bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-13-04: Thymidylate Synthase (TS) and Thymidine Phosphorylase (TP) Expression as Predictive Markers of Capecitabine Mono-Chemotherapy for Patients with Anthracyclin-Taxane Pretreated Metastatic Breast Cancer (MBC)
Authors: Lee SJ , Choi YL , Cho EY , Kim ST , Park YH , Ahn JS , Im Y-H. 
Published: April 2011

Abstract
Background: Capecitabine, one of the widely used cytotoxic agents for breast cancer, achieved high tumor control rate with low toxicity even in heavily-pretreated patients with metastatic breast cancer (MBC). Capecitabine (Xeloda®) is an oral fluoropyrimidine pro-drug that is transformed to fluorouracil (FU) in several steps, the last of which is conversion of 5'-deoxy-5-fluorouridine to FU by TP. And TS is a target enzyme of 5-FU. The primary purpose of this study was to evaluate the role of TS and TP as biomarkers to predict clinical outcomes of capecitabine monotherapy for MBC.
Method: Of Three hundreds fifty-three patients with MBC treated with capecitabine at Samsung Medical Center from 2000 to 2008, ninety patients who were previously treated with anthracycline and taxanes containing regimens and had available tissues for immunohistochemical stainings with estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor-2 (HER2), TS, and TP were included in this analysis. All patients had received capecitabine 2000-2500mg/m2/day for 14days q 3 weeks.
Results: The median age of these 90 patients was 49 (26-76) years. The response rate (RR) was 25.6% and the disease control rate (DCR) was 65.6%. The median progression-free survival (PFS) and overall survival (OS) from the 1st day of capecitabine monotherapy were 4.8 (95% C.I.; 3.1-6.5) and 26.7 (95% C.I.; 17.1-36.3) months, respectively. High TS expression (TS score ≥100) was more common in patients with triple negative (TN) subtype than in those with other subtypes (16% for HR+, 22% for HER2+, 44% for TN, p=0.023). Median PFS was significantly lower in high TS expression (6.6 vs. 3.0 months; p=0.017) and low TP expression (TP&lt;50) patients (6.0 vs. 3.3 months; p=0.013). High TS score and low TP score were identified as unfavorable independent risk factors for PFS to capecitabine monotherapy in Cox regression multivariate analysis (Hazard Ratio (HR) 1.7, p=0.037 for high TS score; HR 1.8, p=0.014 for low TP score). And, high TS and low TP score were associated with poorer overall survival.(29.9 vs. 14.1 months; p=0.008 for TS /29.9 vs. 20.4 months; p=0.043 for TP)
Conclusion: Our data suggests that high TS score and low TP score correlated with shorter PFS for capecitabine monotherapy of patients with anthracycline and taxane pretreated MBC. Potential role of TS, TP expression as predictive markers of capecitabine monotherapy in patient with MBC should be confirmed by prospective studies.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-04.
Abstract P6-14-06: Prospective Testing of Three Different Gene-Signatures for Patient Selection for Dasatinib Therapy in Metastatic Breast Cancer
Authors: Pusztai L , Moulder S , Litton J , Valero V , Ueno N , Melhem-Bertrandt A , Morrow PK , Dotter K , Mattair D , Strauss L , Hortobagyi GN , Qi Y , Symmans WF. 
Published: April 2011

Abstract
Background: Several gene signature-based predictors of response to targeted drugs have been proposed in the literature but none has been prospectively tested as patient selection tools in the clinic. The goal of this trial is to assess the positive predictive value of 3 conceptually different multi-gene signatures as predictors of response to the multitargeted kinase inhibitor dasatinib.
Methods: This clinical trial requires biopsy of a metastatic lesion for gene expression profiling and employs a parallel, multi-arm, two-step, phase II design. Three markers are assessed including a (i) cell-line derived dasatinib-sensitivity signature, (ii) a src-pathway activity signature and (iii) a dasatinib target index calculated as the weighted average expression of all known dasatinib targets. Only markerpositive patients are treated with dasatinib 100 mg po daily and each marker arm is considered as a separate study with early stopping rules for futility (minimum sample size 9, maximum sample size 40/marker arm). A predictor is considered worthy of further study if the clinical benefit rate (i.e. positive predictive value) is ≥25%.
Results: Forty seven patients were accrued from July 2009 through June, 2010, 49 biopsies were performed (soft tissues n=31, liver n=8, bone n=3, lung n=1, adrenal gland n=1), 6 samples had poor cellularity and 3 failed array QC. There was no patient recall, hospitalization or emergency room visit due to biopsy procedure. The median time from biopsy to genomic prediction result was 5 days (range 3-7). Twenty three (57%) patients had positive result for at least 1 predictor (5 were positive for 2) and 20 are receiving therapy (3 withdraw or progressed before therapy began). Responses as of June 2010; Target index arm (n=9): 5 PD (progressive disease), 4 SD (3 stable disease at 8 weeks 1 SD at 16 weeks); SRC Pathway arm (n=5): 3 PD, 2 SD at 8 weeks; Cell line predictor arm (n=6): 2 PD, 1 SD at 8 weeks, 3 not yet reached response evaluation. None of the 3 predictive marker arms have met early stopping yet and accrual is ongoing. Conclusion: Gene-expression signature based patient selection for targeted therapy is feasible and FNA biopsies of metastatic lesions for genomic testing are safe. Updated efficacy results will be reported.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-06.
Abstract P6-14-11: ß-Catenin Inhibitor SST-024 Can Sensitize Breast Cancer Tumor Initiation Cells (TICs) to Ionized Radiotherapy
Authors: Xu W , Debeb BG , Alvarez de Lacerda LC , Woodward WA. 
Published: April 2011

Abstract
Recent studies have shown that tumor initiation cells (TICs) are more resistant to ionized radiotherapy (IR) than differentiated cancer cells. In our lab, we have previously shown that aberrant Wnt signaling can contribute to radio-resistance of TICs in breast cancer. Herein, we use SST-024 (StemSynergy), an inhibitor of ß-catenin and WNT signaling, to test if pharmacologic inhibition of ß-catenin can sensitize breast cancer TICs to IR. Sum-149, an inflammatory breast cancer cell line, Sum-159, a non-inflammatory basal-type breast cancer cell line and IBC-3, a short-term cultured inflammatory breast cancer sample were used in these studies. We found that SST-024 inhibited Sum-149 mammosphere formation, a surrogate for TIC growth in vitro, at IC-50 0.3 nM while IC-50 for Sum-159 was 3 nM and IC-50 for IBC-3 was 4 nM. Similar efficacy against TICs was seen in assessments of alternative TIC surrogates including aldefluor staining by flow cytometry and CD44+CD24- marked cells. On immunoblot analysis SST-024 down-regulated unphosphorylated, active B-catenin and downstream target c-myc as well as EMT marks, including N-cadherin, Snail, Twist and Slug, and DNA repair regulator ATM. Moreover, standard monolayer and 3D mammospheres clonogenic assays demonstrate significant radiosensitization of SUM-149 TICs (mammospheres) as well as monolayer colony formation. In summary,
SST-024 demonstrates significant efficacy against inflammatory breast cancer TICs and sensitize both TICs and non-TICs to IR implying targeting Wnt β-catenin signaling may be a feasible strategy to radiosensitize breast cancer TICs.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-11.
Abstract P6-14-16: A Systematic Review of the Evidence for Treatment of Metastatic Breast Cancer beyond 2nd Line
Authors: Lalla D , Sedelnikova M , Wieffer H , Brammer M , Modha R. 
Published: April 2011

Abstract
Background: Optimal treatment of metastatic breast cancer (MBC) post second-line is not well defined. Therapy options are limited by previous exposure, while HER2 status may remain relevant to decision-making. A systematic review was conducted to identify trials reporting efficacy data, and review the current treatment landscape for HER2+ and - patients for third and later line treatment of MBC.
Methods: A systematic search strategy from Medline, EMBASE and Cochrane (CCTR) databases retrieved citations for two-stage review. Citations that reported 3rd or later line treatment of MBC patients were included. Selected conference proceedings from the last 3-5 years were searched for relevant abstracts and posters. Included studies were restricted to those with data reported for 10 or more patients.
Results: 39 citations from 29 trials, investigating 22 treatment regimens, were identified which reported efficacy data specific for a 3rd or later line population: in 22 trials, this was a sub-group analysis of a mixed line population. 76% of included studies were single arm: only 1 RCT was identified. 21% of included studies investigated the treatment of HER2+ populations; no studies reported outcomes specific for the HER2- population. Overall response rate (ORR) was the most reported outcome. The majority of responses were partial, complete response was rarely observed beyond 2nd line. Overall and progression-free survival were rarely reported. The highest ORR was reported for mitomycin C and capecitabine in HER2 mixed patients. Table 1 presents response rates reported in HER2+ patients.
Conclusions: There does not appear to be a standard regimen used in the treatment of patients beyond the second line. In patients with HER2+ breast cancer, T-DM1 had the highest reported response rate.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-16.
Abstract P6-15-07: A Dose-Escalation Study with a Special Drug Delivery System (SDS) of BEZ235, a Novel Dual PI3K/mTOR Inhibitor, in Patients with Metastatic/Advanced Solid Tumors
Authors: Rodon J , Infante J , Burris H , Tabernero J , Ranson MR , Rouyrre N , Duval V , Silva A , Hackl W , Baselga J. 
Published: April 2011

Abstract
Background: The PI3K pathway plays a major role in cancer cell growth and survival and is the most frequently altered pathway in cancer. BEZ235 is a potent and highly specific oral PI3K/mTOR inhibitor. Administered as hard-gelatine capsule, BEZ235 was well tolerated with a favorable safety profile. Available data showed that BEZ235 led to PRs (1 patient (pt) with NSCLC [PTENnull], 1 pt with ER+ breast cancer [mutation unknown]) and prolonged disease stabilization (4 to &gt;24 months) in pts with PI3K pathway dysregulated tumors (N=9/51), 5/9 with ER+, 1/9 with HER2+ breast cancer. Here, we present data from patients (pts) receiving treatment with a special drug delivery system of BEZ235 (SDS) with improved PK properties (Cao SABCS 2010).
Results: 22 pts have been treated with BEZ235 SDS capsule at 3 dose levels (qd): 400 mg (5); 800 mg (6), 1000 mg (11). Median age was 56 years. The most common tumor types among pts enrolled were: breast cancer (4), CRC (4) and NSCLC (3). 2/22 pts were treated for &gt;3 cycles, 16/22 pts progressed within the first three cycles of treatment. The maximum tolerated dose (MTD) is 1000 mg/d. Dose-limiting toxicities (DLTs) included: 2 Grade (G)3 fatigue (800 mg and 1000 mg) and 1 G3 skin rash (at 1000 mg). The most common treatment-related AEs included: fatigue, diarrhea, nausea, vomiting (G1-3). Preliminary PK data showed a slow absorption rate, Cmax at ∼6 h post-dose (range 2-8 h). The elimination halflife is ∼6 h across doses and visits. Steady state was reached after 8 days of treatment; the mean (SD) exposures at steady state (AUC, rss) for the dose of 400, 800, and 1000 mg/d were 8864 (12210), 19060 (19860), 46010 (36150) ng*h/mL, respectively. The exposure across dose levels (AUC0- 24, SS) was above the exposure required for tumor stasis in PI3K pathway dysregulated tumors, estimated based on CT measurements in patients(Bottino SABCS 2010). Currently, the efficacy of BEZ235 SDS, alone and in combination with trastuzumab, in patients with PIK3CA mutated breast cancer is investigated. As of today 1 clinical PR was observed with BEZ235+trastuzumab in a patient with breast cancer (HER2+, PIK3CA mutated, trastuzumab refractory) with brain and peripheral metastases.
Conclusions: BEZ235 SDS treatment is well tolerated. The MTD is 1000 mg/d. Available PD and efficacy data show that BEZ235 is active in breast cancer (especially PI3K pathway dysregulated tumors). Phase II studies in breast cancer combining BEZ235 SDS with other agents will start soon.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-07.
Abstract P6-15-19: PI3K-MTOR Inhibitor BEZ235 Shows Antitumor Activity Against a Panel of Basal-Like Cells and Potentiates the Antitumor Activity of Taxanes and Vinorelbine
Authors: Montero JC , Esparis-Ogando A , Pandiella A , Ocana A. 
Published: April 2011

Abstract
Background: Intracellular signalling pathways associated with the oncogenesis of basal-like breast cancer are relatively unknown. Basal-like breast cancer constitutes 15% of all breast tumors. Although chemotherapy is the only treatment, no data support the use of one agent over others. Furthermore, combinations of chemotherapies with targeted agents against activated signalling pathways have not been explored. Here we have analyzed the action of the dual PI3K-AKT-mTOR pathway inhibitor BEZ235 on a panel of basal-like breast cancer cell lines. Methods: We used several triple negative breast cancer cell lines, and analyzed the action of BEZ235 on their proliferation and cell survival using MTT metabolization and other apoptosis assays. Biochemical experiments were performed to investigate the molecular bases of the action of BEZ235. Experiments in combination with chemotherapies were also performed to identify synergic combinations.
Results: PI3K-AKT pathway was activated in most of the cell lines studied. Administration of the dual PI3K-mTOR inhibitor BEZ235 decreased AKT phosphorylation in a dose dependent manner. It also reduced signalling through the mTORC1 and mTORC2 complexes. BEZ235 also decreased proliferation of most cell lines with IC50 values &lt;1 μM. Administration of BEZ 235 with taxanes and vinorelbine showed synergy. Conclusions: The PI3K-AKT-mTOR signalling axis is frequently activated in basal-like cells. The efficient antitumoral effect of the inhibition of this route with BEZ235 indicates that targeting this pathway may be a relevant therapeutic strategy in triple negative breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-19.
Abstract PD01-02: Integration of Capecitabine into Anthracycline-and Taxane-Based Adjuvant Therapy for Triple-Negative Early Breast Cancer: Final Subgroup Analysis of the FinXX Study
Authors: Lindman H , Kellokumpu-Lehtinen P-L , Huovinen R , Jukkola-Vuorinen A , Tanner M , Kokko R , Ahlgren J , Auvinen P , Bono P , Joensuu H 
Published: April 2011

Abstract
Background: Standard adjuvant chemotherapy regimens for patients with moderate-to-high risk early breast cancer typically contain a taxane, an anthracycline and cyclophosphamide. The randomised, phase III FinXX study aimed to investigate whether the integration of capecitabine into such a regimen enhances outcome. Here we present final 5-year exploratory analyses from the subgroup of patients with triple-negative early breast cancer (TNBC).
Methods: Patients aged 18-65 years, with histologically confirmed invasive node positive breast cancer or node negative progesterone receptor negative breast cancer &gt; 20 mm, and with a WHO performance status of 0 or 1, with no previous neoadjuvant chemotherapy were randomised. Patients received 3 x XT (capecitabine 900mg/m2 bid d1-15 + docetaxel 60mg/m2 d1)≥3 x CEX (cyclophosphamide 600mg/m2 d1, + epirubicin 75mg/m2 d1 + X 900mg/m2 bid d1-15, q3w) or 3 x T (80mg/m2 d1)≥3 x CEF (C 600mg/m2 d1, E 75mg/m2 d1, 5-FU 600mg/m2 d1, q3w). The primary endpoint was RFS, defined as the time from randomisation to the first time the patient is recorded as having disease recurrence or the date of death if the patient dies due to causes other than disease recurrence. Secondary endpoints included overall survival and safety.
Results: Between January 2004 and May 2007, 1,500 women from Finland and Sweden were randomised (XT→CEX n=753, T→CEF n=747). Of these, 202 patients (13.5%) had TNBC (XT→CEX n=93, T→CEF n=109). After a median follow-up of 59 months, RFS was significantly improved in the TNBC XT→CEX arm versus control (HR 0.48, 95% CI 0.26-0.88; p=0.018). The following endpoints were also significant: 5-year RFS in patients with TNBC versus those without TNBC (HR 0.50, 95% CI 0.36-0.69; P&lt;0.001); 5-year distant disease-free survival in TNBC patients receiving XT→CEX versus control (HR 0.51, p=0.035); overall survival in TNBC patients receiving XT→CEX versus control (HR 0.42, p=0.019). Conclusions: The FinXX trial is the first to report the efficacy of capecitabine in combination with anthracycline-/taxane-containing therapy in the adjuvant treatment of early breast cancer. The exploratory subgroup analysis shows that XT→CEX is more effective than T→CEF in triple-negative BC, a population with a high unmet need; XT→CEX versus control resulted in a significant improvement in RFS and OS after 5 years.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-02.
Abstract PD01-07: Transcriptome Analysis of Triple Negative Breast Cancers Identifies Six Distinct Biological Subgroups and Reveals Therapeutic Strategies
Authors: Lehmann BD , Bauer JA , Chen X , Sanders ME , Shyr Y , Pietenpol JA. 
Published: April 2011

Abstract
Background: Currently, there are targeted therapies for estrogen receptor (ER) positive and HER2-amplified breast cancers. However, treatment options for patients with triple negative breast cancers (TNBCs), tumors that are hormone receptor negative (ER and progesterone, PR) and lack HER2 amplification, has been limited by the heterogeneity and lack of moleclular understanding of the subtypes of this disease. Use of genomic information (gene expression, copy number analysis, methylation arrays, and next-generation sequencing) will unravel the complexity of the disease and identify novel targeted therapies.
Methods and Findings: In order to identify biologically distinct TNBC subgroups and associated molecular drivers, we compiled an extensive TNBC transcriptome dataset from 21 independent breast cancer studies. We performed reiterative k-means clustering analysis on a 386 TNBC gene expression profile training set and identified six stable clusters that display unique gene expression patterns and gene ontologies. An independent set of 201 TNBC gene expression profiles was used to validate the six TNBC subgroups. We identified two basal-like subgroups (BL1 and BL2) characterized by cell cycle and DNA damage response genes, two mesenchymal-like subgroups (M and MSL) enriched in cell differentiation, epithelial-mesenchymal transition and growth factor pathways, an immunomodulatory subgroup (IM) defined by immune cell surface antigens, receptors and signal transduction genes, and a luminal subgroup (LAR) driven by androgen receptor signaling. Using tumor gene expression signatures, we identified representative cell lines to model each of the TNBC subgroups and also pharmacologically targeted prominent signaling pathways.
Conclusions: Through transciptome analysis we subclassified TNBC into six biological subgroups and identified potential therapeutic targets for future exploration. The data generated in this study have significant value for target selection in drug discovery, clinical trial design and selection of biomarkers that will enable the alignment of TNBC patients to the appropriate targeted therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-07.
Abstract PD02-07: Impact of Mesenchymal Stem Cells on Radiation Therapy Response
Authors: Lacerda L , Gupta A , Debeb BG , Xu W , Meyn R , Marini F , Andreeff M , Woodward WA , Klopp AH. 
Published: April 2011

Abstract
Background: Radiation increases engraftment of human bone-marrow derived mesenchymal stem cells (MSC) in tumors and this effect is augmented following repeated doses of radiation. We have recently demonstrated that MSC increase formation of mammospheres, which are enriched with radiation resistant tumor-initiating cells. Thus, we hypothesized that MSC may impact radiation therapy response through enhanced survival of tumor-initiating cells.
Materials & Methods: To evaluate the impact of MSC on radiation response we performed in vitro clonogenic survival assays using 2D and 3D clonogenic assays. Colony (2D) and sphere (3D) formation was quantified following irradiation of different cell lines (breast, lung, head and neck and cervix) at 2, 4 and 6 Gy in the presence of MSC conditioned media. In vivo, MSC were co-injected subcutaneously at increasing percentages with 4T1 murine breast cancer cells in BALB/c mice. The effects of MSC on radiation response were evaluated by examination of tumor size and weight following tumor irradiation at 2 and 5 Gy. Results: In vitro 2D clonogenic cell survival assays demonstrated that MSC conditioned media increased survival of breast (MDA231), lung (H460), head and neck (HN5), and cervical (SiHa) cancer cells following irradiation with 2 and 4 Gy as compared to control fibroblast conditioned media. Moreover, MSC conditioned media increased the number of HMLE (breast normal ephitelial cells) and SUM149 (breast cancer cells) mammospheres formed (55 vs 195and 263 vs 1054, respectively) and increased clonogenic survival of mammospheres after 2, 4 and 6 Gy compared to serum-free media. In vivo, irradiation with 5 Gy reduced murine breast 4T1tumors weight by 75% as compared to control untreated tumors. However, tumors co-injected with MSC did not significantly respond to 5 Gy. Discussion: MSC increase tumor resistance to radiation therapy in vivo and in vitro in 2D and 3D cultures. This effect is mediated at least in part by paracrine factors secreted by MSC. Our results here described suggest that MSC secrete factors which activate survival pathways on cancer cells exposed to sub-lethal radiation doses.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-07.