bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-Progression Survival (PPS) and Overall Survival (OS) According to Treatment Type in Contemporary Phase III Trials in Advanced Breast Cancer (ABC).
Authors: Saad E. , Katz A. , Machado K. , Buyse M. 
Published: December 2010

Abstract
Objective: Progression-free survival (PFS) and time to tumor progression (TTP) have been the most frequent primary endpoints in recent phase III trials in ABC. OS, the most frequent secondary endpoint (Katz ASCO 2009), is largely influenced by subsequent-line therapy, and the role of PFS/TTP as surrogates for OS is still uncertain, perhaps due to the influence of post-progression therapy. Thus, PPS is of interest as a determinant of OS, and may vary according to treatment type.Methods: Using the medical subject headings “breast neoplasms” and “drug therapy”, we searched PubMed for phase III trials on systemic antineoplastic therapies published between January 1, 1998, and December 31, 2007 in one of 11 leading medical journals (Ann Oncol, BCRT, Br J Cancer, Cancer, Clin Cancer Res, Eur J Cancer, JCO, JNCI, Lancet Oncol, Lancet and NEJM). We excluded trials with factorial design, studies on high-dose chemotherapy, papers reporting combined analyses of two or more trials, and companion studies on correlative biology or prognostic factors. PPS was calculated as median OS minus median PFS/TTP for each trial arm. The proportion of OS accounted for by PPS (PPS%OS) was calculated as 100 - [median PFS/TTP/median OS]% for each trial arm.Results: The search yielded 75 trials enrolling a total of 28,973 evaluable patients in 159 trial arms. The following table displays the results, considering trial arms with available medians for both PFS/TTP and OS. PPS%OS is larger in hormone-therapy trials than in chemotherapy trials (P&lt;0.01). Overall, PPS has a stronger correlation with OS than do PFS/TTP (R-squares of 0.83 and 0.24, respectively; both P&lt;0.01), at least in part because PPS is longer than PFS/TTP.Main results Mean ofmedians(months) Trial typeN armsPFS/TTPOSPPSMedian PPS%OSOVERALL1276.920.513.665.7%1. Chemotherapy96718.311.463.7%1.1 Chemo 1st line only597.820.712.964.4%1.2 Chemo 2nd line only146.715.28.559.8%1.3 Other (mixed lines)235.014.19.164.4%2. Hormone therapy296.927.420.574.4%2.1 Hormone 1st line only139.331.121.869.0%2.2 Hormone 2nd line only135.023.218.177.9% Conclusion: The contemporary average median OS in ABC is 20.7 months for first-line chemotherapy ± targeted agents and 31.1 months for first-line hormone therapy ± chemotherapy trials. Subsequent lines of therapy play a major role in determining OS in ABC, and further studies are needed to understand the role of PFS/TTP versus PPS in determining OS, since first-line PFS/TTP have not been convincingly shown to be good surrogates for OS in the literature on ABC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5116.
The Frequency and Determinants of Metabolic Syndrome in Patients with Operable Stage I-III Breast Cancer.
Authors: Aksoy S. , Dizdar [. , Dede D. , Arslan C. , Dogan E. , Tapan [. , Özkan [. , Hesenov S. , Cinel M. , Yaman S. , Kizilarslan M. , Özisik Y. , Altundag K. 
Published: December 2010

Abstract
Background: Metabolic syndrome is a cluster of multiple risk factors including obesity, insulin resistance, hypertriglyceridemia, low HDL (high density lipoprotein), and hypertension. Metabolic syndrome is associated with an increased risk of breast cancer. We evaluated the frequency and determinants of metabolic syndrome in patients with operable stage I-III breast cancer.Methods: In this cross-sectional study we analyzed the frequency and determinants of metabolic syndrome in patients with stage I-III breast cancer. Metabolic syndrome was defined according to NCEP (National Cholesterol Education Program) definitions. Data on metabolic syndrome criteria were collected along with demographic data, tumor size, grade, lymph node, estrogen, progesterone, HER2 status, grade and history of chemotherapy/endocrine therapy.Results: A total of 331 patients were analyzed. Median age was 50.0 years (range 20-84 years). Eighty-five patients were using tamoxifen, 98 patients were using aromatase inhibitors and the remaining 148 patients were not receiving hormonal therapy (newly diagnosed and/or triple-negative patients). According to the NCEP criteria 48.0% of the patients had metabolic syndrome. More patients receiving aromatase inhibitors had metabolic syndrome than those receiving tamoxifen (60.2% vs. 37.6%, p = 0.008). The frequency of MS among those not taking any hormonal therapy was 45.9%. Additionally, post-menopausal patients had higher rate of MS compared to pre-menopausal ones (53.4% vs. 25.0% p=&lt;0.001). Patients with HER2 positive tumors and patients who had a history of oral contraceptive use had lower rates of metabolic syndrome than those with HER2 negative tumors and no oral contraceptive use, respectively (40,0% vs. 53,7% for HER2, p=0.028 and 32,6% vs. 50,3% for oral contraceptive use, p=0.034).There was no significant correlation between the presence of metabolic syndrome and estrogen/progesterone receptor status, tumor size, nodal status, stage, grade, adjuvant chemotherapy, hormone replacement therapy, smoking history.Conclusions: Nearly half of the patients with stage I-III breast cancer had metabolic syndrome. Adjuvant aromatase inhibitor therapy was found to be associated with higher rate of metabolic syndrome whereas history of oral contraceptive use and HER2 positivity were associated with lower rate. Whether the aromatase inhibitors contribute the development of metabolic syndrome or not needs to be elucidated by future prospective studies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5121.
Estrogen Deprivation Results in Altered DNA Methylation Profile in Breast Cancer Cells – Role in Endocrine Resistance?
Authors: Pathiraja T. , Xi Y. , Lee A. , Santen R. , Gannon F. , Kaipparettu B. , Chang J. , Li W. , Oesterreich S. 
Published: December 2010

Abstract
Postmenopausal breast cancer patients benefit from aromatase inhibitors (AIs) that reduce the levels of estrogens which are critical for tumor growth. To date, epigenetic contributions to hormonal therapy resistance have not been well characterized, with only a limited understanding of antiestrogen mediated epigenetic modification of chromatin and altered gene expression. Furthermore, no genome-wide studies have been undertaken to identify altered DNA methylation patterns due to estrogen deprivation, which mimic AI therapy. We hypothesized that estrogen deprivation results in altered methylation, and therefore altered expression of critical target genes in breast cancer cells, which ultimately helps the cell to survive in the absence of estrogen and thus would contribute to acquire AI resistance in breast cancer patients.We used previously established MCF-7 cell clones, termed C4-12 and LTED (Long Term Estrogen Deprivation) that were isolated after being cultured in estrogen-free media for 9 months and 18-24 months, respectively. A genome-wide methylation screen was done using Methyl CpG binding Domain (MBD) pull down assay followed by hybridization into Affymetrix Human Promoter 1.0R Array. Altered DNA methylations were validated by bisulfite genomic sequencing assays and gene expression of some selected genes were studied by qRT PCR.From the array, we found that long term estrogen deprivation results in widespread genomic hyper- and hypomethylation events. 267 and 301 genes were hypermethylated in C4-12 and LTED respectively. In both resistant cell lines, the number of hypermethyled genes was more prominent than hypomethylated genes since only 82 and 97 genes were hypomethylated in C4-12 and LTED respectively. While hypomethylation of genes generally correlated with increased gene expression, hypermethylation did not in many cases. A gene which was heavily methylated in both cell line system, possibly reflecting a more general and important pathway in estrogen-deprivation, was HOXC10. Transient and stable silencing of HOXC10 in MCF-7 cells resulted in increased cell proliferation in estrogen deprived medium, suggesting a potential role of HOXC10 in developing resistance to endocrine therapy.This is the first genome-wide approach to identify gene-specific epigenetic alterations, and the functional consequences of these changes in developing resistance to estrogen deprivation therapy. This approach allows the development of epigenetic signatures of therapeutic resistance to be used concurrently with genomic signatures to better understand the molecular mechanism of endocrine resistance. This study might provide the basis for future clinical trials such as combination therapy of DNA demethylating agents and aromatase inhibitors.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5127.
Circulating Epithelial Tumor Cell (CETC) Monitoring during SERM and Aromatase Inhibitor Treatment for Early Detection of Patients Resistant to Tamoxifen.
Authors: Pachmann K. , Camara O. , Rabenstein C. , Winzer H. , Runnebaum I. 
Published: December 2010

Abstract
The observation, that part of breast cancer patients benefit from ovarectomy led to the realization that in these patients the estrogen receptor crucially contributes to the growth potential of malignant tumors of the female reproductive system. This has led to the development of compounds specifically binding to the estrogen receptor but without activating activity. Although this has led to an impressive improvement in relapse free survival a considerable part of patients some of which being carriers of the CYP2D6 polymorphism will not respond to this targeted treatment. Therefore, in addition to defining the subpopulation with a high probability of responding to the targeted therapy only an immediate control of the response to treatment will ultimately improve outcome.Epithelial tumor cells circulating in peripheral blood are easily accessible and have been shown to reflect the response of the tumor to therapy. They can, therefore, be used to monitor the effect of therapy also in the adjuvant situation when the tumor has been removed by surgery.Here we report on the application of therapy monitoring using CETCs during adjuvant hormone blocking therapy. ER positive breast cancer were prospectively analysed for the number of CETC before therapy, before each new cycle of chemotherapy and during maintenance therapy with tamoxifen of aromatase inhibitor or during switch from one principle to the other. 1ml of blood was drawn into EDTA vials, red blood cells lysed and the white blood cell pellet stained with FITC-labelled anti-Epcam. Green fluorescent cells were detected by image analysis and dead cells excluded due to red PI fluorescence.178 patients were followed initially at quarterly intervals and later at annual intervals for their numbers of CETCs. 131 patients remained disease free during the observation interval of up to 7 years and 47 (26%) suffered distant relapse. Of the patients in complete continuous remission, 58% showed decreasing or stable CETCs whereas in the patients with relapses 73% showed increasing CETCs.45 patients were subsequently switched to aromatase inhibitor treatment, 17 relapsed patients and 28 patients without evidence of disease. Of the relapsed patients 35% have remained progress free all with a re-decrease in CETCs during AI treatment.Thus, gauging of CETCs can help to monitor hormone treatment and in the future contribute to early switch patients to AI if an increase in CETCs indicates resistance to tamoxifen.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5129.
CD44-Activated HER-2 Signalling in Tamoxifen Resistant Breast Cancer Cells Promotes a Migratory Phenotype.
Authors: Baruah B. , Barrett-Lee P. , Smith C. , Nicholson R. , Hiscox S. 
Published: December 2010

Abstract
Background: Acquired endocrine resistance in breast cancer cells is accompanied by altered growth factor receptor signalling. In tamoxifen-resistant ('TamR') MCF7 cells, our microarray analysis has demonstrated elevated levels of CD44, a transmembrane glycoprotein known to interact with, and modulate the function of, a number of growth factor receptors including members of the erbB family and plays a major role in tumor metastasis. Here, we have explored the role of CD44 as a modulator of erbB activity in TamR cells.Methods: Western blotting and immunocytochemistry were used to investigate expression of CD44 together with the activity of erbB signalling pathways following stimulation of CD44 by its ligand, hyaluronan (HA), or stimulation with erbB ligands (heregulin β1) after knockdown of CD44 expression using siRNA. Immunofluorescence microscopy was used to determine association between CD44 and erbB family members. Cell migration was assessed by seeding cells onto fibronectin-coated microporous inserts for 24 hours and also by performing scratch wound assays. Cell proliferation was determined by WST assay in response to trastuzumab (0-100nM) ± HAResults: CD44 was found to be over-expressed in TamR cells where it co-localized with HER-2. Whilst stimulation of HER-2 with heregulin beta-1 promoted an increase in cell migration, heregulin action was significantly attenuated in the absence of CD44 using siRNA. Moreover, treatment of TamR cells with the natural CD44 ligand, HA, promoted HER-2 signalling through MAPK and an increase in cell migration. Furthermore, whilst TamR cells were sensitive to the growth-inhibitory effects of trastuzumab, these effects were diminished in the presence of HA.Conclusions: Overexpression of CD44 sensitizes tamoxifen-resistant cells to heregulin and HA, factors commonly found within the stromal environment, with a resultant increase in migratory behaviour. Interestingly, activation of CD44 by HA appears to suppress the effects of trastuzumab on cell proliferation. Thus, CD44 may prove a valuable therapeutic target in breast cancer that expresses HER-2 and CD44.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5137.
Different Treatment Benefit for Luminal A and Luminal B Advanced Breast Cancinomas Receiving Aromatase Inhibitors.
Authors: Ruiz-Borrego M. , Moreno A. , Salvador J. , Carabantes F. , Torregrosa M. , Olmos T. , Martinez J. , de la Haba J. , Valero M. , Martinez E. , Santaballa A. , Hernández R. , Murias A. , Tortorella A. , Guzmán C. , Palacios J. 
Published: December 2010

Abstract
Background. Aromatase inhibitors (AIs) are indicated for postmenopausal women with hormone receptor (HR) positive metastatic breast cancer. However, at present the only predictive markers associated to AI response is estrogen receptor (ER) expression. Gene expression profiling of breast cancer has identified two biologically ER-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we analyzed a clinically practical immunohistochemistry assay based on ER, progesterone receptor (PR), Ki67 and HER2 expression to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to AI response.Methods and Results. 41 women with HR positive metastatic breast cancer receiving AIs for their advanced disease have been enrolled in this study. Median age was 67 years (range, 39-84). 71% (29 of 41) of patients have received prior adjuvant therapy for their primary breast cancer. 41% of patients developed visceral disease and 58% of patients non visceral disease. 66% (27 of 41) of patients did not receive other prior treatment to the AI for their metastatic disease. 38 patients have received Exemestane and 3 patients Letrozol. Median duration of treatment was.7.9 months (range 1.2-31). Median follow up of patients was more than one year (14 months (range 1.2- 39.5).Best response to the treatment in 37 evaluated patients was: 11% PRs (CI95%: 0.3-21.3), 2.7% CR (CI95%: 0.0-8.2) and 76% of SD (CI95%: 61.2-90.2); 70% of SD ³ 6 months. Clinical benefit (PR+CR+SD) was 89.2% (CI95%: 78.7-99.7).Treatment benefit depending on the molecular subtype has been evaluated at present in 26 patients. 17 cases were classified as luminal B defined as ER and/or PR low expression levels (Allred score for ER or PR equal or less than 4) and/or Ki67 equal or higher than 15%, and/or HER2-positive. 9 cases were classified as luminal A (Allred score for ER and PR equal or higer.than 5, KI67 lower than 15% and HER2-negative). Although this number of cases is still small, median time to progression seems to be lower in those patients belonging to the luminal B subgroup (303 vs. 496 days) (p=0.1785; RR=2.396)Conclusion: Although analysis of more cases is still awaited, preliminary data from this small exploratory study suggest that the benefit with AIs is lower in those patients whose tumors belong to the luminal B molecular subtype.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5141.
Bortezomib Enhances the Efficacy of Fulvestrant by Promoting the Aggregation of the Estrogen Receptor in the Cytoplasm.
Authors: Germain D. , Bahadur U. , Halpern M. , Adelson K. , Raptis G. , Waxman S. , Ishii Y. 
Published: December 2010

Abstract
Background: Aromatase inhibitors (AIs) are standard treatment for Estrogen Receptor (ER)+ breast cancers in post-menopausal women where the main source of estradiol comes from adipose tissue when the aromatase enzyme converts androgens to estrogens. However, in premenopausal women, functioning ovaries flood the body with estrogens, and aromatase inhibitors used alone offer no therapeutic benefit. In addition to tamoxifen and aromatase inhibitors, estrogen receptor down-regulators, are a third type of anti-estrogen. The first of this class to be FDA approved is Fulvestrant, which acts by promoting the proteosomal degradation of the ER. Like tamoxifen, fulvestrant binds directly to the ER but while tamoxifen has both antagonist and agonist effects on the ER, fulvestrant is a pure antagonist. Other important advantages of fulvestrant over tamoxifen are that 1) fulvestrant prevents the ER from binding DNA, 2) fulvestrant is not linked to increased risk of endometrial cancer, 3) fulvestrant promotes permanent degradation of the ER.The molecular machinery leading to the degradation of the ER in the nucleus following fulvestrant treatment is well described and correlates with its ubiquitination in the nucleus. A less well-recognized mechanism, is fulvestrant’s ability to promote the aggregation of the newly synthesized ER in the cytoplasm. Understanding that protein aggregates are toxic when not eliminated by the proteasome, we took advantage of this effect of fulvestrant to ask whether combining fulvestrant with the proteasome inhibitor Bortezomib could enhance the efficacy of Fulvestrant.Results: We found that bortezomib enhances the aggregation of the ER in the cytoplasm following treatment with fulvestrant. Further, these aggregates were found to be insoluble and to activate the unfolded protein response (UPR), a stress response that leads to cell death. Further, bortezomib is able to prevent the activation of cytoprotective responses linked to the acquisition of fulvestrant resistance. Furthermore, in a breast cancer mouse model of tamoxifen resistance, the combination induced tumor regression.Conclusion: We conclude that adding bortezomib to fulvestrant enhances its efficacy by taking advantage of a previously poorly recognized mechanism–fulvestrant’s induction of ER aggregation in the cytoplasm. Further, our data suggest that this strategy will block the ability of cells to acquired resistance to fulvestrant. Our group has developed a clinical trial that will test this combination.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5142.
Genes Regulated by miRNA in Endocrine-Resistant Breast Tumours.
Authors: Larionov A. , Faratian D. , Caldwell H. , Sims A. , Fawkes A. , Murphy L. , Renshaw L. , Dixon J. , Dixon J. 
Published: December 2010

Abstract
RationaleChange in genes expression is one of the major molecular drivers of tumour growth. Mechanisms controlling genes expression include transcriptional factors, mutations, aberrations in gene copy number, epigenetic mechanisms and micro-RNA (miRNA) regulation. The last mechanism has been discovered recently and there is a need to investigate its involvement in genes regulation in endocrine resistant breast tumours.Methods and ResultsTo identify genes regulated by miRNA in endocrine resistant breast tumours we collected frozen biopsies from a series of 51 tumours growing on endocrine treatment (aromatase inhibitors or tamoxifen, post-menopausal patients). Gene expression profiles were obtained using Illumina HT-12 micro-arrays; miRNA expression profiles were obtained using Illumina DASL® Sentrix Array Matrix.Unsupervised hierarchical clustering using 50 most variable miRNAs split tumours into two major clusters (25 and 26 tumours each). We suggest that genes differentially expressed between these two clusters can be potentially regulated by miRNA. The top differentially expressed genes included SAA1, VTCN1, SLC40A1, FBLN1, COL17A1, HDC and CD59.An alternative bioinformatics approach was based on correlations between mRNA and miRNA in the studied tumours. Initially we identified 66 genes negatively correlated with at least one miRNA (r&lt;-0.6). Then we screened the correlated pairs to identify those in which miRNA has target sequence within the corresponding gene. This approach yielded just 2 genes: RAG1 and USP19: RAG1 being potentially regulated by mir92 and USP19 regulated by miR15a.DiscussionEndocrine resistance is a major obstacle in treatment of many breast cancer patients. Molecular mechanisms of the resistance are yet unclear. The abstract presents a sub-group analysis within a larger study, aimed to investigate molecular mechanisms underlying endocrine resistance at both mRNA and miRNA levels. Most of the identified potential miRNA-regulated genes have not been previously reported in the context of breast cancer biology. On our knowledge, this study represents the first systematic attempt to identify genes regulated by miRNA in endocrine-resistant breast cancers.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5149.