bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential utility of angiotensin II receptor blockers in the treatment of estrogen receptor positive infiltrating ductal carcinoma.
Authors: Jin S , Coopersmith R , Byrnes J , White D 
Published: December 2010

Abstract
Abstract #2125
Despite significant advances in diagnosis and treatment, breast cancer remains the world's leading cause of cancer mortality in women. In this study we employed differential expression analysis tools to mine the BioExpress®(1) database of transcriptional profiles and found that Angiogtensin II receptor 1 (AT1-R) mRNA expression was highly correlated with expression of estrogen receptor alpha (ERα) in biopsies from patients with infiltrating ductal carcinoma (IDC). Specifically, AT1-R transcript was up-regulated 12.5 fold in ER+ primary IDC relative to ER- primary IDC (P = 0.0001).&#x2028; Experiments using ER+ (T47D) and ER– (HCC1143) breast cancer cell lines derived from human mammary gland ductal carcinoma demonstrated that only the ER+ line responded to angiotensin II-mediated growth stimulation, and this effect was dramatically suppressed in a concentration dependent manner by AT1-R blockers (ARBs). Additional cell culture experiments evaluating eight cell lines derived from IDC further validated the concept that co-expression of both ERα and AT1-R was required for responsiveness to angiotensin II-induced cell proliferation. We have also found that ARBs significantly enhanced the anti-proliferative activity of both tamoxifen, an ER modulator, and formestane, an aromatase inhibitor. Most importantly, we have shown in a T47D tumor xenograft model that ARBs, candesartan and irbesartan, dose-dependently inhibited tumor progression in NODScid mice. Currently, we are evaluating the synergistic/additive effects of ARBs with tamoxifen in additional T47D xenograft models.&#x2028; In conclusion, our data provides evidence that ARBs may have utility in the prevention and treatment of ER+ IDC. These observations further validate reports that ARBs may suppress tumor cell proliferation, angiogenesis, and cancer progression. To our knowledge our findings represent the first example of a potential means to stratify a patient population for ARB-based tumor therapy using a clinically accepted biomarker, findings which may have significant clinical implications for the treatment of IDC.&#x2028; 1) BioExpress® is a knowledgebase of human disease biology comprising over 20,000 individual patient samples profiled over the entire human transcriptome representing &gt; 400 disease states including approximately 200 human breast cancer samples (169 diagnosed as IDC) and 68 normal breast tissue controls.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2125.
Doxorubicin pharmacokinetics following two different liposomal formulations (CAELYX™ vs MYOCET™) in advanced breast cancer patients.
Authors: Schueller J , Czejka M , Krexner E , Aigner K , Gruenberger B 
Published: December 2010

Abstract
Abstract #2128
Background: Liposomal encapsulation of Doxorubicin (DOX) was designed to minimize healthy tissue distribution by altering pharmacokinetics (PK) thus reducing cardiotoxicity while preserving antitumour efficacy. Study objective was to compare the PK behaviour of the two main liposomal formulations of DOX, i.e. pegylated (Caelyx, C) versus non pegylated (Myocet, M), in a single center study including 17 MBC patients, all Anthracyclin pretreated with additional risk faktors.&#x2028; Methods: Cohort 1 consisted of 10pts (mean age 62, 49-77) treated by C as 1HR infusion of 50mg/m²/4 wks. Plasma samples were collected at timepoints min 0, 30, 60, 120, 180 and d1, 7, 14, 28. In cohort 2, 7 pts (mean age 58, 51 – 70) received M 75mg/m² 1H Infusion / 3wks, plasma levels determined at min 0, 30, 60, 90, 120, 180 and d1, 2, 3. Total amount of DOX was determined following the 1st infusion respectively, analytic procedure included solid phase extraction quantification by HPLC and PK analysis by Win Nonlin Pro. Doxorubicinol was detected after M only.&#x2028; Results: in Cohort1 after C, mean Cmax of 6.8 µg/ml surprisingly occured at a mean tmax of 2.3 d, log conc time curve showed linear decrease of DOX conc suggesting continuous release into the tissue (mean conc d 7 3.3, d 14 1.0, d 21 0.3, d 28 0.09 µg/ml) . No metabolites were found, AUC (does not represent reliable drug exposure and bioavailability of DOX) expressed as µg/ml.d was 54.6. In contrast AUClast of M was calculated as 35µg ml.H and mean Cmax by 7.5 µg/ml at infusion end. DOXol was measured in all M treated patients at a slower metabolisation rate and late appearance compared to conventional DOX. t/2 el of C was 6 times longer than that of M (HR 90 vs 15). Differences in plasma disposition and PK of M vs C are depicted in table 1 and compared to pooled data of conventional DOX derived from former studies (50 mg/m² 30min inf, n=40). Cltot of conv. DOX was 10 fold higher than M and 500 fold higher than C, Vss about 12 times that of M and 70 times that of C. These PK differences underlines a different toxicity profile between PEGL (C, PPE syndrome) and NPEGL (M, myelotox, nausea), both reducing cardiac tox by avoiding peak plasma levels due to prolonged circulation time.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2128.
The thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist troglitazone alters histone post-translational modifications in MCF7 breast cancer cells.
Authors: Davies GF , Ross AR , Juurlink BH , Troy HA 
Published: December 2010

Abstract
Abstract #2140
Troglitazone (TRG), a thiazolidinedione (TZD) PPARγ ligand, is a potent antiproliferative agent in many different cancer cell lines. We have previously demonstrated in multiple drug resistant (MDR) human K562 leukemia cells that TRG, in combination with the anthracycline antibiotic Doxorubicin (DOX), is an effective anticancer agent in MDR cells. The killing of drug resistant leukemia cells was accompanied by increased global histone H3 acetylation. In this report, we investigated the effects of TRG on both histone metabolism and killing of human MCF7 breast cancer cells. MCF7 cells were treated with TRG, as well as additional TZD's, such as Rosiglitazone, Ciglitazone and Pioglitazone. In all cases, a dose-dependent increase in H3K9 acetylation, total H2AX protein levels, and cell killing were noted. Striking similarities in histone modification profiles were also noted between TRG and histone deacetylase inhibitor (HDACi) treatment. A wide spectrum of common histone post-translational modifications (PTMs) were specifically induced by TRG and HDACi treatment, as determined by mass spectrometry.&#x2028; &#x2028; These findings suggested that TRG may possess HDACi activity. In support of this, in vitro HDACi activity assays showed TRG, but not other tested TZDs, possessed HDACi-like activity. Global H3K9 acetylation was also increased by inhibition of the PI3K/AKT pathway (but not the MEK/ERK pathway), raising the possibility that TRG and HDACi's may act via inhibition of AKT. Consistent with this idea, MCF7 cells treated with TRG or HDACi's exhibit reduced phosphorylated AKT. Our data supports a mechanistic model linking TRG with inhibition of histone de-acetylation in human breast cancer cells.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2140.
Development of a targeted topoisomerase I inhibitor for anticancer therapy.
Authors: Cao YZ , Yang J 
Published: December 2010

Abstract
Abstract #2146
Background:&#x2028; DNA topoisomerase I (Top1) has been identified as the molecular target of a variety of drugs, due to the important roles that they play in biological systems. Studies show that breast cancer cell lines are sensitive to Top1 agents such as camptothecin. Recent clinical trials have suggested that breast cancer patients may respond to drugs which target Top1. This suggests that some breast cancers may have elevated expression of the enzyme.&#x2028; Thus, development of Top1 inhibitors may be a good target for anticancer therapy. To better target cancer cells, the drugs can be linked to a pH-sensitive linker such as the N-Ethoxybenzylimidazoles (NEBIs) developed in our lab. The NEBIs are designed to undergo hydrolysis in slightly acidic aqueous solutions at physiological temperature, comparable to the environment found in endosomes, lysosomes, and the extracellular environment of tumors. The hydrolysis of the NEBI causes the dissociation of the drug from a carrier (e.g. Herceptin), and the rates can be tuned by modifying the electron withdrawing and donating groups on the NEBI ring. It was demonstrated that the rates can be tuned to give half-lives ranging from 36 minutes to 9 months.&#x2028; Materials and Methods:&#x2028; We have developed a new class of imidazole-containing drugs which may inhibit Top1 activity. These compounds have a 4-ring, indenoisoquinoline structure and were synthesized by a simple condensation reaction which gives good yield. Ring substituents were modified to achieve molecules of optimal potency. The resulting drugs were subsequently linked to the NEBI, and hydrolysis studies were performed to determine the rate of active drug release.&#x2028; &#x2028; Cytotoxicity of cleaved drugs was screened using the sulforhodamine B (SRB) assay and topoisomerase inhibition assays will be performed in the near future.&#x2028; Results:&#x2028; Cytotoxicity studies showed that the hydrolyzed drugs are toxic to the 10μM range in cancer cells. One of the compounds has recently been approved for the National Cancer Institute screen, in which the activity will be evalutated with 60 different cancer cell lines of diverse tumor origins. Ongoing studies will assess the topoisomerase I inhibition activity of these compounds.&#x2028; Discussion:&#x2028; We have developed a novel prodrug which comprises of a toxic Top1 inhibiting drug attached to a pH-sensitive linker. This may prove to be an effective approach to anticancer therapy. Future studies will be pursued in using folic acid as the drug carrier to target breast cancer cells. Studies show that folate receptor overexpression is associated with poor outcome in women with breast cancer. Furthermore, it has been shown that folate receptors may undergo endocytosis, which will trigger the release of the active drug from the linker.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2146.
The safety of dose-dense liposomal-encapsulated doxorubicin in association with docetaxel (MyTax) in breast cancer.
Authors: Mancini M , Cannita K , Santomaggio A , Tudini M , De Galitiis F , Morelli M , Rispoli A , Martella F , Porzio G , Pelliccione M , Cocciolone V , Lanfiuti Baldi P , Penco M , Romano S , Fratini S , Stifani G , Marchetti P , Ficorella C , Ricevuto E 
Published: December 2010

Abstract
Abstract #2157
Background: Liposomal-Encapsulated Doxorubicin (LED) shows equivalent efficacy, better cardiac tolerability at higher cumulative dose than conventional anthracyclines in breast cancer treatment.&#x2028; Methods: Sixteen pts were enrolled in a dose-finding study of LED (TLC-D99 Myocet ®) associated to Docetaxel (TXT). Twelve pts were treated with a fixed TXT dose (50 mg/m2) and TLC-D99 at three dose levels, 40-45-50 mg/m2, days 1 and 15 every 2 weeks using an intra- and inter-patient approach; four pts wrere treated at the TLC-D99 recommended dose (50 mg/m2). Cardiac monitoring of LVEF was performed every two cycles; Precursor Brain Natriuretic Peptide (proBNP) and cardiac Troponin (c-TnI) before and after 24 h chemotherapy was evaluated.&#x2028; Results: Breast cancer (BC) disease extension: metastatic (MBC), 8; locally advanced BC, 5; T2-T3 BC, 3. Previous chemotherapy: untreated, 11 pts; adjuvant, 5 pts. Enrolled pts for each dose-level: I, 7; II, 9; III, 14. Newly treated pts: I dose-level, 7; II dose-level, 3; III dose-level, 6. Valuable cycles for each dose-level in a total 77 cycles: I, 14; II, 21; III, 42. DLTs were observed in 3 pts, 21%, and 3 cycles, 4%: 2 cardiac, characterized by a 19% LVEF decrease and a symptomatic arrhythmia; one G4 hematologic resistant to G-CSF. DLTs for each dose-level by pts and cycles, respectively: I, 14% (1/7 pts) and 7% (1/14 cycles); II, no DLT in 9 pts and 21 cycles; III, 14% (2/14 pts) and 5% (2/42 cycles). Cumulative G3-4 toxicities by pts and cycles, respectively: cardiac arrhythmia 6% and 1,3%, cardiac general (symptomatic LVEF decrease), 6% and 1,3%; alopecia 81% and 65%; neutropenia resistant to G-CSF, 6% and 1,3%. Cardiac DLTs were observed in 2 elderly pts (&gt;65 y). The 2 cardiac DLTs were observed in 2 out of 3 pts with pre-existing diastolic dysfunction. No pathologic increase of c-TnI levels was detected. Seven pts showed increased pro-BNP after chemotherapy; 1 of these with increased pro-BNP after chemotherapy, persistent the day 1 of each subsequent chemotherapy showed a DLT;&#x2028; G2 toxicities by patients and cycles, respectively: asthenia 37% and 18%, stomatitis/mucositis 12% and 5%, nausea 31% and 12%. Median rDI of TLC-D99 was 25 mg/m2/w and TXT 25 mg/m2/w for pts, respectively. Preliminary efficacy in 16 assessable pts: LA-BC and MBC, 1 CR (pCR) 7 PR (OR 62%), 4 SD and 1 PD; T2-T3 BC, 2 PR and 1 SD.&#x2028; Conclusion: dose-dense TLC-D99/Docetaxel association can be safely recommended at the dose of 50 mg/m2 for each drug. Docetaxel intensification is ongoing.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2157.
Aberrent hedgehog signaling is an early event in breast cancer development.
Authors: O'Toole S , Swarbrick A , Millar E , McLeod D , McNeil C , Qiu M , Lopez-Knowles E , Caldon E , Oakes S , Ormandy C , Morey A , Musgrove E , Henshall S , Sutherland R 
Published: December 2010

Abstract
Abstract #24
Background: The Hedgehog (Hh) signaling pathway is a highly conserved system which regulates development and cell fate. It also contributes to the pathogenesis of a number of human malignancies, including basal cell, prostate and pancreatic carcinoma as well as medulloblastoma. There is emerging evidence that Hh may play an important role in breast cancer.&#x2028; Methods: We examined the immunohistochemical expression of key Hh proteins, sonic hedgehog (Shh), Patched (Ptch) and Gli1 in 3 cohorts of patients; 2 independent cohorts of the histological progression model of breast cancer and a cohort of 292 patients with a median follow up of 5.5 years. We also investigated expression of Shh in the C3/SV40T mouse model of mammary carcinogenesis. We then investigated the effects of recombinant Shh in the MCF10A in vitro model of early breast cancer development. Finally, a mammary reconstitution graft model was employed where donor mammary epithelial cells were briefly cultured and transduced with a retroviral construct carrying a Shh-GFP construct, then transplanted into the cleared mammary fat pad of a recipient mouse.&#x2028; Results: Overexpression of Shh was an early event in human premalignant lesions, with progressive increases (p&lt;0.05) with the development of hyperplasia, atypia and malignancy in both test and validation progression cohorts. Similar results were observed in the mammary gland lesions of the C3/SV40T mouse. In human breast cancer, overexpression of Shh was associated with a poor prognosis (recurrence HR=2.0, p=0.003 and breast cancer specific death (HR=2.4, p=0.002) and also associated with a poor prognosis in chemotherapy (HR=2.4, p=0.03) and endocrine therapy (HR 3.5, p=0.03) treated patients. There was a highly significant (p=0.004) association by chi squared analysis with the basal-like subtype of breast cancer. Based on these data, we investigated the effects of Shh in 2 experimental systems – Shh caused disorganization of MCF-10A acini and was associated with the development of an unusual discohesive phenotype. In the mammary graft model, expression of Shh was associated with ductal epithelial hyperplasia in 58% of ducts, compared to 5% of controls.&#x2028; Conclusion: These experimental data suggest that excessive Shh may cause hyperplasia and dysplasia of normal human and murine mammary gland epithelium. Together with our observations in human breast preinvasive and malignant lesions, these results support a role for aberrant Hh signaling in breast carcinogenesis.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 24.
A UK NEQAS ring study evaluating observer variation in the diagnosis of HER2 amplification using the Kreatech™ HER2 FISH probe.
Authors: Bartlett JM , Campbell FM , Ibrahim M , Thomas J , Wenyck P , Ellis IO , Kay E , Connolly Y , O'Grady A , Cunningham P , Barnett S , Starczynski J , Miller K 
Published: December 2010

Abstract
Abstract #3005
Background: Whilst HER2 testing is well established as a key requirement for all newly diagnosed breast cancers the quality and consistency of HER2 testing remains a point of controversy. Most countries use FISH or ISH based testing for HER2 gene amplification in equivocal (IHC 2+) cases. Data on reproducibility and portability of novel and even established HER2 methods is sparse. We report on a multicentre evaluation of intra and inter-observer/site variation in scoring HER2 results from 45 breast cancers measured in 8 laboratories using the Kreatech™ HER2 FISH probe.&#x2028; Methods: A commercial tissue micro-array (TMA; Stretton Scientific UK) containing 2 replicate cores from 45 breast cancers was circulated to 8 laboratories with varying experience in FISH methodology. Five laboratories (1-5) were UK NEQAS reference labs, 3 further experienced routine diagnostic labs (A-C) participated in the scheme designed to test the site to site reproducibility of the Kreatech™ FISH probe. All laboratories FISHed a 90 core TMA and 7/8 reported results for all assessable cores, 1 lab reported 1 result per evaluable cases (as per the original study design). Results were collated centrally and analyzed for intra and inter-observer between both “reference” laboratories (labs 1-5) and non-reference laboratories (A-C).&#x2028; Results: Overall 81% of cores (range 70-94%) were successfully analysed by Kreatech™ FISH. Intra-observer variation was lower than expected at 4.7% (range 3.5-8.4%) for HER2 ratio. Mean intersite variation in HER2:Chr 17 ratio was significantly lower (8.5%) for reference vs non-reference (13.4%) laboratories (p=0.0013). Of 546 reported cores only 7 (1.3%) were discordant (with 4 borderline). Analysis of site to site variation highlighted possible systematic differences in scoring approaches in 3/8 laboratories including a “reference laboratory”.&#x2028; Conclusions: Intra- and inter-observer variation of absolute HER2 ratios appears to be tightly controlled across 8 laboratories using Kreatech™ HER2 FISH probes. Detailed comparisons of scoring results suggests some systematic differences between a few laboratories in the interpretation of FISH. However the majority of laboratories show extremely tight reproducibility of numeric HER2 FISH results. This study highlights the potential for extremely robust and quantitatively reproducible FISH results from both “diagnostic” and “reference” laboratories. However it also suggests continued quality assessments are essential to good performance.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3005.
“Polysomy 17” by FISH for HER2 in breast cancer is a misnomer: results of chromosome 17 analysis by array comparative genomic hybridization.
Authors: Yeh I , Martin MA , Robetorye RS , Gunn S 
Published: December 2010

Abstract
Abstract #3008
Background: The term “polysomy 17” has been widely used to refer to breast cancer cases in which fluorescence in situ hybridization (FISH) assays for HER2 were performed and found to contain &gt;3 copies of the chromosome 17 centromere (probe CEP 17, D17Z1). The proportion of breast cancers that are reported to have polysomy 17 varies, but some studies report over 40% incidence. In these cases, the centromere is assumed to be representative of the entire chromosome. In this study, we analyzed chromosome 17 in breast cancers using bacterial artificial chromosome (BAC) array comparative genomic hybridization (array CGH) to assess the incidence of whole chromosome 17 polysomy.&#x2028; Design: Fresh frozen tissue from 95 breast cancers was analyzed, including 84 invasive ductal carcinomas, 10 invasive lobular carcinomas, and one case with mixed ductal-lobular features. Frozen sections were reviewed to ascertain tumor content, and genomic DNA was isolated from 25-50 mg of tissue from each case. Samples were then analyzed by array CGH using an array that included whole genome coverage as well 63 probes for chromosome 17. A subset of 29 cases was also analyzed by FISH using the Vysis Pathvysion HER2 assay, which includes a chromosome 17 centromere probe and a HER2 probe.&#x2028; Results: Multiple abnormalities were identified on chromosome 17, including losses and gains in both the p and q arms. Examination of the centromeric region by array CGH showed 6 cases with gains, and 10 cases with losses. Three of six cases with centromeric gains also showed HER2 amplifications. Two cases showed polysomy by FISH. Although other chromosomes in our study exhibited whole chromosome polysomy using array CGH, no cases showed complete polysomy of chromosome 17.&#x2028; Conclusions: A review of the literature for chromosome 17 polysomy in breast cancer reveals that this finding almost exclusively relies on FISH analysis using chromosome 17 centromere probes. Our analysis of 95 breast cases by array CGH did not reveal any gains of whole chromosome 17. These results suggest that whole chromosome 17 polysomy is extremely uncommon in breast cancer. Those cases that are identified to have chromosome 17 polysomy by FISH are better termed “chromosome 17 centromere amplified.”
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3008.
Comparison of fluorescence in situ hybridization and dual color chromogenic in situ hybridization for the assessment of HER2 status on core-needle breast cancer biopsies.
Authors: Suárez-Gauthier A , García-García E , Conde E , Muñoz A , Torres M , Miró C , García-Estevez L , López-Ríos F 
Published: December 2010

Abstract
Abstract #3015
Background: Core-needle biopsies have been shown to be extremely useful for evaluation of prognostic and predictive markers. In breast cancer patients, this is particularly important in the setting of neoadjuvant chemotherapy. However, it is well known that immunohistochemistry can give conflictive results on small biopsies or core-needle biopsies. This study evaluates the concordance between HER2 gene amplification determined by fluorescence in situ hybridization (FISH) and a new dual color cromogenic in situ hybridization (CISH) in a series of core-needle breast biopsies.&#x2028; Material and Methods: A total of 37 invasive breast carcinomas diagnosed on core-nedle breast biopsies were selected from our files. Dual color FISH (Dako, Glostrup) and dual color CISH (Dako, Glostrup) were performed in each case. Scoring of the FISH and CISH slides was identical, counting HER2 and CEN-17 signals from 60 tumour nuclei per case. Finally, the gene to CEN-17 ratio was calculated using the cut-off value of HER2/CEN-17 ratio &gt;2 as amplified.&#x2028; Results: All 37 specimens were analyzed successfully by CISH and FISH. A high concordance was found between FISH and CISH in the assessment of HER2 status. 12 cases were amplified and counted easily with both techniques, showing similar ratios. Polysomy was also detected with both techniques in 5 cases with no amplification.&#x2028; Discussion: Given the presumed heterogeneous expression of HER2 immunohistochemistry on core-needle biopsies, dual color CISH might be an alternative to FISH in this setting. Moreover, CISH allows for a better concurrent analysis of morphology, which is particularly important when studying small samples.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3015.