bluuebunny/crossref_metadata_2025_split huggingface dataset:
First Results from the “Patient's Anastrozole Compliance to Therapy Programme” (PACT) Evaluating the Impact of a Standardized Information Service on Compliance in Postmenopausal Women with Early Breast Cancer (EBC) Receiving Adjuvant Endocrine Therapy.
Authors: Harbeck N. , Hackisch C. , Blettner M. , Lück H. , Hadji P. , Landthaler R. , Martin R. , Schmitt D. , Schulte H. , Rexrodt von Fircks A. , Haidinger R. , Jäger D. , Zaun S. , Kreienberg R. 
Published: December 2010

Abstract
Background: In adjuvant treatment of hormone-responsive breast cancer, existing data document that 23% and 50% of patients were non-compliant after the first and fourth year of tamoxifen (TAM) therapy, respectively. Here, we present the PACT-study that aims to increase awareness, motivation and adherence to oral hormonal therapy, namely the aromatase inhibitor anastrozole, in routine clinical practice by simple interventions such as written standardized mailings and reminder services.Materials and Methods: In this two arm, parallel group trial with a primary duration of 12 months and 60 months follow-up, women with hormone receptor positive EBC receiving anastrozole once daily were randomized to either routine clinical care alone or to receiving additional standardized information for the first 12 months of adjuvant therapy. Primary endpoint is compliance rate in the standard versus intervention arm after 12 months, where compliance is defined by an 80% intake of the total medication. Secondary endpoints include persistence on therapy, reasons for non-compliance, influence of baseline characteristics, and of compliance on clinical outcome parameters.Compliance was evaluated by self report using standardized, detailed questionnaires at baseline and after each year of treatment. In addition, the prescription data for each patient from hospital records and physician recall was collected. Finally, quality of life and patient satisfaction were assessed using standardized questionnaires.Results: From July 2006 until November 2008, 4.924 women were enrolled with a median patient age of 64 years. Besides demographic data and patient characteristics results of patient's self reporting data will be shown for the first time at this meeting.Conclusion: PACT is the largest prospective investigation on compliance regarding an aromatase inhibitor as adjuvant therapy so far. The programme's goals are to clarify what aspects influence patients' adherence to prescribed medication and how motivation for regular intake can be accomplished. Furthermore, PACT seeks to prove if a simple intervention such as a standardized information and reminder services throughout the first year of treatment may improve compliance and thus eventually influence treatment outcomes.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6079.
First-Line Bevacizumab (Bev) Combination Therapy in Triple-Negative (TN) Locally Recurrent/Metastatic Breast Cancer (LR/MBC): Subpopulation Analysis of Study MO19391 in &gt;2000 Patients (Pts).
Authors: Thomssen C. , Pierga J. , Pritchard K. , Biganzoli L. , Cortes-Funes H. , Petrakova K. , Kaufman B. , Smith I. 
Published: December 2010

Abstract
Background: The combination of Bev with taxane-based therapy, anthracycline-based combination therapy, or capecitabine significantly improves progression-free survival versus chemotherapy alone in LR/MBC, as shown in three randomized, phase III trials (E2100, AVADO, RIBBON-1). Pts with TN LR/MBC appeared to derive similar benefit from Bev compared with non-TN pts in subanalyses of the E2100 and AVADO trials. We conducted a subpopulation analysis of TN pts treated with Bev combination therapy in the MO19391 observational study, which included a broader pt population reflecting general oncology practice.Methods: Pts with HER2-negative (or trastuzumab-pretreated HER2-positive) LR/MBC received first-line Bev 10 mg/kg q2w or 15 mg/kg q3w in combination with taxane-based therapy or other non-anthracycline-containing regimen, according to physician preference. Bev was continued until disease progression. The primary endpoint of MO19391 was safety. Secondary endpoints included time to progression (TTP) and overall survival.Results: 484 of the 2041 pts in MO19391 had TN LR/MBC and 1346 had non-TN disease. The remaining 211 had missing or unknown ER, PgR, or HER2 status and were excluded from this analysis. The proportion of pts with disease-free interval (DFI) ≤24 months was considerably higher in the TN population than in non-TN pts. As expected, the safety profile of Bev combination therapy showed no differences between the two subpopulations. The only pre-defined Bev adverse events of special interest reported at grade ≥3 in &gt;1% of TN pts were hypertension (4.5%) and pulmonary embolism (1.4%). Baseline characteristics, treatment exposure, and efficacy are summarized below. Overall survival data are immature. TN (n=484)Non-TN (n=1346)Median age, years (range)52 (24–85)54 (21–93)DFI ≤24 months, %5525&gt;3 metastatic lesions, %6470Mean duration of Bev, months (range)5.6 (0.0–21.0)7.6 (0.0–25.6)TTP* Events, n (%)297 (61)656 (50)Median, months (95% CI)7.1 (6.4–7.6)10.6 (10.0–11.1)Response rate, %*48.354.5Complete response9.66.9Partial response38.847.6*n=483 in the TN group; n=1322 in the non-TN groupConclusions: In this ongoing study, Bev combination therapy demonstrated a 48% response rate and median TTP of 7.1 months in pts with TN LR/MBC. Findings from this observational study are consistent with retrospective analyses of randomized phase III trials. Prospective trials evaluating Bev combination regimens in TN breast cancer (adjuvant and metastatic settings) are ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6093.
A Phase (Ph) I/II Study of CR011-VcMMAE, an Antibody-Drug Conjugate, in Patients (Pts) with Locally Advanced or Metastatic Breast Cancer (MBC).
Authors: Burris H. , Burris H. , Saleh M. , Bendell J. , Bendell J. , Hart L. , Hart L. , Rose A. , Dong Z. , Siegel P. , Crane M. , Donovan D. , Crowley E. , Simantov R. , Vahdat L. 
Published: December 2010

Abstract
Background: Glycoprotein NMB (GPNMB), also known as osteoactivin, is expressed in 25-40% of breast cancers and is associated with an increased risk of recurrence. This is the first study of CR011-vcMMAE, a fully-human monoclonal anti-GPNMB antibody conjugated to the tubulin inhibitor monomethylauristatin E (MMAE), in pts with breast cancer.Methods: Eligible pts with MBC had ³ 2 prior chemotherapy regimens, including a taxane, an anthracycline, and capecitabine; and ECOG PS ≤ 2. Doses were escalated to 1.88 mg/kg IV q3w (the maximum tolerated dose [MTD] in a previous study of patients with melanoma) using a standard 3+3 design followed by a Ph II expansion at the MTD. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint of the Ph II study was 12-week progression free rate, defined as the proportion of patients who were alive and free of progressive disease 12 weeks from the first dose of CR011-vcMMAE. A Simon two-stage minimax design was used (p0=0.1; p1=0.3, α=β=0.1) with 16 patients in the first stage and a total of 25 pts. Secondary endpoints included objective response rate and duration of response. IHC with a goat polyclonal antibody to GPNMB was performed on pt biopsy specimens.Results: In Ph I, 14 pts were treated with CR011-vcMMAE at 1.0 mg/kg (n=3), 1.34 mg/kg (n=5), and 1.88 mg/kg (n=6). In the first 2 pts at 1.34 mg/kg, dose limiting toxicity of worsening peripheral sensory neuropathy was observed. Pts with baseline neuropathy worse than grade 1 were subsequently excluded. There were 3 partial responses, one confirmed, and 1.88 mg/kg q3w was selected for Ph II. In Ph II, 14 pts with MBC (median age 57 years, range 34 - 76) had a median of 5 prior regimens; median follow up was 6 weeks; 12 pts are ongoing (median duration 6 weeks, range 1 - 14 weeks). Two pts were progression-free at 12 weeks, therefore the study has met the criteria for advancement to the second stage. The most common AEs were rash (61%), fatigue (50%) and alopecia (50%). The most common grade 3/4 AEs were neutropenia (17%) and neuropathy (11%). IHC staining of 5 patient biopsies revealed 2 with positive GPNMB expression, including one of the patients with PR.Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced breast cancer. The Phase II study has met the criteria for advancement into the second stage, and enrollment is ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6096.
Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.
Authors: Blackwell K. , Burstein H. , Sledge G. , Stein S. , Ellis C. , Casey M. , Baselga J. , O'Shaughnessy J. 
Published: December 2010

Abstract
Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported.Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed.Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 61.
Combination Regimens of nab-Rapamycin (ABI-009) Effective Against MDA-MB-231 Breast-Tumor Xenografts.
Authors: Desai N. , D'Cruz O. , Trieu V. 
Published: December 2010

Abstract
Background: The mammalian target of Rapamycin (mTOR) is a key intracellular kinase integrating cell proliferation and survival and is an attractive target for cancer therapy. Nab-rapamycin (ABI-009) was developed using proprietary nab-technology and showed dose-linear pharmacokinetics, safety up to 90 mg/kg and effective antitumor activity at 40 mg/kg in the human-tumor-xenograft panel. The goal of this study was to test the effectiveness of different combination regimens for ABI-009 against MDA-MB-231 breast-tumor xenografts.Materials and methods: Subcutaneous human-breast (MDA-MB-231) tumors were grown in athymic nude mice and treated intravenously (IV) with ABI-009 alone at 40 mg/kg (3xwkly/4wks) and in combination with Erlotinib (50 and 100 mg/kg/day/4wks, IP), Cetuximab (20 and 40 mg/kg, 3xwkly/4wks, IP), Doxorubicin (2 and 5 mg/kg, wkly/10 wks, IV), Oxaliplatin (5 and 10 mg/kg wkly/4 wks, IV), SAHA (50 mg/kg, qdx7 or qdx14, IP), and Perifosine (30 and 60 mg/kg, 3xwkly/4wks, PO). The animal weights and tumor measurements were recorded three times weekly and adverse observations recorded.Results: ABI-009 was highly effective as a single agent against MDA-MB-231 breast tumor xenografts with 75% tumor-growth inhibition (TGI). Combination with Erlotinib resulted in TGI of 85% and 95% (50 and 100 mg/kg, respectively), 83% and 87% for Cetuximab (20 and 40 mg/kg, respectively), 83% and 90% for Doxorubicin (2.5 and 5 mg/kg, respectively), 82% and 85% for Oxaliplatin (5 and 10 mg/kg, respectively), 82% and 90% for SAHA (7 and 14 day treatment, respectively), and 92% and 96% for Perifosine (30 and 60 mg/kg, respectively). Notably, Erlotinib and Perifosine were found to synergize with ABI-009 resulting in maximum TGI and tumor growth delay.Discussion: ABI-009 (nab-rapamycin) alone was highly effective against MDA-MB-231 human-breast-tumor xenografts. Antitumor activity of ABI-009 was significantly increased in combination with kinase inhibitors, Erlotinib (EGFR-kinase inhibitor) and Perifosine (AKT inhibitor). Antitumor activity of ABI-009 was also significantly increased in combination with Doxorubicin – a topoisomerase inhibitor, and SAHA – an HDAC inhibitor, but not in combination with Oxaliplatin – a DNA crosslinker. In contrast, combination of ABI-009 with anti-EGFR monoclonal antibody, Cetuximab was not effective. The synergy of these combinations confirmed that rapamycin is active only on TORC1 and that suppression of TORC2 via AKT or PI3K pathways is a means of increasing activity of mTOR inhibitors with potential relevance to breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6106.
Triple-Negative Breast Cancers Express Receptors for GnRH and Can Be Effectively Targeted by the Orally Active GnRH-Antagonist AEZS 115.
Authors: Engel J. , Schreiber A. , Seitz S. , Köster F. , Gaiser T. , Kämmerer U. , Dietl J. , Honig A. 
Published: December 2010

Abstract
IntroductionAEZS-115* is an orally active peptidomimetic antagonist of GnRH, which has been shown to block the pituitary GnRH receptor. In various tumors an autocrine growth promoting loop consisting of GnRH secreted by the malignant cells and tumoral GnRH receptors has been described. The current study investigates the expression of GnRH-receptors in tumor samples of triple-negative breast cancers and evaluates the anti-tumor activity of the GnRH antagonist AEZS 115 in in vitro models of triple negative breast cancers.Study design17 human samples of triple negative breast cancers were tested for GnRH-receptor expression by immunohistochemistry. Human triple negative breast cancer cell lines MDA-MB 468, HCC 1806 and HCC 1937 were analyzed for GnRH receptor expression by immunocytochemistry and western blot analysis. These cell lines were incubated with increasing concentrations of AEZS-115, peptidic GnRH-antagonist Cetrorelix and GnRH-agonist Triptorelin (1, 10, 100 µm) for 48 hours and the number of viable cells was determined by crystal violet staining as well as by ATP-dependent luminometric assay.ResultsPositive staining for GnRH-receptors was detected in all tumor samples (2 high, 12 moderate, 3 weak). Cell lines MDA MB 468, HCC 1806 and HCC 1937 expressed GnRH receptors as demonstrated by immunocytochemistry and western blot analysis. GnRH-antagonist AEZS 115 dose dependently inhibited growth of all three cell lines, while GnRH-agonist Triptorelin and peptidic GnRH antagonist Cetrorelix showed marginal growth inhibition. At 10 µm AEZS-115 inhibited cell growth by 40-60%, at 100 µm growth inhibition was 60-80%. These results obtained by crystal violet staining were confirmed by additional luminometric evaluation of the ATP content after treatment with the respective substances.ConclusionsThe orally active, peptdidomimetic GnRH antagonist AEZS-115 showed substantial anti-tumor activity in these cell lines, while GnRH-agonist Triptorelin and peptidic antagonist Cetrorelix showed only minor growth inhibition. Thus, in triple negative breast cancers the peptidomimetic antagonist AEZS-115 was more potent than the decapeptide Cetrorelix. This finding could be explained by atypical GnRH-receptors on tumor tissue to which the different GnRH-antagonists might bind with different affinity. Due to high receptor expression the GnRH receptor is a promising target in triple negative breast cancers. The good antitumor-activity makes AEZS-115 a promising candidate for in vivo studies in this tumor entity.*Aeterna Zentaris GmbH, Frankfurt/M, Germany.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6108.
A Type I Insulin-Like Growth Factor Receptor Kinase Inhibitor (PQIP) Enhances the Cytotoxicity of Doxorubicin in Human Cancer Cell Lines.
Authors: Zeng X. , Buck E. , Yee D. 
Published: December 2010

Abstract
The type-I insulin like growth factor (IGF-IR) is either activated and/or overexpressed in a wide range of tumor types and contributes to tumorigenicity, proliferation, survival, metastasis and drug resistance. Disruption of IGF-IR signaling alone or in combination with other cytotoxic agents has emerged as an important strategy in cancer therapy. Our laboratory has shown that sequentially combining doxorubicin with anti-IGF-IR antibodies significantly enhances the response of chemotherapy, while the opposite sequence causes cells resistant to chemotherapy. Here, we show that a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF-IR and insulin receptor (IR) kinase activity and proliferation in MCF-7 and MDA435/LCC6 cell lines. Moreover, PQIP treatment blocked both IGF-I and insulin stimulated activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in both cell lines. At doses that inhibited monolayer cell growth, the compound also inhibited cell motility, blocked IGF-I stimulated S-phase progression and induced autophage; at higher doses, it also caused PARP cleavage. Combining PQIP with doxorubicin significantly enhanced cytotoxicity but did not further enhance doxorubicin-induced PARP cleavage in monolayer cell growth. Furthermore, our sequencing studies showed that combining PQIP with doxorubicin simultaneously or doxorubicin followed by PQIP significantly inhibited the anchorage-independent growth in both MCF-7 and MDA435/LCC6 cells. In contrast, pre-treatment with PQIP followed by doxorubicin did not enhance the cytotoxicity of doxorubicin in anchorage-independent growth, which is similar as anti-IGF-IR antibodies in combination with doxorubicin. In summary, these results suggest that the IGF-IR tyrosine kinase inhibitor PQIP can be used alone or in combination with chemotherapy to enhance cytotoxicity of human tumor cell lines, and the timing of IGF-IR inhibition may affect responses to doxorubicin.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6110.
Delivery of Therapeutic Nanoshells to Hypoxic Areas of Tumors Using a Cellular Trojan Horse.
Authors: Choi M. , Bardhan R. , Badve S. , Nakshatri H. , Halas N. , Clare S. 
Published: December 2010

Abstract
Background: The goal of this project is to develop a novel and innovative delivery system for anti-tumor therapeutics which circumvents the impediments to efficient delivery that are present in a solid malignancy. Malformed blood vessels, elevated interstitial pressure, and large transport distances in a tumor, individually or in concert limit or thwart the diffusion of oxygen, glucose and soluble therapeutics. This results in hypoxia, necrosis, and makes regions of the tumor inaccessible to otherwise efficacious therapies. In addition, hypoxia exerts a selective pressure on tumor cells in that only those with an aggressive phenotype are able to survive hypoxia; these cells may be the source of subsequent local recurrence and distant metastasis.Monocytes/macrophages respond to intratumoral hypoxia and necrosis and are recruited by a chemoattractant gradient. Our strategy is to take advantage of the recruitment of monocytes/macrophages by a tumor, and of the monocytes/macrophages innate phagocytosis ability in order to load them with nanoshells, and thereby to create a Trojan horse. This study was designed to determine if monocytes/macrophage loaded with gold-silica nanoshells would respond to the chemoattractant gradient and become tumor associated macrophages. Nanoshells can convert absorbed light into thermal energy, which can be utilized for photothermal ablation. Therefore, our xenograft model system was utilized also to test whether malignant epithelial cells can be successfully be treated by thermal ablation of neighboring macrophages.Materials and Methods: A human breast tumor xenograft, and a separate metastatic brain tumor xenograft were established in nude mice. Monocytes were isolated from human whole blood and loaded with nanoshells. The nanoshells were conjugated with a near-infrared dye. The loaded macrophages were injected via the tail vein into the systemic circulation of the mice. The tumors were imaged by fluorescence imaging and magnetic resonance imaging before and after irradiation with a near-infrared laser (0.5 W, 5mm spot size) for varying lengths of time.Results: The in vivo delivery of the macrophages loaded with nanoshells to the human xenograft tumors was verified. Significant uptake of loaded macrophages in tumor was observed at 24 hours after injection. Uptake was also observed in the lungs, liver and spleen. An increase of ∼ 30°C at the tumor skin was noted following 90 seconds of irradiation of the orthotopic tumor.Discussion: Nanoshell-loaded macrophages respond to the presence of an orthotopic breast tumor and to breast cells metastatic to the brain, exit the circulation and accumulate in the rim of hypoxic cells surrounding necrosis. Photothermal ablation of the tumor cells infiltrated by this innovative therapeutic delivery method produces a targeted therapy in that it targets the tumor hypoxia.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6113.