bluuebunny/crossref_metadata_2025_split huggingface dataset:
P5-06-09: Acquired Sensitivity to TRAIL Mediated Apoptosis in Lapatinib Resistant SKBR3 Cells.
Authors: Eustace AJ , Browne BC , McDermott M , Gallagher C , Watson W , Crown J , O'Donovan N 
Published: June 2012

Abstract
Introduction Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor is approved for the treatment of trastuzumab-refractory HER2 positive metastatic breast cancer. However, not all HER2 positive tumors respond to lapatinib and patients who initially respond frequently relapse. Understanding the molecular alterations associated with acquisition of lapatinib resistance may lead to the identification of targets to overcome resistance. Thus, the aim of this study was to examine changes in apoptosis in a model of acquired lapatinib resistance.
Methods SKBR3 cells were treated with 250 nM lapatinib twice weekly for 6 months to establish the lapatinib resistant cell line SKBR3-L. The effects of TNF-related apoptosis-inducing ligand (TRAIL) and tumour necrosis factor-α (TNF-α) on cell survival and apoptosis induction were examined in SKBR3 and SKBR3-L cells, using the acid phosphatase proliferation assay and the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Cleavage of poly ADP ribose polymerase (PARP) was used to confirm apoptosis. TRAIL-1 and TRAIL-2 receptor expression were measured by flow cytometry (FACS).
Results In SKBR3-L cells, TRAIL treatment (25 ng/ml) significantly inhibited cell survival (94.0 ± 12.0 %) compared to the SKBR3 cells (11.0 ± 2.2%). Treatment with TNF-α (0.5 ng/ml) also resulted in significant inhibition of cell survival (68.2 ± 10.1 %) in SKBR3-L cells compared to SKBR3 cells (9.4 ± 9.0 %). TRAIL (25 ng/ml) induced a low level of apoptosis in SKBR3 cells (7.0 ± 4.0%), whereas in SKBR3-L cells, TRAIL (25 ng/ml) induced significant apoptosis (54.8 ± 2.6%, p &lt; 0.001), as determined by the TUNEL assay. We confirmed by western blotting that TRAIL treatment for 72 hours resulted in higher levels of PARP cleavage in SKBR3-L cells compared to SKBR3 cells. Both western blotting and FACS analysis of TRAIL receptor expression showed that neither TRAIL-1 nor TRAIL-2 receptor expression was significantly elevated in SKBR3-L cells compared to SKBR3 cells.
Conclusions SKBR3-L cells, a model of acquired lapatinib resistance, display significant sensitivity to TRAIL induced apoptosis compared to the parental cell line SKBR3. Thus, targeting TRAIL may represent a novel therapeutic strategy to overcome acquired lapatinib resistance.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-09.
P5-07-05: Hypoxic Mammary Epithelial Cells in Three-Dimensional Culture Develop a Cancer-Like Phenotype.
Authors: Vaapil M , Helczynska K , Påhlman S , Jögi A 
Published: June 2012

Abstract
Due to inadequate vascularization and tumor cell proliferation solid tumors are hypoxic compared to corresponding normal tissues. Tumor hypoxia has been associated with increased metastatic potential and worse patient outcome. The hypoxic response is mainly driven by the hypoxia inducible transcription factors; HIF −1α and HIF-2α. We have reported that hypoxia leads to a less differentiated phenotype in breast cancer and neuroblastoma, and in the clinic low tumor cell differentiation is related to poor prognosis in these diseases. We have shown that high levels of HIF-2α protein correlate to distant metastasis and poor survival in invasive breast cancer. The aim of the present study was to investigate the effect of hypoxia on mammary epithelial cell differentiation and epithelial organization. We employed the well-characterized model of acinar morphogenesis on extra cellular matrix substrate. In this model mammary epithelial cells that are cultured in three-dimensional culture on a laminin-rich matrix differentiate and form acini-like structures with evacuated lumen surrounded by polarized palisade cells. We found that hypoxia (1% oxygen) impaired the process of acinar morphogenesis and the hypoxic cells failed to obtain polarity and that markers of differentiation were affected at expression levels as well as cellular localization. The hypoxic cells remained proliferative whereas normoxic cells lost Ki-67 expression within a week. We found that hypoxia impaired the global histone deacetylation that has been shown by others to take place in the process of acini formation in mammary epithelial cells. Three days post-seeding, during the proliferation stage, both normoxic and hypoxic cells stained positive for acetylated histone 4. When the normoxic cells went through morphological changes and acinar formation, the acetylation of histone 4 was reduced whereas it was maintained in the hypoxic cell-clusters at day 10 post-seeding. Thus, the hypoxic conditions maintained the epithelial cells in an acetylated state, which is generally associated with an open chromatin structure, high level of transcription and an undifferentiated stage. These data indicate that hypoxia promotes loss of differentiation also at a non-malignant stage and render the cells a cancer-like phenotype. We are currently extending this study in primary cells.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-05.
P5-08-06: Comparison of Mammographic Density between Ductal Carcinoma In Situ and Benign Breast Disease.
Authors: Lee JW , Shin EJ , Yi OV , Lee JW , Shin HJ 
Published: June 2012

Abstract
Background: High breast density is an independent risk factor for breast cancer as well as benign breast diseases. However there are few studies about breast density of ductal carcinoma in situ (DCIS) and benign breast disease(BBD). In this study, we investigated patterns of breast density of DCIS and BBD, and comparatively analyzed breast densities of DCIS and BBD.
Material and Methods From 2008 to 2009, 345 patients underwent surgery for DCIS at Asan Medical Center, and 295 patients for BBD at 2010. We retrospectively reviewed each groups and estimated cranio-caudal view of digital mammogram of unaffected breast by computer-assisted thresholding methods, using Cumulus 4, version 4.0. For BBD we included atypical ductal hyperplasia, fibroadenoma, papilloma(atypical/intraductal), phyllodes tumor(benign/borderline), and excluded unavailable mammogram(mostly, because of scanned films from outside hospitals and previously diagnosed breast cancer).
Results Mean ages of each group were 46.51 year old in DCIS group and 41.43 year old in BBD group, and the mean percentage density(PD) were 44.89% and 45.27%, respectively.

There was no significant difference between two groups in total population(p=0.79). We categorized into two groups according to the age, ≥50 and &lt;50, for each DCIS and BBD group. Mean percentage density of below 50 year old was 52.92% in DCIS gruop and 49.58% in BBD group(p=0.031). Mean percentage density above 50 year old was 33.67% in DCIS group and 33.29% In BBD group(p=0.867).

Conclusion The mean values and distribution patterns of PD were similar between BBD group and DCIS group. However, in the subgroup aged under 50, the DCIS group has significantly higher breast density than the BBD group. Although the causal association of breast density with breast cancer has been relatively well documented, this kind of cross-sectional study has an inherent limitation. The absolute difference between the DCIS group and the BBD group under age 50 (3.34% in table2) needs more investigation for its clinical implications.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-06.
P5-10-02: Relevance of Magnetic Resonance Imaging To Predict Disease-Free Survival after Neoadjuvant Chemotherapy of Breast Cancer.
Authors: Loo CE , Vrancken Peeters M-JTFD , Wesseling J , Gilhuijs KGA 
Published: June 2012

Abstract
Purpose: To explore the relevance of magnetic resonance imaging (MRI) to predict disease free survival (DFS) after neoadjuvant chemotherapy (NAC) of breast cancer.
Patients and Methods
Between July 2000 and December 2007, MRI examinations were performed in 188 women before, during and after NAC in the context of a single-institution review board approved study. Patients were consecutively included after informed consent. Interpretation of MRI was revised by an experienced breast MR radiologists and included assessment of lesion morphology, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement).
MRI features and known prognostic markers of breast cancer (age, tumor response at pathology, tumor size at baseline, immunohistochemistry-derived breast cancer subtype (triple-negative; HER2−positive or ER-positive/HER2−negative)) were correlated with DFS. Multivariate Cox regression analysis was used with forward LR feature selection. Kaplan Meier curves were obtained to explore the impact of relevant associations.
Results: Follow-up data were available of 184 women. The median follow-up time was 57,6 months (range 32,4 — 125). In 30 women events were found (26 breast cancer related deaths; 29 distant metastasis and 12 local/regional recurrences).
At multivariate analysis, only breast cancer subtype (p=0.004) and largest diameter of late enhancement at MRI after NAC (p=0.006) retained prognostic value in favour of response at final pathology, age and tumor size at baseline. Cumulative survival at 60 months (kaplanmeier curves) was 70%, 86.7%, and 89.7% for triple-negatives, HER2−positive and ER-positive/HER2−negative subtypes [figure 1], respectively, and 88.5%, 81.4 % and 55.1% for absence of washout/plateau after NAC, between 0 and 30 mm washout/plateau, and ≥ 30 mm washout/plateau, respectively [figure 2].
Conclusions MRI after NAC in conjunction with breast cancer subtype has potential as complementary predictor for DFS. Larger diameters of residual late enhancement at MRI after NAC are associated with inferior DFS at 60 months.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-10-02.
P5-11-04: A New Immunohistochemistry-Based Assay SBrC5 Classifies Invasive Breast Cancer Subtypes – Profiling Five Biomarkers in One Single Test.
Authors: Liu H , Muralitharan S 
Published: June 2012

Abstract
Background: Obtaining expression status of estrogen receptor (ER), progesterone receptor (PR) and Her2 is essential for guiding treatment and predicting outcome for breast cancers. By adding cytokeratin 5/6 and EGFR to the above mentioned three common biomarkers, a five-biomarker breast cancer panel has been validated in previous studies for identifying the basal-like subtype with superior prognostic values than the triple negative subtype1. The current study aimed to evaluate a new immunohistochemical assay, named Subtyping Breast Cancers 5-in-1 Assay (abbreviated as SBrC5, or “the assay” in this poster), for classifying breast cancer subtypes.
Material and Methods: A cocktail of ER, PR, Her2, cytokeratin 5/6 and EGFR antibodies (SBrC5 Cocktail) and the MultiVision Detection Kit (TFS Cat. #: TL-012-MARH) were used in generating the data for this poster. The Multivision Detection Kit is a double staining system with two visualizing colors, red and blue. The assay was performed on a breast cancer tissue microarray containing 75 cases in duplicate. Both color and cellular localization of the staining generated from the assay was used for the result interpretation. There were three staining clusters: 1) Red Nuclei indicated ER or PR positive; 2) Red Membrane indicated Her2 expression; and 3) Blue Membrane or Cytoplasm indicated EGFR or cytokeratine 5/6 positivity respectively. The same breast cancer tissue microarray was also subjected to individual IHC tests of ER, PR, Her2, cytokeratin 5/6 and EGFR. The concordance between the assay and the individual tests was analyzed.
Results: The assay SBrC5 was found to have excellent effectiveness in detecting ER or PR positivity, Her2 over expression, and cytokeratine 5/6 or EGFR positivity. The concordance for the assay when compared to the individual tests for each biomarker were 94.1%, 93.8% and 92.4% for Her2, combined results of ER and PR, and combined results of cytokeratine 5/6 and EGFR respectively. When a similar comparison was made, the sensitivity was 87.9%, 94.3% and 73.7%; the specificity was 100%, 93.1% and 100%.
Discussion: This study has demonstrated that a single test of the assay SBrC5 was able to accomplish the collective task of the individual IHC tests of the five-biomarker breast cancer panel. The assay is able to provide sufficient information for classifying breast cancer subtypes with only a single IHC test. Thus it makes it possible to obtain subtypes information in biopsy settings where the tumor tissue obtained is often insufficient for multiple tests required to accomplish such task by existing methods.
Reference: Maggie C.U. Cheang, David Voduc, Chris Bajdik, et al. Clin Cancer Res March 1, 2008 14; 1368.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-04.
P5-13-16: Reduction in PET Uptake-Value Is an Early Predictor for Response to Neoadjuvant Therapy Including Anthracycline and Taxane in Stage II-IIIa Breast.
Authors: Lao Romera J , Puértolas Hernandez T , Godoy Molias A , Alvarez Alejandro M , Madani Perez J , Garcia Mur C , Ubieto MA , Cebollero de Miguel A , Artal Cortes A , Anton Torres A 
Published: June 2012

Abstract
Background and Aim: Reduction in FDG-PET uptake as response predictor after induction chemotherapy for breast cancer has been described. Our aim was to determine whether a SUV reduction ≥45% in the breast lesion could accurately predict pathological Complete Response (pCR).
Material and Method: Stage II-IIIa breast cancer patients (p) with primary tumor ≥3cm or positive axilla were included provided they were amenable to neoadjuvant chemotherapy with Docetaxel-Doxorubicin-Cyclophosphamide (TAC). A FDG-PET scan was performed on day −1 of the first course and was repeated on day+8 of the same course. SUV-uptake differences (day 8 minus day −1) were correlated to the eventual pathological response according to Miller-Payne criteria.
Results: 42p were included. Median age was 45 years (30-66). 11p (26.2%) were triple-negative tumors. 2p (4.8%) were Her-2 +. By stage, 13p (30.9%) were IIA, 17p (40.4%) IIB and 12p (28.2%) IIIA. 23p (54.7%) were N+ (FNAB positive). Median breast-SUV on first PET scan was 5.51 (1.3−18.50). 40p (95.2 %) completed the scheduled 6 courses. 41p (97.6%) were submitted to surgery. 11p (26.2%) achieved a pCR. 40p (95.2%) were evaluable for the primary objective. 1p (0.02%) died of disease progression before surgery and 1p (0.02%) with pCR could not be assessed by PET. 7 out of 14 p (50%) with uptake reduction ≥45% with respect to the basal value, and 3/26p (11.5%) whose reduction was &lt;45% achieved a pCR (p=0.007). SUV decrease &gt;45% accurately predicted 7/10 pCR (70%) that could be assessed.
Conclusions: Our study confirmed the value of PET-SUV reduction on day 8th as an early predictor of pCR with neoadjuvant TAC chemotherapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-16.
P5-13-23: Individualized Treatment Strategies for HER2−Negative Breast Cancer Subtypes.
Authors: Ishikawa T , Shimizu D , Yamada A , Sasaki T , Morita S , Tanabe M , Kawachi K , Nozawa A , Chishima T , Kimura M , Ichikawa Y , Endo I 
Published: June 2012

Abstract
Background Human epidermal growth factor receptor (HER2)-negative breast cancers are more heterogeneous than HER2−positive cancers, and tailored treatment is therefore required for luminal A and triple-negative breast cancer subtypes (LABC and TNBC). We therefore examined predictive factors for the efficacy of standard chemotherapy in LABC and TNBC subtypes.
Methods A total of 109 LABC and 61 TNBC patients were treated with standard neoadjuvant chemotherapy (NAC) consisting of an anthracycline and/or taxane. The pathological treatment response and prognosis were examined for each subtype. Expression levels of the following factors were examined in association with quasi-pathological complete response (QpCR): estrogen- and progesterone-receptor (ER and PgR) status, HER2, nuclear grade, MIB-1, p53, topoisomerase IIα (topoIIα), cytokeratin (CK) 5/6 and epidermal growth factor (EGFR).
Results QpCR rates in LABC and TNBC were 9.1% (10/109) and 54.1% (33/61), respectively. In LABC, the expression of PgR tended to be inversely associated with pathological response (p=0.087), while in TNBC, increased expression of topoIIa (p=0.006) and MIB-1 (p=0.018) were identified as predictors of QpCR. TopoIIα expression was also significantly associated with pathological response in multivariate analysis (p=0.014). The QpCR rate was higher in TNBC lacking CK5/6 and/or EGFR expression, defined as non-basal subtype (p=0.053).
Conclusions Low expression of PgR may be a possible predictor of the efficacy of chemotherapy in LABC, while a high level of proliferative activity, indicated by topoIIa and MIB-1, is associated with chemosensitivity in TNBC. Further subclassification into basaland non basal-subtypes may also be helpful for the development of individualized treatments.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-23.
P5-14-06: Interaction between Stoma and Tumor Characteristics as a New Prognostic and Predictive Marker in Breast Carcinomas.
Authors: Tagliabue E , Sandri M , Casalini P , Aiello P , Pupa SM , Orlandi R , Balsari A , Triulzi T 
Published: June 2012

Abstract
Background. We recently demonstrated that primary breast tumors can be classified based upon extracellular matrix composition (ECM) (Bergamaschi et al.) suggesting stroma characteristics could influence tumor progression.
Aim of this study is to further investigate the robustness of this classification and its impact in tumor progression and response to therapy.
Methods. The expression profile of ECM-related genes was analyzed by unsupervised hierarchical clustering in 10 independent datasets of breast tumors, counting more than 1000 samples and the prognostic and predictive value of this signature were evaluated in two datasets of not treated patients and in one dataset of neo-adjuvant treated patients, respectively.
Results. Only one of ECM subsets (ECM3) showed a homogeneous gene pattern that consistently allowed the classification of an independent group of tumors in all tested datasets. ECM3 is characterized by highly correlated over expression of 34 ECM genes encoding mainly structural proteins. From 24 to 38% of cases were ECM3-enriched and were mainly estrogen receptor-positive and low grade (p&lt;0.0001). The ECM3 showed inconsistent association with DMFS in the two data sets of not treated patients, whereas the interaction between ECM3 and grade showed strongly and significant association with DMFS (HR=5.35, p=0.0012). In particular, multivariate analysis of covariates available (size, ER, age and ECM) indicated that ECM3 is significantly associated with worse DMFS in grade III patients (HR=2.5, p=0.0386), whereas it is slightly correlated with better DMFS in grade I-II patients (HR=0.6, p=0.088). It is noteworthy that the probability of 10-year DMFS was 90% in ECM3 versus 74% in non-ECM3 patients in differentiated tumors, and 75% in non-ECM3 versus 41 % in ECM3 grade III tumors. The interaction between ECM3 and grade remained significantly associated with DMFS also in ER negative (HR=14.2, p=0.03) and ER positive (HR=3.34, p=0.079) subgroups. ECM3, indeed, was correlated with good and bad prognosis in differentiated and grade III tumors, respectively.
Moreover analysis of a data set of patients treated neoadjuvantly with chemotherapy revealed that, among the grade III tumors, pathological complete response was reached by 9% of ECM3 versus 74% of non-ECM3 tumors (p=0.04). In differentiated tumors no response difference was observed according to ECM.
Conclusions. Our results provide evidence that breast carcinoma progression and response to therapy are influenced by the interaction between tumor and stromal characteristics.
(Partially supported by AIRC).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-06.
P5-14-15: Prognostic Impact of Chemotherapy-Induced Amenorrhea (CIA) in Premenopausal Breast Cancer: A Meta-Analysis of Published Literatures.
Authors: Lu J , Zhou Q , Yin W 
Published: June 2012

Abstract
Background: Various studies have reported inconsistent results on the prognostic effect of chemotherapy-induced amenorrhea (CIA) in premenopausal breast cancer. Therefore, we conducted a meta-analysis to assess the effect of CIA on prognosis of premenopausal women with breast cancer.
Methods: The PubMed database was searched for all relevant studies published before March 2011. Relative risks (RRs) were used to estimate the association between CIA on various survival outcomes. Subgroup analyses were also performed by age, nodal status and hormone receptor (HR) status.
Results: With thirteen eligible studies identified, this meta-analysis included 5790 cases and 2159 controls. This meta-analysis demonstrated that CIA was associated with improved DFS (RR= 0.39, 95%CI: 0.32∼0.47, p&lt;0.001) and OS (RR= 0.30, 95%CI: 0.21∼0.44, p&lt;0.001). In the subgroup analyses, the effect of CIA on DFS and OS also existed in HR-positive subjects (for OS, RR= 0.19, 95%CI: 0.07∼0.49, p=0.001; for DFS, RR= 0.47, 95%CI: 0.35∼0.63, p&lt;0.001) while similar results failed to be observed in HR-negative patients (for OS, RR= 0.62, 95%CI: 0.07∼5.75, p=0.671; for DFS, RR= 1.48, 95%CI: 0.50∼4.37, p=0.474). Furthermore, significant difference was achieved between women with and without CIA, irrespective of age and nodal status.*** Conclusion: This meta-analysis clarifies that CIA might contribute to the improvement of prognosis in HR-positive premenopausal breast cancer patients, which is at least partially responsible for the benefit of adjuvant chemotherapy in premenopausal women through chemical castration.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-15.