bluuebunny/crossref_metadata_2025_split huggingface dataset:
Everolimus (Afinitor®), Trastuzumab (H), and Paclitaxel (P) or Vinorelbine (V) in the Treatment of HER-2+ Metastatic Breast Cancer (MBC) Patients (Pts) Pre-Treated with Lapatinib-Containing Therapy: Pooled Analysis of 2 Phase I Studies.
Authors: Cardoso F. , Dieras V. , Campone M. , Massacesi C. , Manlius C. , Thevenaz P. , Zhang Y. , Jerusalem G. , Sahmoud T. , Andre F. , Gianni L. 
Published: December 2010

Abstract
Introduction: The re-introduction of H-based therapy after progression on a lapatinib-containing regimen has not yet been supported by clear evidence. The aim of this analysis is to describe the safety and efficacy of the regimens everolimus (E) + H, and either P or V in patients pre-treated with lapatinib (L) in relation to those who did not receive previous L (N-L). Methods: Data from pts enrolled in two multicenter phase I studies (NCT00426556 and NTC00426530), with similar study design, were pooled and analyzed according to previous treatment with L. Regimens were: oral E daily (5 or 10mg) or weekly (20 or 30mg) + weekly H 2mg/kg IV, and either P 80mg/m2, IV D1-8-15 q4w (33 pts) or V 25 mg/m2, IV D1-8 q3w (46 pts). Results: Twenty-six (33%) of the overall 79 pts enrolled, received previous L (equally distributed among E dose cohorts). Baseline characteristics of the L and N-L groups, respectively, were: median age: 49 and 53 yo; visceral disease: 85% and 75% of pts; median number of previous chemotherapy lines for metastatic disease: 3 (range: 1-17) and 1 (range: 0-7); prior-taxanes and anthracyclines: 96% and 81% of the L pts, and in 96% and 85% of the N-L pts, respectively; 78 of 79 pts were H-resistant. The 26 pts pretreated with L were all resistant to L and had a median treatment duration of 24 wks (range: 6-123). In the L and N-L groups, the most frequently reported severe toxicities were G3/4 neutropenia in 58% and 75%, febrile neutropenia in 8% and 2%, G3 asthenia/fatigue in 19% and 13%, G3 stomatitis in 19% and 11%, G3 diarrhea in 4% and 6%, respectively. G1/2 rash was reported in 15% and 34% of L and N-L pts, respectively. Mean left ventricular ejection fraction was similar at baseline and at end of treatment (EOT) in L and N-L pts: 63% (+/- 7%) in both groups at baseline, and 60% (+/- 7%) and 64% (+/- 6%) at EOT, respectively. Table 1 summarizes the efficacy observed in the 74 evaluable pts to date. Time to progression (TTP) appears longer in the N-L group and may be a result of less pre-treatment in this group. Conclusions: In our experience patients pre-treated with lapatinib are not at a higher risk of toxicity and do not seem to have a substantially different outcome when re-treated with trastuzumab-containing regimens in combination with everolimus.Table 1. Overall response and time to progression (Kaplan-Meier based) Lapatinib-pretreated (n=25)Not Lapatinib-pretreated (n=49)Best Response, n (%) CR–3 (6)PR5 (20)12 (25)SD16 (64)27 (55)PD4 (16)7 (14)TTP, median (weeks)29 (21-41)38 (29-44)CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TTP, time to progression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5064.
Targeting Cancer Stem Cells and Vasculature by a Novel Anti-Delta-Like 4 Ligand (DLL4) Antibody for Treatment of Triple Negative Breast Cancer.
Authors: Yen W. , Fischer M. , Lewicki J. , Gurney A. , Hoey T. 
Published: December 2010

Abstract
Triple negative (ER-, PR- Her2-) breast cancer accounts for 10% of all types of breast cancer and is known to particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer, however, these treatments often result in high rates of local and systemic relapse. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch pathway will improve treatment outcome. We developed anti-DLL4 antibodies that recognize either the human or murine protein and have potent binding and antagonist activities. We have used these antibodies to investigate the role of DLL4 in triple negative breast cancer and to probe the mechanism in tumor and stromal cells in xenograft models derived from primary breast tumors. These studies showed that anti-DLL4 was efficacious as a single agent and in combination with paclitaxel (Taxol) against triple negative breast tumors including a tumor that developed paclitaxel resistance. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Furthermore, inclusion of anti-DLL4 delayed breast tumor recurrence following termination of paclitaxel treatment. A tumorigenicity study indicated that treatment with anti-DLL4 decreased cancer stem cell frequency as measured by in vivo limiting dilution assay, whereas paclitaxel alone was ineffective. The combination of anti-DLL4 and paclitaxel further decreased cancer stem cell frequency compared to single agents. Our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for breast cancer treatment.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5071.
Growth Inhibition of Human Breast Cancer Cells with an Iron Chelator (Deferasirox) and Docetaxel.
Authors: Lipton A. , Witters L. , Nick H. 
Published: December 2010

Abstract
Treatment of cells with an iron chelator results in G1/S arrest and apoptosis. Tumor cells appear to be more sensitive to iron chelation probably because they express higher levels of the iron containing enzyme, ribonucleotide reductase. Previously, our laboratory has shown that an iron chelator (deferoxamine) inhibited the growth of a variety of cancer cell lines and also prolonged survival in tumor bearing mice. Docetaxel is an antineoplastic agent belonging to the taxane family. Docetaxel induces bcl-2 phosphorylation and subsequent apoptosis and is effective in the treatment of patients with breast cancer. The purpose of this study was to assess the in vitro effects of combining an iron chelator, deferasirox (Exjade: Novartis Pharma AG), and docetaxel on the growth of MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Cells were exposed to deferasirox or docetaxel alone or in combination for 3 days (9 different dose combinations were tested). Cell growth was determined using the colorimetric MTT tetrazolium dye assay. Dose-dependent growth inhibition was observed in both the MCF-7 and the HER-2/neu-tranfected MCF-7 cells after 3 days exposure to deferasirox (IC50: 1.5 and 2.3 μM, respectively) or docetaxel (IC50: 0.9 nM and 2.0 nM, respectively). Exposure to the combination of deferasirox (0.25 – 1.5 μM) and docetaxel (0.1 – 0.5 nM) resulted in synergistic growth inhibition in both the MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Sequencing experiments with the HER-2/neu-transfected MCF-7 cells showed that simultaneous exposure of the cells to deferasirox and docetaxel was superior to pretreating the cells with either of the agents 6 or 24 hours prior to addition of the second agent. These results suggest this combination warrants further investigation as a therapeutic strategy for breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5075.
In Vivo and In Vitro Evidence of Antitumor Activity of UCM-Gi028 [Novel FASN Inhibitor] Against Trastuzumab-Resistant Breast Cancer.
Authors: Urruticoechea A. , Aguilar H. , Cufi S. , Cufi S. , Turrado C. , Relat J. , Oliveras G. , Benhamú B. , Ortega-Gutiérrez S. , López-Rodríguez M. , Colomer R. , Puig T. 
Published: December 2010

Abstract
Introduction. The vast majority of Her-2 positive advanced breast cancer patients develop resistance to Trastuzumab based therapies within the first year of treatment. We have previously shown that inhibition of Fatty Acid Synthase (FASN) activity, an enzyme overexpressed and hiperactivated in breast carcinoma leads to apoptosis in breast cancer cells and its effect is tightly linked to Her-2 signalling pathways. Here we show the anticancer effect of UCM-Gi028, the lead-compound of the first generation of a novel family of synthetic FASN inhibitors, both in vitro and in an animal model of Her-2 amplified breast cancer.Material and Methods. We analysed the cellular and molecular effects of UCM-Gi028 alone or in combination with lapatinib, erlotinib, trastuzumab and gefitinib in a Her-2 dependent breast cancer cell line (AU565) using epigallocatechin-3-gallate (EGCG), a natural inhibitor of FASN, as a comparator. We also generated a long-term trastuzumab resistant pool from AU565 cells (AU565TTZR pool) to evaluate the effect of UCM-Gi028 in this setting. We further characterize the toxicity profile, anti-cancer activity and pharmacodynamic markers in an athymic mice model of Her-2 positive breast cancer cell line xenograft tumors.Results. UCM-Gi028 shows marked synergic antitumoral activity combined with lapatinib, erlotinib, trastuzumab and gefitinib (p &lt;0.05). Response to co-exposure of UCM-Gi028 plus growth-signal inhibitors was significantly correlated with induction of apoptosis and with decrease in the activation forms of HER-2, MAPK and AKT, as markers of drug activity. Importantly, AU565TTZR pool displayed increased sensitivity to UCM-Gi028 compared to previously known FASN inhibitors (EGCG and C75). In the Her-2 positive breast cancer animal model study no weight loss or other relevant toxicity were observed after long term (7 weeks) exposure to UCM-Gi-28. A group of UCM-Gi028-treated mice showed tumour regression compared to control and, importantly, responsive tumours showed inhibition of FASN activity, increased apoptosis and decreased HER-2, AKT and MAPK activity.Discussion. As compared to its related natural compound (EGCG), UCM-Gi-28 shows increased antitumor activity with a favourable toxicity profile, in contrast with other, highly toxic, synthetic FASN inhibitor (C75). UCM-Gi028 antitumour activity remains unchanged in trastuzumab resistant cells. UCM-Gi-28 warrants further pre-clinical and clinical development alone or in combination with other anticancer agents in Her-2 positive breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5079.
Time Dependent Improvement in Survival for Women with Multiple Brain Metastases from HER2 Positive Breast Cancer: The Influence of Systemic Therapy.
Authors: Tillett T. , Huckett R. , Church D. , Braybrooke J. , Whipp E. , Bahl A. , Price C. 
Published: December 2010

Abstract
Background: Women with multiple breast cancer brain metastases (BM) ineligible for neurosurgery or radiosurgery have a poor prognosis and the role of systemic therapy is ill defined.Method: The outcomes for 120 women treated for multiple (≥2) BM between 2002-2008 at this regional cancer centre have been analysed according to time of BM diagnosis (Cohorts (A) 2002-5 & (B) 2006-8) and HER2 status of the primary tumour (+ or -). We have previously shown that A+ patients experienced longer survival than A-, the advantage apparently restricted to a subgroup of A+ who continued trastuzumab after BM diagnosis (Church et al, Am J Clin Oncol 2008, 31(3) 250-4).Results: There was no difference in survival between B- and A- cohorts (B- patients (n=25) survival median 119 days; A- patients (n=53) median survival 118 days; p=0.57). In contrast there was a time dependent improvement in survival favouring B+ patients (n=19, median 520 days,) over A+ patients (n=23, median 148 days, p &lt;0.02). B+ and A+ cohorts differed significantly in the consistency of their exposure to both trastuzumab (T) and chemotherapy (CT) post BM (p&lt;0.02). Subsequently, patients in the B+ cohort was more frequently treated with additional lines of CT and 5 patients in the B+ cohort (versus none in A+) went on to receive second line anti-HER2 therapy (lapatinib).CohortT + CTLines of CT≥ 2LapatinibMedian survival12 month survivalA+ (n=23)39% (9pts)22% (5)0% (o)148 days30%B+ (n=19)79% (15pts)58% (11)26% (5)520 days80% p&lt;0.02p&lt;0.03p&lt;0.02p&lt;0.02 A+ and B+ were not significantly different with regard to presence of systemic metastases (SM) or time from SM to BM (median A+ 304 days; B+ 334, p=0.3)Conclusion: Following our earlier observation on the A+ cohort, the improvement in survival for B+ may reflect increased optimism of patients and physicians regarding the role of systemic therapy. Although no randomised trial has been performed, it is increasingly apparent from these and other data that HER2+ patients with multiple BM benefit from continued incorporation of systemic therapy into clinical management strategies and, at variance with historic experience, survival &gt; 1 year can now be expected. Randomised trials, specifically to identify the best agents to accompany anti-HER2 therapy, will be required to further extend this benefit.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5092.
Efficacy and Safety Data of Taiwan Breast Cancer Patients Enrolled in the Lapatinib Expanded Access Program (LEAP).
Authors: Chen S. , Huang C. , Tsao C. , Liu M. , Yeh D. , Hou M. , Chang T. , Hsien R. , Chao T. , Tai C. , Lin Y. 
Published: December 2010

Abstract
Background: LEAP is a single-arm, open-label, expanded access study of lapatinib in combination with capecitabine in 42 countries. The primary objective of LEAP was to provide patients with pre-approval access to lapatinib based on positive clinical data from a pivotal Phase III trial.Methods: Enrolled patients had locally advanced or HER2 positive metastatic breast cancer (MBC), progressive disease (PD, by modified RECIST) following prior therapy with anthracycline-, taxane-, and trastuzumab-containing regimens, including some patients previously treated with capecitabine, and were ineligible for ongoing lapatinib trials. Patients received lapatinib (1250 mg/day) and capecitabine (2000 mg/m2/day, days 1-14, every 21 days). Baseline characteristics, including prior therapies, were collected. Response was assessed using RECIST criteria.Results: From Mar 2007 to Sep 2008, 238 patients were enrolled at 10 centers in Taiwan. At the 11 June 2009 data cut-off, data were collected and analyzed for 166 patients. Patients received an average of 5 prior cytotoxic therapies, including trastuzumab and capecitabine.Of 166 patients, 3 (2%) had complete response, 49 (30%) had partial response, 62 (37%) had stable disease, 42 (25%) had PD, and 10 (6%) were unknown. The median duration of treatment was 5.5 mo and the median time to progression was 5.3 mo, respectively. Per protocol, only serious adverse events (SAEs) were reported. Thirty SAEs were reported for 238 patients; 6 (20%) were considered treatment-related by investigators, were not fatal, and included stomatitis (2), vomiting (2), diarrhea (1), and cellulitis (1). As of 11 June 2009, 66 (40%) patients were alive and 149 withdrew from LEAP, the majority (85%) because of progressive disease.Conclusion: Although data were collected retrospectively via case report forms, these results reflect the real world setting in Taiwan for the treatment of erbB2+ MBC patients and confirms that lapatinib, in combination with capecitabine, demonstrates efficacy in this patient population including those who are heavily pretreated.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5093.
Safety of First-Line Letrozole Compared with Lapatinib Plus Letrozole in Patients with Postmenopausal Hormone Receptor Positive Metastatic Breast Cancer: EGF30008 Study.
Authors: Ro J. , Pippen J. , Pivot X. , Manikhas A. , Fehrenbacher L. , Makris A. , Florance A. , Maltzman J. , O'Rourke L. , Johnson S. 
Published: December 2010

Abstract
Background: EGF30008 was a double-blind, placebo-controlled phase III study which evaluated the benefit of adding lapatinib (L) to letrozole (Let) alone in patient (pts) with hormone receptor positive (HR+), metastatic breast cancer. Median progression-free survival (PFS) in pts with HER2+ tumors was significantly increased from 3 to 8.2 mos with dual therapy (HR [95% CI] =0.71 [0.53, 0.96], P=.019). Safety data presented at the 2008 San Antonio Breast Cancer Symposium demonstrated that the combination of L+Let was manageable and predictable, with no unexpected toxicity.Methods: 1286 pts were randomized 1:1 to treatment with Let versus L+Let. Safety data were collected from start of study drug until 30 days after discontinuation. The safety population was based on the actual treatment received (Let n=623; L+Let n=655). Updated adverse events (AEs) associated with L were evaluated at both pt and event level as a function of time on study. AEs were categorized into 4 groups: diarrhea, rash, cardiac, and hepatobiliary events. Multiple AE terms were classified within these groups.Results: Safety data through 03Feb09 are reported (additional 8 mos data beyond trial reporting). Let group: median exposure of Let=37.57 weeks (range 0.9-251.1). L+Let group: median exposure of Let= 40.43 (range 0.1-248.6) and median exposure of L=40.14 weeks (range 0.3-248.6). Overall, there were 537 AE events (86%) in the Let alone group, and 629 (96%) in the L+Let group. Incidence, counts, and time to first occurrence of AEs associated with HER1 and HER2 inhibition are summarized below. Let (n=623)L+Let (n=655)Rash Pts with AE, n95 (15%)328 (50%)- Max Grade 30.012 (4%)- Max Grade 40.00.0AEs (n events)123638- Leading to study withdrawal1 (&lt;1%)11 (2%)Median time to 1st onset, days7720Diarrhea Pts with AE, n127 (20%)419 (64%)- Max Grade 36 (5%)59 (14%)- Max Grade 40.02 (&lt;1%)AEs (n events)1721026- Leading to study withdrawal2 (1%)22 (2%)Median time to 1st onset, days6114Hepatobiliary Pts with AE, n50 (8%)102 (16%)- Max Grade 39 (18%)33 (32%)- Max Grade 43 (6%)4 (4%)AEs (n events)103405- Leading to study drug withdrawal3 (3%)13 (3%)Median time to 1st onset12463LVEF decreases Pts with AE, n18 (3%)34 (5%)- Grade 32 (11%)8 (18%)- Grade 40.01 (3%)AEs (n events)1941- Leading to study drug withdrawal4 (21%)8 (20%)Median time to 1st onset, days323165 Graphs of AEs as a function of time as well as details on pts with multiple events will also be provided.Conclusion: Relatively few AEs were grade 3/4 or led to study drug discontinuation. Incidence, severity, and recovery of each toxicity as a function of time will be presented. The safety profile of L+Let remains consistent with the 8 additional months of data since initial reporting of study results.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5094.
Effects of Arzoxifene on Breast Cancer Incidence in Postmenopausal Women with Osteoporosis or with Low Bone Mass.
Authors: Powles T. , Diem S. , Wickerham L. , Cox D. , Amewou-Atisso M. , Agnusdei D. , Muram D. , Mitlak B. , Cummings S. 
Published: December 2010

Abstract
Precinical and early clinical data indicate that arzoxifene, a third generation SERM, is more potent and bioavailable than raloxifene. Here we report the results of the phase 3, multicenter, placebo-controlled, double-blind GENERATIONS trial of 9354 postmenopausal women with osteoporosis (N=5252) or low bone mineral density (BMD) (N=4102), randomly assigned to arzoxifene 20mg/d (N=4676) or placebo (N=4678). The primary endpoints were the incidences of radiographic vertebral fracture in the osteoporotic population (at 36 months) and invasive breast cancer in all study participants (after all participants had completed 48 months of treatment). Breast cancers were detected by annual mammograms and/or clinical breast examination and adjudicated centrally by an independent committee. The primary analysis compared the incidence of adjudicated invasive breast cancer between treatment groups using a log-rank test. Both treatment groups were evenly balanced for risk of breast cancer including age, previous benign breast biopsies, family history of breast cancer, estimated Gail risk and BMD. The trial met both primary endpoints with a 41% reduction in the incidence of vertebral fractures (p&lt;0.001) and 56% percent reduction in incidence of invasive breast cancer (p=0.002). Table 1 summarizes the breast cancer findings after the 48 month follow-up. The incidence of invasive breast cancer in the placebo group was higher in the women who had a Gail score &gt; 1.66 compared to ≤ 1.66 (1.5% vs. 0.6%) and in those with low bone mass versus osteoporosis (1.2% vs. 0.7%), but the risk reduction with arzoxifene was similar between Gail risk groups (HR 0.32 vs 0.57. p-value for interaction=0.31) and between low bone mass and osteoporosis groups (HR 0.34 vs 0.57. p-value for interaction=0.35). Other findings included no significant reduction in non-vertebral fractures or cardiovascular events. Generally, arzoxifene was well tolerated, although there was a significant increase in venous thromboembolism, gall bladder disease, pulmonary obstructive/infective disorders, hot flushes, muscle cramps and gynecological-related events in the arzoxifene group. We conclude that arzoxifene reduces the incidence of invasive breast cancer as well as vertebral fracture. The results of the GENERATIONS trial provide further support for a significant risk reduction of invasive breast cancer by SERMs in post menopausal women.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 51.
Tamoxifen Resistance in Estrogen Receptor Positive (ER+) Breast Cancer Is Driven by Estrogen Receptor Negative (ER-) Cancer Stem-Like Cells.
Authors: O'Brien C. , Howell S. , Gee J. , Lykkesfeldt A. , Nicholson R. , Clarke R. 
Published: December 2010

Abstract
Introduction: Intrinsic and acquired resistance to endocrine therapy significantly reduces survival rates of women with ER+ breast cancer. In the normal breast, multipotent stem cells are ER-. We hypothesised that tumourigenic breast cancer stem-like cells (CSCs) are ER- and therefore function independently of estrogen, representing a novel mechanism of resistance to endocrine therapy.Methods: Three ER+ cell lines, MCF-7, T47D and BT474 were assessed for ER expression by immunocytochemistry (ICC) in monolayer and after CSC enrichment. Putative CSC number was assessed by the non-adherent mammosphere (MS) assay, in the presence and absence of tamoxifen, and by Fluorescence Activated Cell Sorting (FACS) for the markers CD44+/CD24-/low/epithelial specific antigen(ESA)+. The effect of acquired Tamoxifen resistance on the CSC population of two independent Tamoxifen-resistant (TAM-R) MCF-7 variants, from Cardiff (TAM-RCARD) and Copenhagen (TAM-RCOP) was compared to parental, tamoxifen sensitive (TAM-S) controls. In the MS assay both the number and size of colonies were assessed.Results: A small sub-population of ER_ cells were demonstrated in MCF7 (6.1 ± 1.4%), T47D (6.8± 0.5) and BT474 (3.7±1.3) cells by ICC. However, the majority of putative breast CSCs (CD44+/CD24-/low/ESA-) in MCF7 cells were ER_ (73.2 ± 4.6 % p= 0.0007). There was a significant increase in the proportion of ER- cells in TAM-R cell lines (TAM-RCARD 11.6 ± 1.4% p=0.01 and TAM-RCOP 22 ± 4.8% p=0.02 respectively) compared to the parental TAM-S controls. Both TAM-R cell lines demonstrated increased mammosphere forming efficiency (MFE) compared to TAM-S cells (TAM-RCARD 4% vs. 2.5% p=0.03, and TAM-RCOP 8% vs. 3% p=0.007). The putative CSC population (CD44+/CD24-/low/ESA+) was enriched more than 2.5 fold in TAM-R compared to TAM-S parental controls. Compared with controls, the absolute MFE was not affected by Tamoxifen treatment, although mammospheres formed were significantly smaller.Conclusions: The majority of the putative CSC populations in ER+ breast cancer do not express ER. There is an increase in the proportion of putative ER- CSCs in TAM-R MCF7 cell lines. The reduction in MS size suggests that Tamoxifen targets transit amplifying cells but does not reduce the absolute number of CSC in ER+ breast cancers. These findings demonstrate a novel mechanism of endocrine resistance in ER+ breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5125.