of the ROR score in predicting DR for postmenopausal patients with ER+ EBC treated with tamoxifen or tamoxifen followed by anastrozole when the PAM50 test is performed in a routine hospital pathology laboratory.
Background: The multi-analyte gene-expression tests (Oncotype DX, MammaPrint) that are currently used in clinical practice to assess prognosis after endocrine therapy in primary ER+ breast cancer are performed in a central referral laboratory. PAM50 is a 50-gene test in development that is designed to be performed in local routine hospital pathology laboratories and has been optimized to separate intrinsic disease subtypes which are used to generate a ROR score. This ROR score has been clinically validated and demonstrated to contain more prognostic information than Oncotype Dx RS in the TransATAC patient population (Dowsett, SABCS, 2011).
Methods: 1,251 women from the prospective randomized ABCSG-8 trial were entered into this study: the entry criteria were the availability of their FPET block and informed consent. Three unstained 10 micron sections and 1 H&E slide for each patient were sent to an independent academic pathology laboratory at BCCA where tissue review, manual micro-dissection and RNA extraction were performed. PAM50 analysis was then conducted on 250 ng of the extracted RNA using the NanoString nCounter® technology: both intrinsic subtype and ROR score were calculated. The median follow up of the patients entered into this study is 10 years. 912 are node negative and 339 are node positive. The baseline characteristics of the patients entered showed them to be a representative sample of the overall ABCSG-8 trial population. The primary analysis is designed to test whether the continuous ROR score adds prognostic value over and above the standard clinical variables, using a likelihood ratio test.
Results: Results are currently being derived and will be presented in full at SABCS.
Discussion: This large clinical trial serves both as a clinical validation study of the PAM 50 test and as a demonstration that a complex multi-analyte gene-expression test can be performed in a routine hospital pathology laboratory while meeting the same quality metrics as a central referral laboratory. The results of the primary analysis, when combined with the results already reported from the Trans ATAC population, yield Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC and form the basis of the design of the clinical utility studies of the PAM 50 test.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-02.
Abstract P2-10-09: The incidence of false negative of HER2/Neu status in primary breast cancer in the era of standardized testing: a Canadian prospective study.
Authors: Hanna W , Barnes PJ , Chang MC , Gilks B , Magliocco A , Rees H , Robertson S , SenGupta SK , Nofech-Mozes S 
Published: August 2014

Abstract
The efficacy of trastuzumab in the treatment of primary breast cancer has mandated accurate and timely testing of all patients with a new diagnosis of breast cancer. Testing is centralized in designated laboratories across Canada with adherence to guidelines and mandatory participation in quality assurance programs. The Canadian testing algorithm recommends starting with immunohistochemistry (IHC) followed by in situ hybridization (ISH) for equivocal cases. Early HER2 testing showed that approximately 25–30% of invasive breast cancer is HER2 positive. Recent data shows that the HER2/neu positive rate in breast cancer in Canada is 17.6%.
Design: The study was designed to assess the rate of false-negative HER2 tests based on the IHC-first algorithm used in 8 pathology centres across Canada. Surgical excisions with invasive carcinoma were tested using the standardized local methodology for both IHC and ISH. The cases were scored by the local breast pathologist and in 2 of 8 centers image analysis was used in the evaluation of ISH. We compared consecutive HER2-negative IHC results (score 0/1+) to the corresponding ISH (either silver or fluorescence) result. False negative cases were defined as a negative IHC with an ISH ratio of≥ 2, since these patients are eligible for trastuzumab therapy.
Results: 715 cases were analyzed by IHC using Ventana 4B5 (287), HercepTest (253), or SP3 (175), and by ISH kits: Vysis FISH (303), Ventana SISH (412). The HER2 and CEP17 counts were available in all cases.
There were 4 cases with an ISH score ≥2 (4B5: 2/4, HercepTest 1/4, SP3 1/4). In 3 additional cases the absolute HER2 copy number was ≥6 but the HER2/CEP17 amplification ratio was &lt;2 due to an increased number of CEP 17 signal (“polysomy 17”) or amplification of the pericentromeric region. The overall rate of false negative cases was 0.98% (7/715). These cases had a low level of amplification (ratio 2 to 2.45) or an absolute HER2 count of 6–8.
Conclusion: Our observation confirms that IHC is an adequate test to predict negative HER2 status in primary breast cancer in surgical excision specimens, even when different antibodies and IHC platforms are used. The study supports and justifies the Canadian algorithm of IHC followed by ISH in equivocal cases in view of the extremely low percentage of false negative cases observed. This reflects the strict adherence to internal protocols and mandatory participation in quality assurance programs. These results provide further confirmation that the vast majority of patients eligible for trastuzumab are not deprived from an effective treatment by using this algorithm.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-09.
Abstract P2-10-13: CD4 positive tumor-infiltrating lymphocytes are associated with improved prognosis in node-negative breast cancer
Authors: Schmidt M , van de Sandt L , Boehm D , Sicking I , Battista M , Lebrecht A , Solbach C , Koelbl H , Gehrmann M , Rahnenführer J , Hengstler JG 
Published: August 2014

Abstract
Background: The prognostic significance of CD8 positive cytotoxic lymphocytes in breast cancer is well accepted. However, the role of CD4 positive lymphocytes is ambiguous. We examined the prognostic relevance of CD4 positive tumor-infiltrating lymphocytes in previously published node-negative breast cancer cohorts using RNA expression.
Methods: Microarray based gene-expression data for CD4 (203547_at) were analyzed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CD4 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes (ER+/HER2−, ER−/HER2−, HER2+). Independent prognostic relevance was analyzed using multivariate Cox regression.
Results: Higher RNA expression of CD4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.66, 95% CI 0.49–0.90, p = 0.0074). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.32, 95% CI 0.14–0.75, p = 0.0091) as compared to ER+/HER2− (HR 0.62, 95% CI 0.29–1.32, P&gt;0.05) and ER−/HER2− (HR 0.61, 95% CI 0.28–1.35, P&gt;0.05) carcinomas of the breast. CD4 showed independent prognostic significance (HR 0.60, 95% CI 0.37–0.96, p = 0.032) in multivariate analysis. In addition to CD4, only histological grade of differentiation (HR 2.43, 95% CI 1.50–3.94, P &lt; 0.001) and tumor size (HR 1.87, 95% CI 1.19–2.94, p = 0.007), but not age, HER2 status or hormone receptor status retained an independent prognostic association with MFS.
Conclusion: CD4 positive tumor-infiltrating lymphocytes have independent prognostic significance in node-negative breast cancer. A higher expression is associated with improved outcome.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-13.