bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic Evaluation of Zoledronic Acid for the Prevention of Osteoporotic Fractures in Post-Menopausal Women with Early Breast Cancer Receiving Aromatase Inhibitors in the United Kingdom.
Authors: Logman F. , Heeg B. , Botteman M. , Kaura S. , van Hout B. 
Published: December 2010

Abstract
Background: Aromatase inhibitors (AIs) are increasingly used as adjuvant therapy in early-stage breast cancer (EBC) and are associated with accelerated bone-loss. Adjuvant therapy with zoledronic acid (ZOL) has been shown to prevent aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women (PMW) with EBC. This analysis assessed, via a model projecting lifetime incidence of osteoporotic fractures as a function of BMD, the cost-effectiveness of adjuvant ZOL for the prevention of fractures in PMW with hormone receptor positive breast cancer (stage I-IIIa) who receive adjuvant letrozole 2.5 mg daily for 5 years and who had a baseline bone mineral density (BMD) T score of ≥-2. Methods: A Markov model was developed to project the lifetime incidence of osteoporotic fractures, quality-adjusted life years (QALY), and healthcare costs as a function of BMD for women with EBC (aged 60 years) receiving adjuvant AIs (for up to 5 years) alone or with ZOL upfront or delayed. Two strategies of adjuvant ZOL therapy compared to no treatment were modelled: starting ZOL treatment only when BMD levels decreased (“delayed ZOL”) and starting ZOL 4mg i.v. q 6mo simultaneously with AI therapy (“upfront ZOL”). ZOL efficacy was derived from the ZO-FAST study (N=1,060) which reported a 5.41% (p&lt;0.0001) difference in percentage BMD change between both strategies after 3 years. Data for the no-treatment arm came from a separate trial of AI in which patients did not receive ZOL. The model runs in annual cycles, over a lifetime horizon. Future costs and effects were discounted at 3.5% annually. Results: Compared to no treatment, delayed ZOL therapy was associated with an estimated QALY gain of 0.026 (CI95%:0.007 – 0.045) and an additional cost of £ 419 (CI95%: £ 367 – £ 473). Delayed ZOL therapy vs. no treatment was estimated to cost £ 16,069 per QALY. Compared to no treatment, upfront ZOL was associated with a gain of 0.079 QALY (CI95%: 0.059 – 0.100), at an additional cost of £ 1,742 (CI95%: £ 1,676 – £ 1,810). The corresponding cost per QALY gained was therefore estimated at £ 21,973. Compared to delayed ZOL therapy, upfront ZOL resulted in a gain of 0.053 QALY (CI95%: 0.039 – 0.062) and additional costs of £ 1,323 (CI95%: £ 1,280 – £ 1,366). The cost-effectiveness ratio for upfront vs. delayed therapy was therefore £ 24,868 per QALY gained. Conclusions: Based on this analysis, upfront ZOL is shown to result in better health outcomes (QALYs) than either delayed ZOL or no therapy. Both ZOL therapy strategies were shown to result in highly acceptable cost-effectiveness ratios compared to no treatment.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1111.
Hyperbilirubinemia in Lapatinib Treated Patients Is Associated with Gilbert's Syndrome UGT1A1 Polymorphism.
Authors: Spraggs C. , Budde L. , Briley L. , Bing N. , Newstat B. , Rappold E. , Mooser V. , Cardon L. , Stein S. 
Published: December 2010

Abstract
Background: Lapatinib, an oral EGFR/HER2 tyrosine kinase inhibitor, is approved in combination with capecitabine for the treatment of patients with advanced or metastatic HER2-positive breast cancer who have been treated previously with an anthracycline, taxane and trastuzumab. Treatment associated elevations in transaminases and bilirubin have been observed in lapatinib clinical trials. A common TA repeat polymorphism in the promoter region of uridine diphosphoglucuronyl transferase (UGT1A1*28, TA7 allele) reduces UGT1A1 enzyme levels and has been associated with hyperbilirubinemia for a range of drugs. We sought to determine the effect of the UGT1A1*28 variant on bilirubin elevation in lapatinib treated patients.Patients and Methods: Association between the UGT1A1 TA repeat polymorphism and total bilirubin levels (TBL) was examined in lapatinib treated patients using data pooled from 12 trials in advanced and metastatic breast cancer. A total of 899 lapatinib treated (as monotherapy or combined with chemotherapy) patients provided a germline DNA sample and were available for this analysis. UGT1A1 TA repeat genotype was determined by PCR amplification and sequencing. For case-control analysis, patients were defined as having normal TBL at baseline, with on-treatment TBL ≥1.5 and ≤1 times upper limit of normal for cases and controls, respectively, and at least 13 weeks of treatment for controls.Results: The UGT1A1 TA repeat polymorphism strongly correlated with lapatinib associated hyperbilirubinemia. A significant association (P=1.03x10-5, 60 cases and 396 controls) was observed. For hyperbilirubinemia cases, 21/60 (35%) were carriers of two TA7 alleles and 28/60 (47%) were carriers of one TA7 allele. Overall, when compared with other genotypes, the odds ratio (95% confidence interval) of the TA7/TA7 genotype for developing hyperbilirubinemia was 10.7 (5.3-21.6).Conclusion: These data suggest that UGT1A1*28 accounts for the major proportion of total bilirubin elevation observed during lapatinib treatment. This is consistent with an underlying predisposition to Gilbert's syndrome. Given the life-threatening nature of advanced and metastatic breast cancer and the benign clinical course of Gilbert's syndrome, these data support treatment continuation with lapatinib for patients with mild to moderate, isolated, indirect bilirubin elevation, when accompanied by appropriate ongoing safety evaluation (eg, bilirubin fractionation, ALT evaluation) to exclude liver injury risk in these patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1112.
Significance of Viral Reactivation in Hepatitis B Virus Carriers with Early Breast Cancer Receiving Anthracycline- or Taxane-Containing Chemotherapy.
Authors: Kim S. , Ro J. , Park I. , Lee K. , Jeong J. 
Published: December 2010

Abstract
Background :It is known that cancer patients in healthy hepatitis B viral (HBV) carrier status are prone to develop hepatic dysfunction during cytotoxic chemotherapy. The objectives of this study were to determine the frequency of healthy HBV carrier status and subsequent viral reactivation resulting in hepatic dysfunction during cytotoxic chemotherapy, and its significance in early breast cancer patients.Methods :Among 3,433 patients with operable breast cancer diagnosed at the National Cancer Center, Korea between January 2001 and March 2009, 3,337 patients were tested for HBsAg. Retrospectively, medical records were reviewed for 139 (4.2%) patients who were positive for HBs Ag.Results :Of 139 patients, 112 patients received anthracycline or taxane based neoadjuvant (n=25) or adjuvant (n=87) combination chemotherapy. Prophylactic lamivudine therapy was administered in 33 patients (29.5%).Thirty of 112 (26.8%) patients developed reactivation of HBV with deterioration of hepatic function during chemotherapy. The rate of reactivaton was not different with or without further taxane therapy (43% vs. 44%, p=0.408).Although there was no significant difference in the rate of chemotherapy delay between two groups, the incidence of early termination of planned chemotherapy was higher in B viral reactivation group (23.3% vs. 4.9%, p=0.008). Within a median follow-up duration of 39 mo (range 1 mo to 95 mo), the rate of disease recurrence was comparable between two groups (10% vs. 18.3%, p=0.390).Lamivudine prophylaxis decreased the rate of HBV reactivation without statistical significance (15.1% vs. 35.4%, p=0.101). Despite more patients without prophylaxis developed G 3/4 AST/ALT elevation (40% vs. 84%, p=0.068), the majority of patients recovered to G 1/2 AST/ALT level within 12 months with anti-viral or supportive treatment (0% vs. 14.3%, p=1.00). One patient without lamivudine prophylaxis developed fulminant hepatic failure after 3rd cycles of neo-adjuvant chemotherapy and received living donor liver transplantation. After that, she received radical mastectomy and maintained adjuvant anti-hormonal therapy.Conclusions :Although lamivudine prophylaxis in HBV healthy carrier decreased the rate of viral reactivation during neo- or adjuvant chemotherapy, the majority of patients irrespective of prophylaxis recovered hepatic function in a year with conservative treatment. Early detection and intensive supportive care are as important as anti-viral prophylaxis in HBV healthy carrier when treated with cytotoxic chemotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1113.
Prospective Study of Ice Gel Pack as Less Expensive Alternative for Prevention of Skin and Nail Toxicity in Patients with Breast Cancer Receiving Docetaxel.
Authors: Matsumoto K. , Hino C. , Fukuda K. , Hamamoto M. , Tanioka M. , Hirokaga K. , Maekawa Y. , Negoro S. , Takao S. 
Published: December 2010

Abstract
Background: Docetaxel (DTX)-induced nail and skin toxicity can be prevented by frozen glove. We investigate whether we can use cooling gel pad (CGP), which is available less than 10 dollars in Japan, as less expensive alternative.Method: Patients (pts) with breast cancer receiving DTX as preoperative or post operative chemotherapy were eligible for this study. Two CGPs, which were refrigerated for eight hours beforehand, were used to cover patient's hand from 15 minutes before to 15minutes after DTX administration. To reduce discomfort from icing, pts were wearing cotton glove during CGP usage. If pts felt CGP as too cold during the cooling process, they were allowed to remove CGP tentatively until they felt comfort. Another hand was not covered as the control. Nail and skin toxicity were assessed at each cycle by CTCAEver.3.0 and documented by photography. Fisher's exact probability test was used. Satisfaction and discomfort of CGP covering was assessed by pts using two item questionnaires. All patients gave written informed consent. The protocol was approved by institutional review board.Result: From October 2006 to September 2008, 50 pts were enrolled to this study. All the patients were female, and received DTX 75mg/m2 in every three weeks schedule for four cycles. Most of patients received DTX after anthracycline-containing regimen. Both nail (10% v 66%, p&lt;0.0001) and skin (0% v 34%, p&lt;0.0001) toxicity was reduced in CGP covered hands. Nail toxicity was grade (G) 0 in 90% v 34%, G1 in 10% v 42%, G2 in 0% v 22%, and G3 in 0% v 2%, for CGP covered and the control hand, respectively. Skin toxicity was G0 in 100% v 66%, G1 in 0% v 4%, G2 in 0% v 30% in CGP covered hand and the control hand, respectively. About the timing of toxicity occurrence, “after the first cycle” was most common, 13 pts (39%) in nail change and 7 pts (41%) in skin toxicity. In the questionnaires, 94% were satisfied with CGP covering.Discussion: The iced CGP cover method reduced the incidence and severity of nail and skin toxicity associated with DTX, even if patients wear cotton glove and remove CGP for a while, in case of excess coldness. This method has no adverse effect, and patients were satisfied with the effect. The iced CGP may be considered as a new, effective and less expensive method for prevention of nail and skin toxicity caused by DTX.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1114.
Abnormalities of 53BP1 in Basal-Like Breast Cancer.
Authors: Aly A. , Yang Q. , Bilal E. , Yao M. , Bhanot G. , Toppmeyer D. , Haffty B. , Ganesan S. 
Published: December 2010

Abstract
Background: Abnormalities in the DNA repair mechanism have been proposed to play a central role in the development of breast cancers. However the specific mechanism underlying DNA repair defects in sporadic breast cancer are mostly unknown. As 53BP1 plays a critical role in DNA repair response and has been identified as a potential tumor suppressor, its expression in basal-like breast cancer cell lines and clinical samples was investigated.Experimental Design: mRNA expression of 53BP1 was investigated in publicly available gene expression data sets. Protein expression of 53BP1 was evaluated in a large set of clinically annotated breast cancer specimens by immunohistochemistry. Analysis of 53BP1 and related proteins was performed in a set of human and mouse breast cancer cell lines.Results: Gene expression analysis demonstrated that a subset of basal-like breast cancer had decreased expression of 53BP1. Analysis of over 400 breast cancers in a tissue microarray showed that loss of 53BP1 staining was almost exclusively found in tumors that lacked ER, PR and HER2 expression; this "triple-negative" phenotype is characteristic of BLC. Approximately 42% of "triple-negative" breast cancers have abnormally low levels of 53BP1, while &lt;2% of tumor that express either ER or HER2 lack 53BP1 expression. Tumors that have low 53BP1 expression are associated with worse distant metastasis free survival when compared to tumors with normal 53BP1 expression. A set of breast cancer cell lines with abnormal 53BP1 expression was also identified. 53BP1 abnormalities were present in some tumors and cell lines with known BRCA1 mutations.Discussion: These data suggest that a subset of basal-like breast cancers lack normal 53BP1 expression and imply that these tumors may have profound defects in DNA repair/check point function that could be exploited therapeutically. As 53BP1 abnormalities were found in some tumors with known BRCA1 mutations, this suggests that loss of 53BP1 may cooperate with abnormalities in the BRCA1-related DNA repair pathways in the pathogenesis of basal-like breast cancers. Data regarding the molecular mechanisms underlying 53BP1 abnormalities in breast cancer cell lines and samples will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1122.
Estrogen and IGF-I Independently Down-Regulate Critical Repressors of Breast Cancer Growth.
Authors: Casa A. , Casa A. , Malik S. , Malik S. , Lazard Z. , Kuiatse I. , Tsimelzon A. , Creighton C. , Hilsenbeck S. , Lee A. , Lee A. , Lee A. , Oesterreich S. , Oesterreich S. , Oesterreich S. 
Published: December 2010

Abstract
Background: Estrogen receptor and insulin-like growth factor (IGF) signaling pathways are important for both normal mammary gland development and breast cancer pathogenesis. Despite this evidence, cross-talk between these two critical mitogenic and survival pathways remains poorly understood, particularly at the level of downstream gene transcriptional networks.Methods: We performed microarray analysis on ER-positive MCF-7 breast cancer cells following stimulation with either estradiol (10nM) or IGF-I (10nM) for 3hr or 24hr. We defined an E2-IGF gene expression signature and examined the effect of the gene signature on time to recurrence in ER+ tumors in the publicly available NKI dataset. Q-RT-PCR was used to validate the effects of IGF-I and E2 on mRNA of repressed genes. To examine gene regulation further, MCF-7 cells were incubated with various signaling inhibitors and gene expression measured.Results: We found 183 probesets to be co-regulated by E2 and IGF-I after 3hr of stimulation and 454 probesets to be co-regulated at the 24hr time point. Patients with tumors that had the same set of genes up- and down-regulated had a poor outcome (p=7.04E-07). E2-IGF co-regulated genes showed a significant enrichment for down-regulated genes (p&lt;0.001). The top 10% of down-regulated genes contained four (BLNK, SOCS2, CCNG2, and ING4) that have previously been shown to have tumor suppressor function and/or show loss in human breast tumors. We confirmed that E2 and IGF-I indeed repressed levels of these candidate genes. Blockade of ER by ICI 182780 (ICI) completely reversed E2-mediated repression but had little or no effect on IGF-mediated repression of these genes. Similarly, blockade of IGF-IR was able to completely reverse IGF-I-mediated repression of all four genes, but had essentially no effect upon E2-mediated repression. Inhibition of the PI3K pathway with LY294002 (20μM) affected short-term (3hr) down-regulation of BLNK and SOCS2 by both E2 and IGF-I, and CCNG2 by IGF-I. By 24 hours, LY completely reversed both E2 and IGF-I mediated repression of CCNG2, and significantly reversed both E2 and IGF-I repression of BLNK and SOCS2. Blockade of MEK1/2 with U0126 (10μM) had no effect on short-term repression by E2 or IGF-I, though after 24hr it affected both E2 and IGF-I repression of BLNK and SOCS2.Conclusions: E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. E2 and IGF-I down-regulate several critical tumor suppressor genes. While the down-regulation is independent of each other at the level of ER and IGF-IR, for some genes, there is convergence on the PI3K pathway for repression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1126.
Let-7 Inverts the Chemoresistance of Breast Tumor-Initiating Cells.
Authors: Yu F. , Wu J. , Gong C. , Su F. , Song E. 
Published: December 2010

Abstract
Background: Cancers may arise from rare self-renewing highly tumorigenic “stem” cells, which are thought not only to be the source of the tumor, but also to be responsible for resistance to cancer therapy and subsequent tumor recurrence. Our preliminary data strongly suggest that let-7 is a master regulator of BT-IC self-renewal and multipotency. It is likely that let-7 regulates many other genes/pathways during BT-IC differentiation. However, we do not know whether let-7 might also regulate other putative aspects of “stemness” such as chemoresistance.Material and Methods: Quantified qRT-PCR was used to test the expression of let-7a in chemoresistant breast tumor tissue from patients, as well as the chemosensitive samples. The location of let-7a in primary breast cancer samples from patients with chemoresistance were compared to the samples without chemoresistance by in situ hybridization analysis.SK-3rd Cells, which is a cell line enriched in breast tumor-initiating cells, were cultured in suspension to form mammosphere which could be induced to differentiation with adhesive culture. Lentivirus-mediated let-7a transduction was used to increase the expression level of let-7a.Let-7 target gene expression (HRAS and HMGA2) was determined by qRT-PCR and western blot. The response of BT-ICs to chemotherapy was determined by MTT, Annexin V and Tunel.Results: The expression level of let-7a microRNA in chemoresistant patients were significantly lower than the patients without chemoresistance (P&lt;0.05). The let-7a mimics can effectively enhance the expression of let-7a in mammospheric SK-3rd cells, and reduced the expression level of H-RAS and HMGA2 proteins, which are the targets of let-7. Mammospheric SK-3rd cells tranfected with let-7a mimics had a lower proliferation rate and a higher apoptosis rate under epirubicin treatment.Conclusion: Lack of expression of let-7 regulates BT-IC resistance to chemotherapy. Therefore, let-7a may be an effective maker to predict the response of tumor to chemotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1136.
Increased Nuclear Localization of Transcription Factor Y-Box Binding Protein 1 Accompanied by Up-Regulation of P-Glycoprotein in Breast Cancer Pretreated with Paclitaxel.
Authors: Fujita T. , Nagura N. , Koshikawa K. , Nishimura H. , Ito K. , Izumi H. , Kohno K. , Fujimori M. 
Published: December 2010

Abstract
Purpose: The Y-box binding protein 1 (YB-1) regulates expression of P-glycoprotein (P-gp) encoded by the MDR1 gene. There have been no previous studies regarding the involvement of YB-1 in the development of resistance to paclitaxel. The present study was performed to examine how paclitaxel affects the localization and expression of YB-1 in breast cancer.Experimental Design: We evaluated the expression and localization of YB-1 and P-gp in breast cancer tissues obtained from 27 patients before and after treatment with paclitaxel. The effect of paclitaxel on localization of cellular YB-1 was examined by using GFP-YB-1. Interaction of YB-1 with the Y-box motif of the MDR1 promoters was studied by EMSA. The effects of paclitaxel on MDR1 promoter activity were examined by luciferase assay.Results: Of 27 breast cancer tissues treated with paclitaxel, nine (33%) showed translocation of YB-1 from the cytoplasm to the nucleus together with increased expression of P-gp during the course of treatment. Twelve breast cancer tissues (44%) showed neither translocation of YB-1 nor increased expression of P-gp. Nuclear translocation of YB-1 was correlated significantly with increased expression of P-gp (P=0.0037). Confocal analysis indicated that paclitaxel induced nuclear translocation of green fluorescent fused YB-1 in MCF7 cells. Furthermore, binding of YB-1 to the Y-box of MDR1 promoter was increased in response to treatment with paclitaxel. In addition, MDR1 promoter activity was significantly up-regulated by paclitaxel in MCF7 cells (p&lt; 0.001).Conclusions: The results of the present study suggested that YB-1 may be involved in the development of resistance to paclitaxel in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1141.
Methylation Status of Promoters 0K, 0N and a Newly Identified Promoter Regulate ERβ1 Expression in Breast Cancer.
Authors: Al-Nakhle H. , Smith L. , Hughes T. , Cummings M. , Hanby A. , Shaaban A. , Burns P. , Speirs V. 
Published: December 2010

Abstract
Gene expression is regulated at multiple levels, including transcriptional silencing by methylation. ERβ1 is downregulated in breast cancer compared to normal breast and mechanisms surrounding this are unclear. Two novel ERβ mRNA isoforms with distinct 5'-UTRs have been identified, ERβ-0K-1 and ERβ-0N-1. The aim of study was to examine whether methylation at these promoter regions plus a novel promoter identified by our group were involved in ERβ1 regulation (figure 1).Bisulfite modification and direct sequencing analysis were performed for promoters 0K, 0N, and a novel mini CpG island upstream of ERβ exon1 in two ERβ1- and one ERβ1+ breast cancer cell lines. Distinct methylation patterns were observed. Promoter 0N was completely methylated in BT20, partially methylated in MDAMB453 and unmethylated in T47D, while the mini CpG island was methylated in all 3 cell lines. In contrast, promoter 0K was unmethylated. Furthermore, a negative correlation between ERβ1 mRNA expression and the methylation status of promoter 0N was observed in breast cells. To further investigate whether methylation of the ERβ1 promoter was responsible for the loss of ERβ1 expression, BT20 and MDAMB453 cells were treated with either 5-aza-dC, TSA or both, concentrations of which had been previously optimised for each cell line. In BT20 cells which had complete methylation of 0N, both agents were required for induction of ERβ1 and ERβ-0N-1 but not ERβ-0K-1 expression, both of which are part of the 5'UTR region. However in MDAMB453 treatment with 5-aza-dC was sufficient to induce ERβ1 and ERβ-0N-1 expression with no additional re-expression seen with TSA and no effects on ERβ-0K-1. This suggests that promoter 0N is responsible for driving the transcription of ERβ1. On going work is confirming these observations in clinical samples. Our results suggest that promoter 0N plays an important role in regulation of ERβ1 mRNA expression in breast cancer. Our results add to growing literatures which demonstrate ERβ1 is regulated at multiple levels in breast cancer and that DNA methylation is an important mechanism for silencing ERβ1 gene expression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1148.