bluuebunny/crossref_metadata_2025_split huggingface dataset:
SIRT7 expression and epigenetic status determine variability in telomere length in breast cancer.
Authors: Zino S , Moran CP , McGlynn LM , George W , Payne AP , Shiels PG 
Published: December 2010

Abstract
Abstract #4052
Background: As cancer is a disease of ageing, factors involved in biological ageing may be informative in investigating the underlying mechanisms of cancer pathogenesis. How biological age is affected by epigenetic changes remains to be fully determined. This is pertinent to cancer pathogenesis, as epigenetic changes can increase the risk of neoplasia. We have investigated the biological age of breast tumours, using telomere length and the expression of sirtuin 7, a gene involved in the regulation of ribosome biosynthesis and previously demonstrated as potentially prognostic in breast cancer. We have evaluated these for association with epigenetic status.&#x2028; Materials and Methods: Telomere lengths and Sirtuin 7 (SIRT7) expression were determined using Q-PCR. Epigenetic status was determined using a Methylamp Global DNA methylation kit. Statistical analysis was performed using SPSS v15.&#x2028; Results: Chronological age was negatively associated with telomere length (p=0.013) and positively associated with methylation levels (p=0.007). Furthermore, telomere length showed a negative association with global methylation levels (p=0.002). Individuals with shorter telomeres were older and demonstrated higher levels of global DNA methylation. SIRT7 expression was positively associated with telomere length (p=0.01), but showed no association with methylation levels. Linear regression analysis indicated that SIRT7 expression accounted for 52.2% of the observed variability in telomere length (p=0.001) and methlyation for 33.4% (p&lt;0.001). Multiple linear regression analysis indicated that methylation status and SIRT7 expression combined accounted for 69.4% of the observed variability in telomere length. Chronological age was not a significant contributor in either analysis.&#x2028; Discussion: Cells with critically short telomeres present a high risk of becoming neoplastic, as they are biologically aged. This study has demonstrated that both SIRT7 expression and global methylation levels significantly influence telomere attrition in breast cancer. This is consistent with a scenario whereby the rate of biological ageing in breast tumours is influenced by telomere mediated epigenetic changes and mechanistically by cellular proliferation requirements. The latter is manifest through SIRT7 regulated ribosome biogenesis. These findings support the use of SIRT7 as a potential prognostic tool and therapeutic target in breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4052.
The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of the focal adhesion kinase and p130Cas in breast cancer cells.
Authors: Zhao Y , Min C , Vora S , Trackman PC , Sonenshein GE , Kirsch KH 
Published: December 2010

Abstract
Abstract #4073
The lysyl oxidase (LOX) gene encodes an enzyme (LOX) critical for extracellular matrix maturation. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. In particular, the pro-peptide domain (LOX-PP) of the secreted precursor protein (Pro-LOX) was found to inhibit the transformed phenotype of breast, lung and pancreatic cancer cells. LOX-PP expression in these carcinoma cells reverted Her-2/neu- and Ras-mediated epithelial to mesenchymal transition (EMT), leading to increased expression of E-cadherin and γ-catenin, and reduced levels of Snail, vimentin and/or BCL2, as well as invasion through Matrigel. Furthermore, LOX-PP expression reduced tumor formation of Her-2/neu driven breast cancer cells in a xenograft model. However, the mechanism of action remains to be determined. Here the ability of LOX-PP to attenuate the integrin signaling pathway in NF639 breast cancer cells driven by Her-2/neu, which signals via Ras, was tested. Ectopic Pro-LOX and LOX-PP expression inhibited fibronectin-stimulated protein tyrosine phosphorylation. Importantly, phosphorylation of the focal adhesion kinase (FAK) on Tyr397 and Tyr576, and the activation of its downstream target p130Cas were substantially reduced. Furthermore, these changes were also reflected by a reduced amount of endogenous p130Cas in the Triton X-100 insoluble protein fraction, and attenuation of fibronectin-activated haptotaxis. Interestingly, expression of mature LOX enzyme enhanced fibronectin-stimulated integrin signaling. Of note, treatment with recombinant LOX-PP reduced haptotaxis of NF639 and human MDA-MB-231 and Hs578T breast cancer cells. Thus, the tumor suppressor function of LOX-PP is likely mediated, in part, by blocking integrin signaling and fibronectin-stimulated cell migration.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4073.
Assessment of breast cancer risk prediction models in a high-risk population.
Authors: Chun J , Schnabel F , Ogunyemi O 
Published: December 2010

Abstract
Abstract #4074
Background: A variety of risk assessment models have been developed to quantify a woman's risk for developing breast cancer. Although the Gail model (GM) is the most widely utilized model, there are limitations. The Tyrer-Cuzick model (TCM), which has been validated in the United Kingdom (UK), addresses these limitations but its performance in other populations is unclear. The purpose of this study was to evaluate the predictive ability of the TCM in a cohort of high-risk women from the New York metropolitan area and compare the results to the GM.&#x2028; Methods: The Women At Risk (WAR) Registry provided the study population. Due to the age limitation of the Gail model, we excluded women who were under 35 and over 80 years of age. Calculation of lifetime Gail scores included the following: age, race, age at first menses, age at first live birth, number of first degree relatives with breast cancer, number of previous breast biopsies, and atypical hyperplasia. These variables were also included in the lifetime Tyrer-Cuzick scores as well as information on menopausal status, use of hormone replacement therapy, LCIS, and age at diagnosis for relatives with ovarian and breast cancer. The Receiver Operating Characteristic (ROC) and estimated area under the ROC curve (AUC) with 95% confidence intervals (CI) were used to assess prediction accuracy of both models.&#x2028; Results: Out of a total study population of 1523 women, 82 (5%) developed breast cancer during a median follow-up of 56 months. The median age of women without breast cancer was 49 years, and the median age of women who developed breast cancer was 54 years. The AUC and 95% CI for the Gail model was 0.547 (0.479 to 0.615) and 0.501 (0.433 to 0.569) for the Tyrer-Cuzick model. Our results indicate poor discriminatory accuracy for both models, which performed no better than pure chance (0.5).&#x2028; &#x2028; Discussion: Quantitative breast cancer risk assessment models are critically important in developing effective risk management strategies. Although the TCM addresses some limitations of the GM, it is unclear how well it performs in populations outside the UK due to the wide variation in international breast cancer rates. In addition, the TCM excludes more recently identified risk factors such as breast density. Bayesian techniques may ultimately lead to a better risk assessment tool as they allow continual modification of the model as new risk factors are identified. Accurate breast cancer risk prediction is a complex undertaking and further studies are warranted in order to achieve truly comprehensive and widely applicable models.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4074.
17β-estradiol levels during an entire menstrual cycle in response to adult stature and insulin, of possible importance for breast cancer risk. The EBBA-I study.
Authors: Espetvedt S , Emaus A , Tretli S , Jasienska G , Ellison P , Furberg A , Wist E , Thune I 
Published: December 2010

Abstract
Abstract #4078
Background: The normal breast cells develop into malignant cells as a result of a complex interplay between genetic, environmental, nutritional and hormonal factors. Attained adult stature and insulin levels, risk factors for breast cancer, may also vary in response to the same factors. Thus, we hypothesize that 17β-estradiol, a key factor in the carcinogenesis of the breast, may vary in response to adult height in combination with insulin levels of possible importance of breast cancer risk.&#x2028; Methods: Among 204 healthy women, aged 25-35 years who participated in the Norwegian EBBA-I study, 17β-estradiol concentrations were measured in daily saliva samples throughout one entire menstrual cycle using radioimmunoassay (RIA). Attained height (cm) was measured, and serum concentrations of insulin were determined in fasting blood samples. The associations between adult height, insulin and 17β-estradiol levels throughout a menstrual cycle were studied using multivariate linear regression analyses and linear mixed models for repeated measures. Adjustments for potential confounding factors were performed.&#x2028; Results: A 37.2 % increase in 17β-estradiol levels was observed during the entire menstrual cycle among women with an adult height ≥170 cm (upper tertile) and insulin levels ≥ 90 pmol/L (upper tertile) compared to women with the same attained adult height, and insulin levels &lt; 90pmol/L. The association was even more pronounced when we looked into those women with attained adult height ≥170 cm (upper tertile) and serum insulin ≥ 101 pmol/L (upper quartile) (Fig. 1). Adjustments for potential confounding factors were performed.&#x2028; &#x2028; Conclusion: Our findings support that premenopausal levels of 17β-estradiol vary in response to adult height and insulin levels, suggesting that women who become taller are put at risk for higher estradiol levels throughout the entire menstrual cycle when their insulin levels rise, of possible importance for breast cancer risk.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4078.
Final results of the RAPP-01 phase III trial comparing doxorubicin and docetaxel with doxorubicin and cyclophosphamide in the adjuvant treatment of high-risk node negative and limited node positive (≤3) breast cancer patients.
Authors: Brain EG , Debled M , Eymard J , Bachelot T , Extra J , Serin D , Combe M , Fourme E ,   Group of RAPP-01 Investigators
Published: December 2010

Abstract
Abstract #4101
Background&#x2028; Taxanes have been approved in the adjuvant setting for the treatment of node positive (pN+) breast cancer (BC) patients (pts), given either sequentially or in combination with anthracyclines. Controversies remain regarding their role in high-risk node negative (pN0) disease.&#x2028; Methods&#x2028; In 1999, we initiated a randomised phase III trial comparing 4 cycles of adjuvant doxorubicin + docetaxel (AT, 50/75/mg/m²) with 4 cycles of standard doxorubicin + cyclophosphamide (AC, 60/600/mg/m²) in a mixed population of high-risk pN0 and limited pN+ (≤3) early BC pts. Chemotherapy was delivered postoperatively q3w without prophylactic G-CSF, followed by radiation therapy according to standard guidelines and endocrine treatment for 5 years in pts with ER±PgR-positive tumours. This trial was closed prematurely for toxicity in 2003 and we have reported the safety data (JAMA 293:2367, 2005). We now report on time to recurrence (TTR, primary endpoint defined as locoregional relapse, controlateral BC or distant metastasis, which ever occurs first) as well as the effect of treatment by stratification factors [pN and Ki67 (&lt;25% vs ≥25%)].&#x2028; Results&#x2028; Of 700 pts planned, 627 were enrolled between 6/1999 and 1/2003. Baseline characteristics of all pts were well-matched, with 43% of pN0 and 44% of Ki67 ≥25%. At a median follow-up of 64 months, there was no statistically significant difference in TTR between AT and AC. In the AT group, there were 28 TTR events (5-year TTR 91%, 95%CI: [88-94%]) and 16 deaths all causes (2 toxic deaths); the AC group had 31 TTR events (5-year TTR 90.9%, 95%CI: [88-94%]) and 18 deaths all causes.&#x2028; &#x2028; Conclusions&#x2028; With 5-year median follow-up, there is no difference in TTR between pts treated with AT or standard AC in adjuvant setting. Specific nodal or Ki67 status do not confer any additional benefit from either regimen. Both regimen provide an excellent 5-year TTR rate (&gt;90%). Multivariate analysis including all prognostic covariates will be performed and presented at the meeting. Given the high risk of life-threatening complications already reported, AT is not manageable without preventive strategies (e.g. G-CSF) and cannot be considered as a standard combination for intermediate risk early BC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4101.
Phase III two by two factorial comparison of doxorubicin and cyclophosphamide followed by a taxan vs. a taxan alone, and paclitaxel vs. docetaxel in operable node positive breast cancer – results of the first interim analysis of NSASBC02 trial.
Authors: Watanabe T , Kuranami M , Inoue K , Masuda N , Aogi K , Oono S , Iwata H , Mukai H , Tanaka S , Yamaguchi T , Ohashi Y 
Published: December 2010

Abstract
Abstract #4103
Background: Evidence suggests that anthracycline-containing regimens can be excluded in some patients(pts) with operable breast cancer. It is also suggested that docetaxel (D) is more effective than paclitaxel (P) in metastatic breast cancer (BC) pts.&#x2028; Methods: Eligibility included axillary lymph node positive BC age less than 70 years old. Pts were randomized to receive either AC(doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every(q) 3 weeks(wks) x 4 followed by P 175 mg/m2 q3 wks x 4 (ACP), same AC followed by D 75 mg/m2 q3 wks x 4(ACD), P 175 mg/m2 q3 wks x 8 (PTX) or D 75 mg/m2 q3 wks x 8(DTX). Comparison included taxane (ACP+PTX vs. ACD+DTX) and with AC or without AC (ACP+ACD vs. PTX+DTX). The primary endpoint was disease free survival (DFS) and the secondary endpoints included overall survival, adverse events(AE) and quality of life (QOL). The trial was powered to prove the non-inferiority of regimens without AC to those with AC(threshold hazard ratio 1.321) in terms of DFS.&#x2028; Results: A total of 1,060 eligible pts were accrued from 84 centers between Dec. 2000 and Mar.2006. 270 DFS events and 106 deaths after a median follow-up of 46.5 months were observed. The hazard ratio (HR) of DFS between ACD+DTX and ACP+PTX was 0.81(95% Confidence Interval (CI); 0.64-1.03) (p=0.08). The HR of DFS between PTX+DTX and ACP+ACD was 1.26 (95% CI; 0.99-1.60) ( p=0.67) in all eligible pts but was 1.85 (95% CI; 1.11-3.07)(p=0.017) in pts with HER2 overexpressing BC and 1.11(95% CI; 0.85-1.46)( p=0.44) in pts with HER2 non-overexpressing BC. AEs of grade 3 or 4 were observed in the lowest incidence in PTX arm and edema was observed in 11% of pts in DTX arm(p=0.01), neutropenic fever was more frequent in D cotaining arms(Table1). Conclusions: DFS was better in the arms containing D than in the arnms with P. AC improved DFS in the subset of pts with HER2 overexpressing BC but not in non-selected population. Higher incidence of severe AEs was observed in the arms containing D than in arms with P.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4103.
Safety of bevacizumab (BV) plus docetaxel (D) in patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC) who developed brain metastases during the AVADO phase III study.
Authors: Dirix LY , Romieu G , Provencher L , Grimes D , de Souza Viana L , Paterson A , Mauriac L , Kirsch A , Pernas S , Miles DW 
Published: December 2010

Abstract
Abstract #4116
Background: BV (Avastin®) is a monoclonal antibody specific to VEGF. The randomised, double-blind AVADO study has demonstrated that two different BV doses combined with D significantly improved progression-free survival in pts with LR or mBC compared with D + placebo (PL); unstratified hazard ratio (HR) up to 0.72, stratified HR up to 0.61 censored for non-protocol therapy. BV combined with D did not result in increased risk of GI perforations, thromboembolic or bleeding events. Patients with CNS metastases are currently excluded from clinical trials with BV due to a potential risk of haemorrhage. This retrospective analysis investigated the adverse events (AEs) reported in pts who developed brain metastases while participating in the AVADO trial.&#x2028; Methods: The AVADO study compared D 100mg/m2 plus PL with D plus BV at either 7.5 or 15mg/kg in 736 pts with HER2-negative inoperable LR or mBC; no chemotherapy 6 months prior to randomisation (≥12 months if taxane-based); ECOG PS 0–1; adequate LVEF, and no CNS metastases at study entry. D was administered q3w for up to 9 cycles. BV/PL was administered q3w until disease progression or unacceptable toxicity.&#x2028; Results: Of the 730 pts in the safety population, a total of 24 pts developed brain metastases at some point during the AVADO trial. There was no difference in number of pts who developed brain metastases between trial arms. The mean time to development of brain metastases was 172 days with PL, 197 days with BV 7.5mg/kg and 242 days with BV 15mg/kg. One patient receiving BV 15mg/kg was diagnosed with brain metastases on Day 1 and excluded from the study. No CNS bleeding AEs were reported for pts with brain metastases and other grade 3–5 AEs in these pts occurred at a similar frequency in all trial arms.&#x2028; &#x2028; Conclusions: In concordance with the overall toxicity assessment, treatment with BV did not appear to be associated with CNS haemorrhage in pts with brain metastases. Frequency of grade 3–5 AEs was not increased in pts with brain metastases treated with BV compared with those treated with PL. Analysis of a larger dataset may provide further information on the safety of BV therapy in pts with brain metastases.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4116.
Phase 1b study of motesanib diphosphate (AMG 706) in combination with paclitaxel or docetaxel for the treatment of locally recurrent, unresectable or metastatic breast cancer.
Authors: Kaufman PA , de Boer R , White S , Mainwaring P , Koczwara B , Drury S , Ye Y , Sun Y , Sikorski R , Kotasek D 
Published: December 2010

Abstract
Abstract #4117
Background: Motesanib is a novel oral angiogenesis inhibitor designed to selectively target the tyrosine kinase activity of VEGF 1, 2 and 3; PDGF and Kit receptors. Here we report safety, preliminary efficacy and pharmacokinetics (PK) from an ongoing phase 1b dose-finding study of motesanib plus either paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer.&#x2028; Methods: Eligible pts with ECOG 0 or 1 and ≤1 prior chemotherapy regimen for metastatic breast cancer received (until toxicity or disease progression) escalating doses of motesanib (50 or 125mg) QD orally continuously from day 3 of cycle 1 plus either P (Arm A) at 90mg/m2 on days 1, 8 and 15 of each 28-day cycle; or D (Arm B) at either 100mg/m2 on day 1 of every 21-day cycle or at 75mg/m2 with motesanib maximum tolerated dose (125mg QD). Objective response (OR) per RECIST was assessed every 8 (Arm A) or 6 wks (Arm B).&#x2028; Results: To date, 33 pts have received ≥1 dose of motesanib: Arm A, n=10; Arm B, n=23. Median age is 51 (range, 28-66) years. There were 5 DLTs (all grade 3) in 4 pts: abnormal liver function tests and deep vein thrombosis (Arm A, 125mg QD), fatigue (Arm A, 125mg QD), gallbladder enlargement (Arm B, 125mg QD+75mg/m2 D) and migraine (Arm B, 125mg QD). 28 pts (85%) had motesanib-related AEs; the most common were (worst grade): diarrhea, Arm A/B 60%/61% (grade 3, 0%/13%); fatigue, 30%/26% (grade 3, 10%/4%); hypertension, 20%/22% (grade 3, 10%/4%); and nausea, 10%/26% (no grade 3). Treatment-related AEs of interest in Arm A/B included epistaxis (10%/18%; all worst grade 1) and deep vein thrombosis (10%/0%; all worst grade 3). There were no grade 4 or 5 related AEs. Two deaths on study occurred (Arm B; 50 and 125mg QD n=1 each); both were not considered to be motesanib related. Motesanib PK parameters were generally within the range previously described for single-agent motesanib. PK profiles of P and D showed high interpatient variability, with AUC higher in some pts after motesanib coadministration. In pts with measurable disease at baseline (Arms A&B, n=7&18), best OR at time of last data cut-off was: confirmed PR in Arm A n=2 (29%), in Arm B n=5 (28%); SD in Arm A n=2 (29%), in Arm B n=9 (50%); durable SD ≥24 wks in Arm A n=0, in Arm B n=3 (17%). Median (range) duration of response currently is 169 (58-169) days in Arm A and 198 (96-337+) days in Arm B.&#x2028; Conclusions: Motesanib combined with P or D appears to be tolerable with evidence of antitumor activity in pts with advanced breast cancer. No marked effect on motesanib PK has been noted with coadministration of either P or D. Updated safety and efficacy data, including PFS, will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4117.
Fluvastatin has biologic effects on stage 0 and 1 breast cancer.
Authors: Garwood ER , Kumar AS , Baehner F , Garber JE , Troyan S , Olopade OI , Moore D , Au A , Flowers C , Campbell M , Hylton N , Esserman LJ , Rush-Port E 
Published: December 2010

Abstract
Abstract #4122
Introduction: Statins are safe, reduce cardiovascular risk, and impact pathways critical to cancer progression. We and others have shown lipophilic statins cause apoptosis and growth suppression in vitro and in vivo, and though epidemiologic data are mixed, statin effect appears most evident in estrogen receptor (ER) negative or grade 3 disease. To look for a direct biologic effect of lipophilic statins, we conducted a perioperative pilot window trial in women with breast cancer (BC).&#x2028; Methods: 40 subjects with stage 0,1 BC were randomized to high dose (80mg/day) or low dose (20mg/day) fluvastatin for 3-6 weeks prior to surgery. Paired tissue (core biopsy and surgical specimen), peripheral blood and MRI were obtained. Primary endpoint was Ki-67 (proliferation) change. Secondary endpoints included cleaved caspase-3 (CC3, apoptosis), longest diameter (LD) by MRI, and C-reactive protein (CRP) change. Subgroup analyses was planned by grade (3 vs. 1,2), statin dose; and ER status. Immunohistochemistry (IHC) on paraffin tissue used standard streptavidin biotin methods. A single breast pathologist reviewed all slides; a single radiologist read all MRIs, both blinded to timepoint.&#x2028; Results: Median serum cholesterol decreased by 16% (-23% and -12% for high and low dose, respectively p=0.012), indicating drug effect and compliance. 29 patients had sufficient tumor for paired IHC, 14 and 15 were grade 3 and 1,2, and 10 and 19 were ER - and +, respectively. In grade 3 (73% of which were ER-) vs. 1,2 tumors, there was a significant decrease in Ki-67, -7.2% (interquartile range (IQR) -13.4%, 0% ) vs. -0.3% (IQR -3%, .8%), respectively, p=0.04. CC3 (apoptosis) increased, 60% vs. 13% for grade 3 vs. 1,2 tumors, respectively, p=0.015. ER- and ER+ cases had a similar reduction in Ki67 with a median drop of 2% (IQR -13.4%, 1%) and 1.2% (IQR -6.6%,0.8%), respectively, p=0.56. While CC3 was increased in ER- vs. + (55% vs. 29%), the difference was not statistically significant. There was no dose dependent effect on Ki-67or CC3.There was no evidence of Ki67 or CC3 change when all grades were analyzed together (median drop 1.2%) and no change in CRP. Of 14 subjects with paired MRIs, 4 grade 3 cases showed a significant decrease in LD, marked ductal dilatation and increased necrosis.with statin exposure.&#x2028; Conclusions: A lipophilic statin, fluvastatin, reduced cholesterol and had measurable biologic changes (reduced proliferation, size and increased apoptosis) in stage 0,1 BC after only 3-6 weeks of exposure, specifically in the grade 3 subset. Results support the study of statins for chemoprevention for women at risk for or with stage 0 grade 3 BC, where new agents are needed.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4122.