bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4-20-01: Multicentric Phase II PACS 09/Beverly1 Trial: First Efficacy and Safety Results of Neoadjuvant Chemotherapy Combined with Bevacizumab in HER2−Negative Patients with Non-Metastatic Inflammatory Breast Cancer.
Authors: Viens P , Petit T , Dalenc F , Pierga JY , Delozier T , Romieu G , Bonneterre J , Ferrero J-M , Kerbrat P , Mouret-Reynier M-A , Bachelot T , Soulie P , Lerebours F , Eymard J-C , Deblock M , Lortholary A , Hardy-Bessard A-C , Boher J-M , Asselain B , Charafe-Jauffret E , Lemonnier J , Martin A-L , Andre F 
Published: June 2012

Abstract
Background: Inflammatory breast cancer (IBC) is a relatively rare form of breast cancer. Because this disease exhibits angiogenic properties, bevacizumab (BEV) may improves the efficacy of neoadjuvant chemotherapy (CT) in IBC.
Methods: Pts with HER2−negative IBC (IHC 0 or 1+ or FISH/CISH-, T4d, any N) were included to receive 4 cycles of FEC100 + BEV 15 mg/kg, d1 q3w, followed by 4 cycles of Docetaxel 100 mg/m2 + BEV 15 mg/kg q3w. Complete surgery was performed 4–6 weeks after the last dose of CT, followed by radiotherapy and endocrine therapy for hormone receptor positive (HR+) pts. BEV was re-introduced as adjuvant therapy for 10 cycles, giving a total of 18 cycles of BEV. The primary endpoint of the PACS09/Beverly1 trial was to evaluate the pathologic complete response (pCR; Sataloff classification) rate in HER2−negative non-metastatic IBC patients(pts).
Results: Between Jan 2009 and Sep 2010, 101 pts were included (100 pts were evaluable). Main baseline characteristics were: median age 49 years; postmenopausal status, 39 pts; SBR 2, 32 pts SBR3 61 pts, both HR-negative, 55 pts. 85 pts completed neoadjuvant therapy according to the protocol, ***.90 pts underwent complete mastectomy, 4 had a breast-conservative surgery. After neoadjuvant treatment, investigator-assessed pCR rate was 27% (18%-36%, CI 95%). Interestingly, a significantly greater proportion of pCR rate was observed in the HR-negative group compared to HR-positive group (38% vs 13% respectively; p=0.007). Results from central review of pCR are currently in progress. Main Grade 3,4 toxicities were: neutropenia (61 pts),febrile neutropenia (36 pts),mucitis (23 pts) Neither gr3/4 HTA nor cardiac failure or proteinuria was reported. There were no treatment-related deaths.
Conclusions: These data suggest that the use of BEV with neoadjuvant CT is active in HER2−negative IBC (pCR rate 27%), with an acceptable safety profile. Interestingly, the HR-negative subgroup is significantly more responsive than the HR-positive subgroup.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-20-01.
P4-20-05: Inflammatory Breast Cancer: Comparison of Epidemiology, Biology, and Prognosis between Japan and the United States, a Hospital-Based Study.
Authors: Yamauchi H , Natori A , Hayashi N , Soejima K , Takahashi O , Fukui T , Nakamura S , Cristofanilli M , Ueno N 
Published: June 2012

Abstract
Background: Inflammatory breast cancer (IBC) is a challenging disease characterized by low incidence, rapid progression, and poor survival. The epidemiology of IBC has been slow to emerge, given that the rarity of IBC makes large prospective clinical trials difficult. Compared to non-IBC, well-established features of IBC include a younger age of onset and lower frequency of hormone receptor positivity. Higher body mass index (BMI) is a purported risk factor. Previous reports also suggest that IBC is associated with more racial disparities, including incidence and age at diagnosis. The epidemiology of IBC in East Asia, however, has not been investigated. We performed a comparative study of IBC in Japan versus the United States to determine its epidemiologic and clinical features and to evaluate the differences in epidemiological factors between the two countries.
Patients and Method: Patients who visited St. Luke's International hospital (SLIH) in Tokyo, Japan and The University of Texas MD Anderson Cancer Center (MDA) in Texas, USA between 2003 and 2009 were identified. Epidemiological and biological data were collected from electronic medical records. Patient and tumor characteristics were tabulated and stratified by hospital. Kaplan-Meier curves were created for survival estimates and log-rank test was used for cross-group comparisons. Cox proportional-hazard analysis was used to identify a subset of significant prognostic variables that related to overall survival.
Result: 34 patients at SLIH and 531 patients at MDA were identified. Mean age at diagnosis was 52 years old (range, 32–81, SD, 10.8) and 50 years old (range, 22–87, SD, 11.6), respectively (P=0.476). Mean BMI was 22.9 kg/m2 (range, 17.3−30.5, SD 3.3 ) and 31.0 kg/m2 (range, 13.6−88.9, SD, 7.8) respectively (P&lt;0.01). Clinical Staging was not significantly different; Stage IIIB 38.2%, Stage IIIC 26.5%, and Stage IV 32.4% at SLIH versus 48.6%, 23.7%, and 27.3% at MDA (P= 0.167). Estrogen receptor (ER) and progesterone receptor (PR) negative cases were, respectively, 50.0% and 64.7% at SLIH and 50.5% and 64.2% at MDA (ER, P= 0.935; PR, P=0.908). Her-2 over-expression cases were 38.2% at SLIH and 28.6% at MDA (P=0.174). A significant difference in nuclear grade was seen between SLIH and MDA: 20.6% at SLIH were Grade 3 versus 68.7% at MDA (P&lt;0.01). Median overall survival at SLIH was 3.6 years versus 2.3 years at MDA (P=0.570). No prognostic factors were associated with overall survival.
Conclusion: Though IBC at SLIH differed significantly from IBC at MDA by several epidemiologic and biologic factors, there was no significant difference in survival. To define the epidemiological, prognostic, and risk factors of IBC in Japan, as well as in the world, further studies are needed.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-20-05.
P5-01-01: Identification, Validation and Assessment of Transcriptional Relevance of a PDGFR-Activation Signature in (Inflammatory) Breast Cancer.
Authors: Van Laere SJ , Van Golen KL , Joglekar M , Ueno NT , Finetti P , Van Dam PA , Viens P , Birnbaum D , Bertucci F , Vermeulen PB , Dirix LY 
Published: June 2012

Abstract
Introduction. Breast cancer can be divided into several subgroups characterized by unique patterns of pathway activation. Platelet-derived growth factor receptor (PDGFR) signalling has not yet been included in this classification scheme, although it has been reported to be a potential target for therapy. In this study, we have constructed a PDGFR-activation signature and investigated its relevance in breast cancer.
Materials and Methods. Sixteen PDGFR-modulated genes were identified by intersecting two published PDGFR-modulated gene lists. The resulting gene signature was applied onto a publicly available gene expression data set of GIST (GSE17743) using principle component analysis. The segregation of PDGFR- and KIT-mutated GIST samples was investigated using permutation analysis and classification sensitivity and specificity were assessed. Using the regression coefficients from the first principal component, a PDGFR-activation score was constructed and applied onto a second data set in order to validate the score (GSE1923). Finally, the score was applied onto a gene expression data set of 389 breast cancer ***samples, including 137 samples from patients with IBC.
Results. Sixteen PDGFR-modulated genes (NR4A1, EGR3, JUNB, IER3, TIEG, JUN, BCL3, MYC, NR4A3, PLAU, MCL1, DUSP1, DUSP5, DUSP6, SGK, GADD45A) were able to discriminate PDGFR-mutated GIST samples from KIT-mutated GIST samples with a sensitivity of 75% and a specificity of 85%. Application of the PDGFR-activation score onto a data set of control and PDGF-treated glioblastoma cells showed a significant increase in the PDGFR-activation score in the treated condition (P=0.0302). Application of the PDGFR-signature onto our series of IBC and nIBC samples demonstrated a significant and molecular subtype-independent increase in PDGFR-activation in IBC (P=0.0015; FDR=3%). In addition, in our series of nIBC samples only, PDGFR-activation was associated with decreased DMFS and RFS (P=0.0038 and P=0.0137 respectively). In fact, PDGFR-activation was an independent prognosticator in a multivariate model incorporating the molecular subtypes.
Discussion. We identified a gene signature composed of 16 genes able to predict PDGFR-activation in tissue samples by gene expression analysis. PDGFR-activation is significantly increased in samples from patients with IBC, an aggressive form of locally advanced breast cancer. In addition, in nIBC, PDGFR-activation is associated with DMFS and RFS, independently of the molecular subtypes suggesting that PDGFR-activation might add another level of clinically relevant heterogeneity in breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-01.
P5-01-13: High Levels of Nuclear Heat Shock Factor 1 (HSF1) Are Associated with Poor Prognosis in Breast Cancer: Results from the Nurses' Health Study.
Authors: Santagata S , Hu R , Lin NU , Mendillo ML , Collins LC , Hankinson SE , Schnitt SJ , Whitesell L , Lindquist S , Tamimi RM , Ince TA 
Published: June 2012

Abstract
Purpose: Heat shock factor 1 (HSF1) is the master transcriptional regulator of the cellular response to heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown.
Patients and methods: Breast cancer samples from 1,841 participants in the Nurses’ Health Study (NHS) were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan-Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan-Meier analysis using publicly available mRNA expression data.
Results: Nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P&lt;0.0001). Overall, in multivariate analysis, high-HSF1 levels were associated with increased breast cancer-specific mortality (HR, 1.62; 95% CI, 1.21−2.17). This association was seen in the ER-positive population (HR, 2.10; 95% CI, 1.25−2.47), even in early-stage lymph node negative cases (HR, 1.98; 95% CI, 1.17−3.33). In public expression profiling data, high-HSF1 mRNA levels were also associated with an increase in ER-positive breast cancer-specific mortality.
Conclusions: Increased HSF1 is associated with reduced survival in breast cancer. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer and that HSF1 may provide a useful therapeutic target.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-13.
P5-02-03: Lipid Raft Disruption by Docosahexaenoic Acid Induces Apoptosis in Transformed Human Mammary Luminal Epithelial Cells Harboring HER-2 Overexpression.
Authors: Ravacci GR , Tharcisio  , Junior T , Logullo AF , Torrinhas RS , Brentani MM , Waitzberg DL 
Published: June 2012

Abstract
Background, In HER-2 overexpressing breast cells, HER-2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR and HER-3. For signal activation and transduction to occur, the HER-2 receptors must be located in lipid rafts. Therefore, HER-2 overexpression must be accompanied by increased lipid rafts on the cell membrane to ensure constant signal transmission.
Methods, To test this hypothesis, we used HB4a — untransformed human mammary epithelial cell strain — and HB4aC5.2 cells — HB4a cells co-transfected with ErbB-pJ5E.c-2 (normal full length human HER-2 cDNA). We analyzed the lipid rafts, cholesterol and fatty acids from cell membrane by confocal microscopy and gas chromatography. The proteins associated to HER-2 activity and lipid rafts formation, such as Akt, ERK ½ and FASN were analyzed by western blotting. To evaluate the lipid rafts importance for HER-2 signaling, we treated cells with docosahexaenoic acid (DHA) to disrupt the lipid rafts. Thereby, all analysis was repeated and cells death and apoptosis were analyzed by flow cytometry. Values were obtained by the mean and standard deviation of five independent experiments and developed in triplicate, by using one-way analysis of a variance (ANOVA) test, followed by Bonferroni post-test, to identify significant (p&lt;0.05) differences between cell lines and results with different concentrations of DHA treatment. Results, HB4aC5.2 cells have five copies of pJ5E.c-ErbB-2 inserted into their genome and express approximately 900 times more HER-2 than HB4a cells. HER-2 overexpression in HB4aC5.2 cells was accompanied by increased lipid rafts in cell membranes, hyperactivation of downstream Akt and ERK1/2 proteins, and rate of cell growth increase as compared to the HB4a strain. In addition, HER-2 overexpression was associated to increased activation of FASN, a key enzyme involved in cellular lipogenesis. The final product of FASN activation, palmitate, is used to synthesize saturated phospholipids, necessary to form lipid rafts. Treatment of HB4aC5.2 cells with DHA, an omega-3 fatty acid, disrupted the lipid rafts by its increased incorporation into the cell membrane; inhibited HER-2 activation by decreasing Akt, ERK1/2, and FASN proteins; and induced apoptosis. The same treatment maintained the structure of HB4a cell lipid rafts, accompanied by a low percentage of DHA-induced apoptosis.
Conclusion, Although little is yet known about lipid rafts, our data support the theory that disturbances in these micro-domains may represent a useful tool in controlling cell signaling triggered by HER-2 receptors and contribute to a better understanding of the role of this receptor in HER-2 positive breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-03.
P5-02-04: Disruption of Endothelial Cells Barrier Integrity by Invasive Breast Cancer Cells.
Authors: Haidari M , Zhang W , Chen Z , Mortazavi A , Dixon R 
Published: June 2012

Abstract
Despite its critical role in cancer metastasis the molecular mechanisms regulating breast cancer cells transendothelial migration are poorly understood, but clearly depend on the invasive capacity of tumor cells and their ability to breach the endothelial cell barrier. Vascular endothelial-cadherin (VE-cadherin) is found specifically in the endothelial cell adherens junction and has been implicated in playing a fundamental role in controlling the transport across the endothelial barrier. Tyrosine phosphorylation of VE-cadherin has been implicated in the disruption of endothelial cells adherens junctions and diapedesis of metastatic cancer cells. We tested this hypothesis that interaction of breast cancer cells with endothelial cells initiates the signal transductions that disrupt the endothelium barrier integrity. Our studies demonstrated that the attachment of MDA-MB-231 human breast cancer cells to Human Umbilical Vein Endothelial Cells (HUVECs) leads to tyrosine phosphorylation of VE-cadherin and the formation of gaps between endothelial cells. These were accompanied by activation of two tyrosine kinases, Src and proline rich tyrosine kinase (Pyk-2). In addition, immunoprecipitation studies indicated that the endothelial cells adherens junction structure was disrupted through MDA-MB-231-induced dissociation of VE-cadherin and β-catenin complex. Activation of RhoA and HRas by over expression of constitutively active forms of the genes leads to tyrosine phosphorylation of VE-cadherin and Pyk-2 in HUVECs. Over expression of dominant negative forms of RhoA, HRas, Raf and ERK2 but not Rac1 and Cdc42 attenuated breast cancer cell-induced tyrosine phosphorylation of VE-cadherin and Pyk-2 in HUVECs. Indicating that breast cancer cell-induced VE-cadherin tyrosine phosphorylation and disruption of adherens junction in endothelial cells is mediated by RhoA and HRas\Raf\MEK\ERK signaling cascade. Understanding the precise molecular mechanisms that facilitate breast cancer cells transendothelial migration could develop novel therapeutic strategies targeting cancer cell metastasis by improving the protective role of endothelial cells.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-04.
P5-05-01: Vitamin D Status in Newly Diagnosed Breast Cancer Patients Inversely Correlates with Tumor Size and Moderately Correlates with Outcome.
Authors: Hatse S , Lambrechts D , Verstuyf M , Smeets A , Brouwers B , Vandorpe T , Brouckaert O , Peuteman G , Laenen A , Kriebitzsch C , Dieudonné A-S , Paridaens R , Neven P , Christiaens M-R , Bouillon R , Wildiers H 
Published: June 2012

Abstract
Aims: To study the impact of Vitamin D (VitD) status and genetic variability in key VitD regulatory genes on patient and breast tumor characteristics, and on breast cancer related outcome.
Methods: We examined serum 25-hydroxyvitamin D3 (25OHD) levels in a cohort of 1800 early breast cancer patients treated in Leuven between 2003 and 2010. Serum was collected at diagnosis for all patients; germline DNA from peripheral blood was also available for the majority of them. Serum 25OHD was measured by radioimmunoassay, and single nucleotide polymorphisms (SNP's) were assessed by Sequenom. Statistical analysis was done by multivariable regression models including age, BMI and season and by a Cox proportional hazard model for analysis of disease-specific survival and disease-free interval.
Results: Lower 25OHD serum levels were significantly correlated with larger tumor size (0,4 ng/ml decrease in 25OHD per 1 cm increment in tumor size, p=0.0063) but not with lymph node invasion, estrogen receptor and HER2 status, or tumor grade. Serum 25ODH level was significantly affected by genotypes of rs10741657 and rs1993116 (25-hydroxylase; CYP2R1) and of rs222040, rs7041 and rs4588 (D-binding protein; DBP), yet its observed association with tumor size did not differ between distinct genotypes. Although not statistically significant, patients with higher 25OHD levels tended to have slightly improved survival. Also, a significant increase in relapse risk became apparent after 3 years for patients with 25OHD&lt;30 ng/mL.
Conclusion: Vitamin D Level in breast cancer patients inversely correlates with tumor size and moderately correlates with outcome.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-01.
P5-05-07: The Msp1 Polymorphism of Cytochrome P-450 CYP1A1 in Asymptomatic Women with Breast Cysts.
Authors: Fenile R , Nazário A , Facina G 
Published: June 2012

Abstract
The objective of this study was to determine the prevalence of the cystic form of fibrocystic breast changes among women from different age groups correlated with the presence of the Msp1 polymorphism of cytochrome P-450 CYP1A1. Methods: A retrospective, case-control study (was carried out with ultrasound examination) was performed on 197 women divided into two groups: 44 women with cystic breast disease (cases) and 153 women without breast disease (controls), the majority Caucasian, aged 41–50 years, having regular menstrual cycles, pregnancies and complaining of mastalgia. Genetic analyses were carried out by performing polymerase chain reaction to detect the Msp1 polymorphism in CYP1A1. Results: Cystic breast disease as diagnosed by ultrasound was present in 22% of the population studied. In the genetic analysis of CYP1A1, we observed the homozygous wild-type genotype in 68.2% of cases and 66% of controls. The heterozygous genotype occurred in 31.28% of cases and 26.8% of controls. The homozygous mutant genotype was seen in zero cases and in 7.2% of controls. There were no statistically significant differences in the genotype frequencies observed between the case and control groups (p = 0.42). Conclusion: The prevalence and the general epidemiological profile of cystic breast disease in this group were consistent with the values previously reported the literature. There was a higher frequency of heterozygotes in the case than in the control group, but this was not true for the homozygote mutant genotype. There was no statistically significant association detected between the CYP1A1 Msp1 polymorphism and fibrocystic breast disease.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-07.
P5-06-02: Response and Acquired Resistance of BRCA1-Deficient Triple-Negative Breast Cancer Xenografts to Alkylators or PARP Inhibitors.
Authors: ter Brugge P , van der Burg E , Kristel P , Boon U , Moutinho Freixas C , Esteller M , Hogervorst F , Gevensleben H , Turner N , Wesseling J , Jonkers J 
Published: June 2012

Abstract
Background. BRCA1 mutated breast tumor cells are defective in DNA repair by homologous recombination and therefore especially sensitive to treatment with DNA double-strand break (DSB) inducing agents, such as alkylators or PARP inhibitors. However, such tumors can eventually develop therapy resistance. Understanding therapy resistance mechanisms may help in designing treatment strategies to overcome therapy resistance.
Methods. We have developed BRCA1-deficient triple-negative breast cancer (TNBC) xenograft models by implantating fresh human breast tumor pieces and subsequent serial passaging. These models show epigenetic loss of BRCA1 due to promoter hypermethylation or genetic inactivation of BRCA1 due to a frameshift mutation (c.2210delC) resulting in a premature stop codon (p.Thr737LeufsX15). We have used these BRCA1-deficient TNBC models to study response and acquisition of resistance to alkylating therapy (cisplatin, melphalan) and the clinical PARP inhibitor olaparib.
Results. Treated tumors were sensitive to the alkylators cisplatin or melphalan or the PARP inhibitor olaparib, in some cases resulting in complete remission with no palpable tumor left. However, relapses did occur in most cases and repeated treatment of recurrent tumors eventually led to aquired resistance.
Since restoration of BRCA1 function has been suggested as a mechanism of therapy resistance (Swisher et al., Cancer Res 2008; 68: 2581), we determined BRCA1 expression in therapy-sensitive and -resistant tumors by Western blot analysis. While no full length BRCA1 protein could be detected in the therapy-sensitive tumors, expression of full length BRCA1 protein was found in the majority of cisplatin resistant and olaparib resistant tumors. BRCA1 reexpression in the therapy-resistant BRCA1-c.2210delC tumors was caused by genetic restoration of the reading frame due to reversion to the wildtype sequence or additional deletions near the c.2210delC mutation. BRCA1-re-expression in the therapy-resistant TNBC xenografts with epigenetic loss of BRCA1 was caused either by loss of BRCA1 promoter methylation or by complex rearrangements at the BRCA1 locus.
Conclusion. Although BRCA1-deficient TNBC xenografts are initially very sensitive to alkylating agents and olaparib, resistance to treatment develops in almost all treated tumors. This acquired resistance is frequently associated with re-expression of BRCA1 due to secondary mutations or loss of promoter methylation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-02.