bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-14-02: A Phase 3 Randomized, Controlled Trial of Myocet, Trastuzumab and Paclitaxel vs. Trastuzumab and Paclitaxel for 1st Line Therapy of HER2+ Metastatic Breast Cancer
Authors: Baselga J , Manikhas A , Roman L , Semiglazov V , Goldfarb RH , Forenza S , Matera J , Azarnia N , Hudis C , Rozencweig M 
Published: April 2011

Abstract
Background: Myocet™ (M) is a non-pegylated liposomal doxorubicin which exhibits reduced cardiotoxicity as compared to conventional doxorubicin. A phase 1/2 non-randomized multi-site trial combining M, trastuzumab (H) and paclitaxel (T) has resulted in high response rate, prolonged time to progression and improved overall survival, with no clinical cardiac toxicity in patients (pts) with first line metastatic breast cancer (MBC) over-expressing human epidermal growth factor-2neu (HER2+) (Cortes et al Clin Cancer res 2009:15:307).
Methods: This multicenter study was designed to demonstrate the efficacy and cardiac safety of M+ H + T vs. the standard of care, H + T, in pts with HER2+ MBC with no prior chemotherapy for MBC. After stratification by hormone receptor status, prior or no prior anthracycline (A) therapy, age ≥50 or &gt;50 y and geography, patients were randomly allocated to receive either M (50 mg/m2 q 3 wks for 6 cycles), H (4 mg/kg loading dose followed by 2 mg/kg q wk) and T (80 mg/m2 q wk) or H + T until progression or toxicity. The primary efficacy outcome is progression-free survival (PFS), as determined by a blinded independent review committee (IRC). The primary safety outcome is the incidence of NYHA class 3 or 4 heart failure or cardiac death, independently adjudicated. Secondary endpoints are overall survival and tumor response, also determined by the IRC according to RECIST. 332 pts were needed to detect a 30% difference in PFS with 80% power.
Results: Between 2006 and 2009, 363 HER2+ women from 12 countries were enrolled. Median age is 53 yr (range 22-79); 80% are Caucasian; with ECOG performance status of 0 (62%) and 1 (38%); 42% are ER and/or PR positive; 40% received adjuvant chemotherapy, 24% hormone therapy, and 37% radiotherapy; 33% received prior A, median lifetime cumulativedoxorubicin and epirubicin dose (range) were 240 (45-360) mg/m2 and 360 (69-600) mg/m2, respectively. The final analysis of PFS is scheduled for 3Q10.
Conclusions: The safety and efficacy data will be presented at the meeting. Clinical Trials.Gov Identifier: NCT00294996
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-02.
Abstract P6-14-09: Acute-Phase Reactions Following Treatment with Zoledronic Acid or Denosumab: Results from a Randomized, Controlled Phase 3 Study in Patients with Breast Cancer and Bone Metastases
Authors: Stopeck AT , Lipton AA , Campbell-Baird C , von Moos R , Fan M , Haddock B , Braun A. 
Published: April 2011

Abstract
Background: Intravenous (IV) bisphosphonates (BP) are currently used to treat bone metastases and prevent skeletal-related events (SRE) in patients with advanced breast cancer. In a phase 3 study, denosumab, a fully human monoclonal antibody against RANKL, was shown to be superior to zoledronic acid (ZA) in delaying or preventing SREs in patients with breast cancer and bone metastases. This prespecified analysis compares ZA and denosumab for the incidence of acute-phase reactions (flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias, and myalgias) during the first 3 days after initial treatment in that study.
Methods: Eligible patients were randomized in a double-blind, double-dummy fashion to receive IV ZA 4 mg (adjusted for creatinine clearance as specified by the Zometa label) or subcutaneous denosumab 120 mg every 4 weeks. Most patients (99%) were women; mean (SD) age was 57 (12) years, and baseline characteristics were balanced between groups. Safety analyses were conducted in patients who received ≥1 dose of denosumab (N=1020) or ZA (N=1013). Patient records were searched for adverse events (AEs) and serious AEs that occurred during the first 3 days after the first administration of study drug, using 37 prespecified MedDRA 12.0 preferred terms potentially indicating acute-phase reactions. Per study protocol, AEs were considered serious if they were fatal, life-threatening, required or prolonged in-patient hospitalization, resulted in a persistent or significant disability, or were considered to present a significant medical hazard.
Results: AEs associated with acute-phase reactions in the first 3 days after treatment occurred in fewer patients in the denosumab group (10.4%) than in the ZA group (27.3%; P&lt;0.0001), and no events were attributed to denosumab. The most common acute-phase reaction AEs included pyrexia (0.9% denosumab, 11.5% ZA), fatigue (2.4% denosumab, 4.0% ZA), bone pain (1.3% denosumab, 3.6% ZA), chills (0.3% denosumab, 3.6% ZA), and arthralgia (1.5% denosumab, 3.2% ZA). No patients (0%) in the denosumab group and 10 patients (1%) in the ZA group reported serious AEs associated with acute-phase reactions during the first 3 days. These events included pyrexia (n=7); bone pain (n=2); and asthenia, back pain, chest pain, chills, headache, and malaise (n=1 each). For 6 of the 10 patients, events of pyrexia, chest pain, chills, and bone pain were resolved within 4 days. Three patients with serious acute-phase reaction AEs discontinued ZA treatment after the first dose. Conclusion: Patients treated with denosumab experienced no serious AEs of acute-phase reaction and significantly fewer overall AEs of acute-phase reaction than patients receiving ZA.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-09.
Abstract P6-14-13: A Flavone from Traditional East Asian Natural Extract Inhibits STAT3 and Tumor Growth in a Syngeneic Mouse Breast Cancer Model
Authors: Senthil M , Akmal YM , Xing Q , Yan J , Yim JH. 
Published: April 2011

Abstract
Background: Recent studies have shown that increased dietary consumption of flavones and isoflavones is associated with reduced risk of developing cancer. Natural plants/herbs used in Traditional East Asian
Medicine (TEAM) have been recognized as potentially efficacious natural treatments against cancer and are enriched with isoflavones and flavones, as well as other interesting compounds. We used a novel high throughput screening method to identify natural extracts that may have a potential anti-cancer effect and identified the TEAM natural product Scutellaria baicalensis and a known active component, the flavone, baicalein. The objective of our current study is to investigate the anti-cancer effects of baicalein in vitro and in vivo.
Methods: In vitro testing was performed in mouse (C3L5) and human (SKBR3) breast cancer cell lines. Cell viability was assessed by MTT assay. Apoptosis was assessed using FITC-Annexin V and PI staining with bivariate reading by flow cytometry at 48 h. A syngeneic mouse breast cancer model (C3H/HeJ — C3L5) was used for in vivo testing. Mice bearing subcutaneous tumors were either treated with daily intraperitoneal injection of vehicle or baicalein (20 mg/kg) five days a week for three weeks (n=6/group). Tumor size and weights were measured.
Results: Baicalein had a marked cytotoxic effect in C3L5 cells with an IC50 of less than 10mM (data not shown). FITC-Annexin V and PI analysis with flow cytometry for C3L5 cells treated at 10μM for 48h showed a marked increase in the Annexin V positive fraction indicative of apoptosis.
In vivo studies demonstrated a significantly decreased tumor growth in mice treated with intraperitoneal baicalein when compared to the control group (P&lt;0.05).
Baicalein treated cells demonstrated STAT3 inhibition on western blot analysis by decreased presence of phospho-STAT3 (data not shown).
Conclusions: Baicalein, a flavone from TEAM demonstrates significant anti-cancer effects due to apoptosis in breast cancer. STAT3, a well-known anti-apoptotic signaling intermediate, is inhibited in activation as reflected by decreased phosphoSTAT3 which may account for these effects.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-13.
Abstract P6-15-01: A Phase 1b Study To Assess the Safety and Tolerability of the PARP Inhibitor Iniparib (BSI-201) in Combination with Irinotecan for the Treatment of Patients with Metastatic Breast Cancer (MBC)
Authors: Moulder S , Mita M , Bradley C , Rocha C , Harris L. 
Published: April 2011

Abstract
Background: Inhibition of poly (ADP-ribose) polymerase-1 (PARP1), a key regulator of DNA repair and cell proliferation, potentiates the anti-tumor activity of DNA-damaging chemotherapy agents, including irinotecan, a topoisomerase inhibitor (Ossovskaya et al. AACR 2009). Combination of gemcitabine and carboplatin with the PARP inhibitor iniparib has demonstrated promising efficacy and safety in patients with triple-negative MBC (O'Shaughnessy et al. SABCS 2009). Single agent irinotecan is active in heavily pre-treated metastatic breast cancer (MBC), with response rates (RR) up to 23% (Perez et al. JCO 2004;22:2849). A Phase 1 dose-escalation study of iniparib in advanced solid tumors showed no dose-limiting toxicities (DLTs) at iniparib doses of 0.5 to 8.0 mg/kg (Kopetz et al. ASCO 2008). That study was expanded here to determine the maximum-tolerated dose (MTD) of irinotecan that can be used in combination with fixed dose iniparib in patients with locally advanced or MBC.
Methods: Patients were treated with a 3+3 study design to determine safety of iniparib (8 mg/kg IV twice-weekly on Days 1, 4, 8, and 11 every 21 days) in combination with escalating doses of irinotecan (80 — 125 mg/m2 IV on Days 1 and 8 every 21 days). RRs were measured per modified RECIST criteria. Serial pharmacokinetic (PK) assessments were performed during Cycle 1, and archived paraffin-embedded tumor samples were collected to correlate markers of hypoxia (CAIX) with PARP1 expression (as measured by immunohistochemistry [IHC]) and response. Results: The median age of 34 patients who received therapy was 50 years (range, 32-84), and the median number of prior therapies was 2 (range, 0-6). Preliminary analysis show that tumors from 22 (65%) patients were ER-/PR-/HER2- (triple-negative), 10 (29%) were ER+/HER2-, and 1 (3%) was HER2+. One DLT of Grade 3 diarrhea with lower GI bleed was observed, thus establishing the optimal regimen from this study at 8 mg/kg iniparib + 125 mg/m2 irinotecan. Other toxicities included neutropenia, anemia and diarrhea. Of 26 patients evaluable for response, 5 (19%) had partial response (PR), 10 (38%) had stable disease (SD) for &gt;4 cycles of therapy, and 9 (35%) developed progressive disease (PD) as best response. Of 10 patients who had reached 6 cycles at time of analysis, 5 (50%) had SD. Median follow-up time was 11 weeks. PK and IHC evaluations are ongoing and will be presented, along with mature response data. Conclusions: An MTD of 8 mg/kg iniparib and 125 mg/m2 irinotecan was identified in patients with MBC. Iniparib in combination with irinotecan was well tolerated and showed promising efficacy, with evidence of clinical benefit (RR + SD ≥6 cycles) in 50% in patients with treatment-refractory MBC. (ClinicalTrials.gov number, NCT00298675)
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-01.
Abstract P6-15-08: KGFR Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer
Authors: Pento T , Meghna MM , Kesinger JW , Brueggemeier RW , Hackett J , Xiao Z , Lerner MR , Brackett DJ , Awasthi V , Li P-K. 
Published: April 2011

Abstract
Background: Keratinocyte growth factor (KGF) produces a rapid increase in the proliferation and motility of estrogen receptor (ER)-positive breast cancer cells (Zang, XP and Pento, JT, Clin. & Exptl. Metastasis 18: 573-80, 2001). It has been demonstrated that the KGF receptor (KGFR) is up-regulated in breast cancer; thus, KGF/KGFR signaling appears to be an early event in breast cancer progression (Zang, XP, Lerner, ML, Bahr, SJ, Brackett, DJ and Pento, JT, Cancer Genomics & Proteomics, 3: 369-72, 2006). Molecular modeling was used to create group of KGFR selective tyrosine kinase inhibitors (TKI) (Pento, JT and Li, PK, Drugs of the Future, 32: 965-72, 2007). The present study examined the effect of a group of these compounds on KGF-mediated proliferation and Erk signaling in MCF-7 breast cancer cells. In addition, the oncolytic potential of compound L-27, a potent KGFR TKI, was examined in an orthotopic xenograft model of human breast cancer.
Methods: A group of high affinity KGFR TKI were tested for their ability to inhibit KGF-mediated proliferation and Erk phosphorylation in MCF-7 cells using MTS and ELISA assays. In addition, immuno-cytochemistry was used to examine the influence of the 5 most potent inhibitor compounds on the density of cell membrane KGFR. The effects of a KGFR TKI on breast cancer growth and progression in vivo was examined using an orthotopic xenograft model, with clones of MCF-7 cells which were transfected with a KGF-producing plasmid to enhance cell growth and metastasis and a GFP reporter to quantify tumor growth and metastasis. PET imaging was also used to identify metastatic development.
Results: From the initial group of 53 compounds, 5 compounds were observed to produce greater than 50% inhibition of KGF-mediated cancer cell proliferation, reduce Erk phosphorylation and the density of the KGFR on the membrane surface of the cancer cells. Compound L-27, one of the most potent KGFR inhibitors, reduced the growth of MCF-7 tumors and metastatic development in the xenograft model in a dose-related fashion at doses of 4, 10 and 25 mg/kg. Animal weights in the treatment groups remained the same as the control group; indicating a lack of toxicity at the doses employed.
Discussion: The novel compounds tested in this project reduce or abolish KGF-mediated proliferation, Erk signaling and KGFR membrane density in vitro. In addition, compound L-27, a potent KGFR inhibitor in vitro, was found to reduce the progression of MCF-7 tumor xenografts in vivo. In conclusion, the KGFR TKI represent a novel class of anticancer agents for the prevention of metastatic progression and may provide a new therapeutic approach for the treatment of breast and other cancers. Acknowledgement: This work was supported by the grants from DoD (DAMD17-01-1-0591) and the NCI (CA-89740) and (CA-125493).
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-08.
Abstract P6-15-11: Role of Proteasome Activators in the Inhibition Breast Tumors and Suppression of Metastasis
Authors: Asea A , Kaur P , Neumann W , Asea E , Nagaraja G. 
Published: April 2011

Abstract
Background: Breast cancer is the second leading cause of cancer-related death of women in the U.S. A number of genes involved in the process of growth, proliferation, apoptosis and DNA repair have aberrant expression in tumor cells. Metastasis is major cause of the decline in the quality of life breast cancer patients. Heat shock protein, Hsp25 is known to participate in tumorigenesis, and is highly expressed in breast tumors biopsies. However, the exact role of Hsp25 is incompletely understood. Materials and Methods: We have silenced the expression of Hsp25 using lentiviral constructs of short interfering RNA in highly metastatic mouse 4T1 cell line. Mouse tumor formation and metastasis assay was done by subcutaneous injection of 4T1-controlshRNA and 4T1-Hsp25shRNA cells into the mammary pad of female BALB/c mice. Tumor progression/regression was monitored by using an in vivo animal imaging system (MaesteroTM In-vivo imaging system, CRI, Woburn, MA, USA). Microarray analysis was done by using protocols of Applied microarray, Inc, USA. In vivo antitumor assay and adoptive transfer of CD8+ T cells was done by using standard protocol.
Results: Microarray investigation on Hsp25 silenced cells demonstrated an upregulation of tumor suppressor gene (N-myc downstream regulated gene 2) and down regulation of metastasis gene (urokinase-type plasminogen activator) signatures. Subcutaneous injection of Hsp25 silenced 4T1 tumor (4T1-Hsp25shRNA) cells into immunocompetent female BALB/c mice results in complete tumor regression, absence of pulmonary metastasis and enhanced CD8+ CTL-dependent tumor killing. In vivo depletion of CD8+ T cells allowed the 4T1-Hsp25shRNA tumors to grow; however, there was no observable metastasis to the lungs. These results were confirmed by in vitro cytotoxicity assays in which CD8+ T cells recovered from mice injected with 4T1 -Hsp25shRNA cells, but not 4T1-controlshRNA cells effectively lysed 4T1 targets. Furthermore, the adoptive transfer of 4T1-Hsp25shRNA reactive CD8+ T cells into mice injected with 4T1-controlshRNA cells enabled them to effectively reject 4T1 tumors.
Discussion: Our study strongly indicate Hsp25 as a therapeutic target for breast cancers.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-11.
Abstract P6-15-12: Preclinical Evaluation of a STAT3 Inhibitor in Breast Cancer
Authors: Walker SR , Nelson EA , Chaudhury M , Madoux F , Subramaniam P , Chase P , Koenig M , Roush WR , Hodder P , Frank DA. 
Published: April 2011

Abstract
Breast cancer often arises from inappropriate activation of transcription factors involved in normal mammary development, such as the signal transducers and activators of transcription (STAT) family of transcription factors. STAT3, which plays an important role in mammary remodeling, is activated (as assessed by tyrosine phosphorylation) in approximately 70% of primary breast cancers, with many of these tumors being highgrade. Furthermore, inhibition of STAT3 leads to a loss of tumorigenicity of breast cancer cells. Therefore, targeting STAT3 in breast cancer would be a potentially beneficial form of therapy.
To identify small molecule STAT3 inhibitors, we developed a high throughput cell-based assay to identify compounds that inhibit STAT3- dependent transcriptional activity. We screened approximately 200,000 compounds, and specificity for STAT3 was ensured by eliminating molecules that inhibited either STAT1- or NF-kappaB-dependent transcriptional activity. From this screen, we identified 4-[4-(phenylmethyl) piperidin-1-yl] thieno[2,3-d]pyrimidine (PMPTP) (Probe ID ML116) as a potent inhibitor of STAT3 transcriptional activity, which has no effect on STAT1 or NF-kappaB-dependent transcriptional activity. Treatment with PMPTP of MDA-MB-468 breast cancer cells, which contain constitutively activated STAT3, leads to inhibition of expression of STAT3 target genes including bcl-x and mcl1. Furthermore, PMPTP is a potent inhibitor of viability of MDA-MB-468 breast cancer cells. By contrast, SK-BR-3 cells, which do not contain constitutively active STAT3, were only minimally affected. This suggests that PMPTP reduces the viability of cells that depend on constitutively active STAT3. PMPTP has no effect on STAT3 tyrosine or serine phosphorylation or STAT3 nuclear translocation, suggesting that PMPTP may be inhibiting STAT3 at the level of DNA binding or co-factor recruitment.
Importantly, PMPTP lowers the apoptotic potential of breast cancer cells thereby making them more susceptible to other forms of therapy. Building on this observation, we identified a number of beneficial combinations of PMPTP with cytotoxic drugs currently used in breast cancer therapy as well as novel anti-cancer agents. Additionally, we analyzed a number of structural analogues of PMPTP, and we identified two compounds that had approximately 4-fold increased potency in inhibiting the viability of breast cancer cells containing STAT3 activation.
Taken together, these findings identify PMPTP as a potential new form of therapy for breast cancers containing activated STAT3, which can be enhanced using conventional and non-conventional chemotherapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-12.
Abstract P6-15-15: MM-111 - A Novel Bispecific Antibody Targeting HER-2/HER-3 Z Heterodimer: Safety and Tolerability in a First-In Human Phase I/II Study in Patients with Refractory HER2-Positive (HER-2+) Cancers
Authors: Beeram M , Denlinger CS , Tolcher AW , Goldstein LJ , Patnaik A , Papadopoulos K , Murray J , McDonagh C , Andreas K , Niyikiza C , Moyo VM. 
Published: April 2011

Abstract
Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use (Sergina et al Nature 2007, Garrett et al SABCS 2009 abstract 63). MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates ligand binding. In preclinical models of HER-2+ gastric, breast, ovarian and lung cancers, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. This first-inhuman phase 1-2 study evaluates the safety and tolerability of MM-111 and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). The safety data obtained during the Phase 1 dose escalation portion of this study provide the basis of this report.
Methods: Patients (pts) with histologically confirmed HER-2+ advanced solid tumors progressing or recurring on standard therapy; aged ≥18 years; ECOG PS ≥2 and adequate organ function were eligible for phase I. Pts with stable CNS lesions were also eligible. A Modified Fibonacci schema was used for dose escalation in Phase I. Primary endpoints for Phase 1 were determination of maximum tolerated dose/maximum feasible dose while secondary endpoints included determination of dose-limiting toxicity, adverse events, and pharmacokinetic (PK) and immunogenicity profiles of MM-111. MM-111 was administered intravenously weekly in 4-week cycles.
Results: 12 pts (11 ABC and 1 gastric cancer) were treated: median age 59 (range 36-82), median PS 1 (range 0-1), 11♂:1♀, median numberof prior therapies 7 (3-12). A total 19 courses (median 2; range 1-2) of therapy was administered at 4 dose-levels (3 mg/kg, 6mg/kg, 12mg/kg and 20 mg/kg respectively). Common adverse events reported included pain (n=7) fatigue (n=4), dyspepsia (n = 3) and pyrexia (n = 3). There were no treatment interruptions due to adverse events. No dose limiting toxicities were observed and there has been no evidence of cardiotoxicity or immunogenicity to date. PK data indicate dose proportionality at the dose-levels explored and supports weekly dosing.
Conclusions: MM-111 is well tolerated at the doses levels studied and the PK profile suggests that weekly dosing is feasible. Enrollment to phase II is anticipated to commence shortly.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-15.