bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-16-13: Cardiac Safety of Non-Pegylated Liposomal Doxorubicin and Docetaxel as 1st Line Treatment in Metastatic HER2 Negative Breast Cancer (Myotax Study).
Authors: van Warmerdam L , Schiphorst P , Nieboer P , Dercksen M , de Jongh F , Schmidt R 
Published: June 2012

Abstract
Background: Doxorubicin (DOX) is an effective, but cardiotoxic agent in metastatic breast cancer (BC). Incidence of heart failure (HF) is 2–4% and increases considerably with cumulative doses over 450–550 mg/m2. In Myocet® DOX is encapsulated in liposomes. It is delivered predominantly to areas with increased capillary permeability such as tumors and reduces cardiac exposure. We conducted an open non-comparative study to assess cardiac safety of Myocet® combined with docetaxel.
Materials and methods: Females with locally advanced or metastatic HER2 negative BC. 6 cycles of Myocet® 60 mg/m2 and docetaxel 75 mg/m2 q3w as 1st line therapy. Left ventricular ejection fraction (LVEF) and disease status were assessed after cycle 2,4 and 6. Primary endpoint: signs and symptoms of HF (NYHA III-IV) or LVEF &lt;50% and decrease ≥5% (with symptoms) or ≥10% (without symptoms). Results: 68 patients (pats) were included. Mean (sd;range) age 56,3 y (10,2;32-79), mean disease duration 5,5 y (5,1 y;1 mo-19 y), 31 pats had anthracyclines (AN) in the past. 49 pats completed all 6 cycles. Mean LVEF (%) over time are presented in table 1.

4 pats (3 AN pretreated) met the LVEF criteria for cardiotoxicity (no signs/symptoms of HF) after the 6th cycle. In 3 pats (all AN pretreated) a significant drop in LVEF was given as (one of the) reason(s) for premature discontinuation, but LVEF criteria for cardiotoxicity were not met. 73 grade ≥3 toxicities occurred in 32 pats; most frequent: neutropenia (±fever) 19 pats. Premature discontinuations (no. of pats): progressive disease 9, cardiotoxicity 3, other toxicity 4, death 2, other reason 1. In 10 pats the dose of Myocet was reduced. The best response was scored for 50 pats with at least 1 measurable lesion: CR 4, PR 28, SD 14, PD 4.
Mean LVEF in the entire group decreased during the study from 63 to 59 (9,2) %. The decrease in the AN pretreated group was 7% and in the not pretreated pats 3%. 4 pats met the LVEF criteria for cardiotoxicity and 3 others were withdrawn for cardiotoxicity without meeting the criteria. 6 of these pats were AN pretreated. None of them had signs/symptoms of HF. PR or better was observed in 64% of pats.
Conclusion: Liposomal DOX might provide more cardiac safety compared to conventional AN, but pats pretreated with conventional AN seem to be more prone to LVEF decrease. No signs or symptoms of HF have been observed. The combination of Myocet® and docetaxel is efficacious and sufficiently well tolerated and is currently investigated in combination with trastuzumab in HER2 positive pats.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-13.
P3-16-18: Phase 2, Open-Label Study of EZN-2208 (PEG-SN38) in Patients with Previously Treated Metastatic Breast Cancer.
Authors: O'Shaughnessy JA , Osborne CRC , Steinberg MA , Holmes FA , Kim HS , Kocs DM , Richards PD , Vukelja SJ , Berkowitz N , Buchbinder A 
Published: June 2012

Abstract
Background
EZN-2208 is a water-soluble PEGylated conjugate of SN38 that results in parenteral delivery, increased solubility, higher exposure, and longer apparent half-life of SN38, as well as more profound deoxyribonucleic acid (DNA) damage and inhibition of angiogenesis. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38 in the blood.
Methods: This trial evaluated EZN-2208 delivered as a 1-h IV infusion weekly for 3 wks in 4-wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (Xeloda®) (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety and toxicity. Response was evaluated using RECIST (v1.1).
Results: 148 patients received EZN-2208 in the AT (n=65; median age = 56 y [31-84 y]) or ATX (n=83; median age = 55 y [36-83 y]) cohorts. All 65 patients in the AT cohort had received 0–2 lines of prior cytotoxic therapy for MBC; for the ATX cohort, 31 patients (37%) had received 0–2 prior lines of cytotoxic therapy for MBC, 50 patients (60%) had received 3–4 prior lines, and 2 patients (2%) had received 5 prior lines. Preliminary results follow; final data will be presented at the meeting. Median (range) cycles of EZN-2208 was 2.3 (0.3-14) for AT and 2 (0.3-15) for ATX. Best overall response is shown in the table. RR (PR+uPR) was 22% for AT and 10% for ATX.
Median (95% CI) time to progression was 3.8 mo (3.6−7.4) for AT and 3.3 mo (1.8−3.7) for ATX. Median (95% CI) duration of response was 4.0 mo (3.7−5.6) for AT and 5.2 mo (1.9-..) for ATX. 6-mo PFS (95% CI) was 34% (19%-50%) for AT and 19% (9%-29%) for ATX. Median PFS (95% CI) was 3.8 mo (2.7−5.6) for AT and 2.9 mo (1.83.7) for ATX. Median OS (95% CI) was 9.1 mo (6.1−12.7) for AT and 7.9 mo (6.4−12.9) for ATX. Grade 3 or 4 drug-related adverse events (&gt;10% of patients in either arm) included neutropenia (43%, 33%), diarrhea (11%, 8%), and leukopenia (11%, 6%).

Conclusions: EZN-2208 is active in patients with previously treated MBC. The activity is similar regardless of ER status and is promising in the TNBC population. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in this population is warranted.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-18.
P3-17-06: Final Results of a Controlled, Randomized 3-Arm Phase II Trial of EndoTAG”-1, a Cationic Liposomal Formulation of Paclitaxel Targeting Tumor Endothelial Cells, in Advanced Triple-Negative Breast Cancer (TNBC).
Authors: Awada A , Bondarenko IN , Tarasova O , Bonneterre J , Nowara E , Ferrero JM , Bakshi AV , Weidenthaler H , Wilke C , Piccart MJ 
Published: June 2012

Abstract
Background
EndoTAG™-1 (ET) is an innovative therapy of paclitaxel (P) embedded in cationic liposomes displaying antitumor activity by targeting negatively charged activated endothelial cells of tumor vessels.
Methods: 140 patients (pts) with locally relapsed (r) or metastatic (m) centrally verified TNBC were randomized to i.v. weekly ET (22mg/m2 ) plus P (70mg/m2) (ET+P), biweekly ET alone (44mg/m2) or weekly P (90mg/m2) in a 2:2:1 ratio. Pts had ≤ 1 prior chemotherapy (CT) for r or m disease and ≥ 6 months (mo) after taxane. A cycle (cy) comprised 3 weeks(w) of therapy and 1 w rest. Pts were treated for a minimum of 4 cy or until disease progression/unacceptable toxicity.
Primary endpoint was progression-free survival (PFS) rate at week 16 based on blinded central imaging and local assessment. Secondary endpoints included median overall survival (mOS), tumor response (RECIST), Quality of Life (QoL) and safety. The study was not powered for intergroup comparisons.
Results: Pts baseline characteristics were overall well distributed. Appr. 80% of all pts were treated 1st line for r or m TNBC. Results of PFS rates at week 16 are shown in table. Based on central review, median PFS at week 16 was 4.2 mo for ET+P [95% CI: 3.5−9.1], 3.4 on ET [2.0−3.8] and 3.7 on P [1.9−6.7]. Antitumor activity was highest for ET+P with a clinical benefit rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥6 mo at data cut off date of week 41) of 53% (26/49 evaluable pts), 31% (15/49) on ET and 36% (9/25) on P. The best overall response (CR, PR, SD at any time) on ET+P was 80% (39/49), on ET 65% (32/49) and 68% (17/25) on P.
Analysis of median OS is shown in table. Analysis of the not predefined subgroup (centrally TNBC + ECOG 0/1 + first line population) showed an impressive median OS of 17.8 mo for ET+P. No differences were reported for QoL. No additional toxicities to those known for ET and P were observed except uncomplicated grade 3/4 neutropenia in the ET + P arm.

Conclusions: At cut-off date week 41, the final analysis demonstrated ET+P as a promising combination compared to single agent arms. ET+P was well tolerated. These data will be the basis for a confirmatory phase III study.
Acknowlegments: B. Glasschroeder, U. Elsasser
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-06.
P4-01-11: Autocrine Human Growth Hormone (hGH) Reduces the Sensitivity of Breast Cancer Cells to Treatment with Tamoxifen and Fulvestrant.
Authors: Perry JK , Chen H , Bougen NM , Liu D-X , Lobie PE 
Published: June 2012

Abstract
Despite recent advances in breast cancer treatment regimes, intrinsic or development of resistance to conventional breast cancer therapies is still a significant clinical challenge. Expression of growth factors by tumour cells has been proposed as one mechanism for developing resistance to radiotherapy and chemotherapeutic agents.
The growth hormone/insulin-like growth factor-1 axis is emerging as an important mediator of tumour development in human breast cancer. Recent studies have demonstrated that humans with growth hormone receptor deficiency are protected from developing cancer. Studies investigating human growth hormone (hGH) expression in human breast cancer have demonstrated that hGH expression is associated with specific histopathological features and survival outcomes for patients. Increased hGH expression is significantly associated with lymph node metastasis, tumour stage, proliferative index, worse relapse free survival and reduced overall survival in mammary carcinoma. In recent studies we have demonstrated that autocrine hGH promotes cell proliferation, cell survival and oncogenicity of human mammary carcinoma cells, enhancing anchorage independent cell growth, and supporting tumour formation in immunodeficient mice. Autocrine hGH also promotes mammary carcinoma cell migration/invasion and epithelial to mesenchymal transition and tumour vascularisation in xenograft studies.
In this study we investigated whether autocrine hGH promotes resistance to anti-estrogen therapeutic drugs, sensitivity to tamoxifen and fulvestrent using the human breast cancer cell lines MCF-7, T47D and BT474. Stable transfection with an expression vector containing the hGH gene enhanced MCF-7, T47D and BT474 cell viability, total cell number and anchorage independent growth following treatment with tamoxifen or fulvestrant when compared to control transfected cells. Conversely, treatment of BT474 cells with an hGH receptor antagonist (B2036), increased BT474 cell sensitivity to treatment with tamoxifen or fulvestrant. Using an estrogen response element (ERE) luciferase assay, we observed that autocrine hGH enhanced basal estrogen receptor (ER)-mediated transcriptional activity.
Our results demonstrate that forced expression of hGH in mammary carcinoma cells enhances ER-mediated signal tranduction and promotes resistance to tamoxifen and fulvestrant, while functional antagnonism of hGH increased cell sensitivity. Consequently, antagonism of the hGH receptor may help maintain sensitivity to anti-estrogen therapy and improve the prognosis of patients with hormone sensitive breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-11.
P4-01-13: Biology of Aggressiveness and Tamoxifen Resistance in Hormone Receptor-Positive Very Young Age Breast Cancer.
Authors: Han W , Ro J , Jung S 
Published: June 2012

Abstract
It has been known that young breast cancer patients have worse outcomes compared with older premenopausal or postmenopausal patients. Survival difference between young and older breast cancer patients is evident only in hormone receptor positive breast cancer regardless of tamoxifen treatment according to our previous report. However, the biology of aggressiveness and endocrine resistance of breast cancer in very young women is largely unknown. The purpose of this study is to find molecular characteristics of hormone receptor positive breast cancers of very young age women (&lt;35) compared with those of older premenopausal women.
We extracted mRNA from fresh frozen hormone receptor positive primary breast cancer tissues of 24 young age breast cancer patients (&lt;35 years) and 31 older premenopausal women (40 to 49 years) by standard method. All tumor specimens analyzed contained more than 50% tumor cells. Hormone receptor status was determined by immunohistochemistry (IHC). Gene expression microarray experiment was done in the 55 samples using Illumina HumanRef-8 v3 Expression BeadChip (Illumina, Inc., San Diego, CA). Functional and pathway analysis of differentially expressed genes were done using DAVID (http://david.abcc.ncifcrf.gov/home.jsp) and Ingenuity pathway analysis (IPA, http://www.ingenuity.com). Ki-67 assay was done using IHC in 4,957 ER+ breast cancer patients of Seoul National University cohort and 1,863 ER+ patients from National Cancer Center, Korea.
355 genes were upregulated (&gt;1.5 fold) and 209 genes were down-regulated in breast cancer tissues of young age patients (&lt;35) compared with those of older patients. In pathway analysis of the highly expressed genes in young patients, cell cycle function and pathway was significantly activated. The genes of central role in this pathway were MYC and CCND1. In IHC assay for 4,957 ER+ Seoul National University dataset, the proportion of high Ki-67 expression (&gt;=10%) was positively correlated with decreasing age: 26.4%, 24.0%, 21.3%, 14.8%, 12.0% of women aged &lt;30, 30–34, 35–39, 40–49, 50–59, respectively (p&lt;0.001). The same correlation pattern between younger age and high Ki-67 expression was also seen in another 1,863 patient cohort.
In conclusion, we showed that genes involved in cell cycle pathway were upregulated in very young age (&lt;35) ER+ breast cancer using microarray study. It was validated in large data set using Ki-67 IHC assay. High proliferation and fast cell cycle could be a mechanism of worse outcome and tamoxifen resistance of ER+ very young age breast cancer patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-13.
P4-01-21: An Estrogen-Inducible Transcription Factor FOXP1 Promotes Estrogen-Dependent Cell Proliferation of Breast Cancer Cells and Is Associated with 5-Year Disease-Free Survival in Patients with Tamoxifen-Treated Breast Cancer.
Authors: Shigekawa T , Ijichi N , Ikeda K , Horie-Inoue K , Shimizu C , Saji S , Aogi K , Tsuda H , Osaki A , Saeki T , Inoue S 
Published: June 2012

Abstract
Estrogen signaling pathways are involved in the growth and development of breast tumors through the activation of estrogen receptor a (ERα). ERα is expressed in most breast cancers and involves in estrogen-dependent proliferation by acting as transcription factors activating the expression of target genes. Various coregulators and transcription factors are associated with ERα-mediated transcriptional control of target genes. Therefore, a comprehensive understanding of estrogen signaling pathways in breast cancer is required for both treatment and diagnosis of the disease. Forkhead box P1 (FOXP1) is a member of the forkhead box transcription factor family and has been reported to be associated with various types of tumors. Here, we investigated the expression pattern of FOXP1 by immunohistochemistry in a series of 133 invasive breast cancers and compared it with clinicopathological factors. The expression of FOXP1 was detected in nuclei in 89 cases (67%) and correlated positively with tumor grade and hormone receptor status, including ERα and progesterone receptor (PgR), and negatively with pathological tumor size (pT). And in ERα-positive MCF-7 breast cancer cells, we demonstrated that FOXP1 mRNA was upregulated by estrogen and that ERα recruitment to ER binding sites within the FOXP1 gene region identified by ChIP-chip analysis was increased. We also demonstrated that proliferation of MCF-7 cells was increased by exogenously transfected FOXP1 and decreased by FOXP1-specific siRNA. Moreover, in MCF-7 cells, FOXP1 enhanced estrogen response element (ERE)-driven transcription. Finally, FOXP1 immunoreactivity was significantly more elevated in relapse-free breast cancer patients treated with tamoxifen than in relapse patients treated with it. Taken together, these results suggest that FOXP1 plays an important role in proliferation of breast cancer cells by modulating estrogen signaling and that FOXP1 immunoreactivity might be associated with the estrogen dependency of breast cancer clinically, which may predict favorable prognosis in the patients treated with tamoxifen.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-21.
P4-02-08: Obesity-Induced Aromatase Expression in the Breast Microenvironment Promotes Estrogen Receptor Activity Independent of Circulating Estradiol Levels.
Authors: Bowers LW , Brenner AJ , Li R , Tekmal RR , deGraffenried LA 
Published: June 2012

Abstract
Epidemiological studies indicate that obesity increases the risk of postmenopausal breast cancer by approximately 50%. In the past, researchers have hypothesized that elevated estrogen synthesis by the peripheral adipose tissue may be the principal mediator of breast tumorigenesis in this population, which primarily develops estrogen receptor alpha (ERα) positive breast cancer. However, obesity is also accompanied by an elevation in growth factor and cytokine signaling, and these pathways have been linked to tumorigenesis. In addition, certain growth factor and cytokine family members can promote aromatase expression in both the epithelial and stromal tumor compartments. Consequently, we hypothesized that obesity increases the risk of postmenopausal breast cancer via elevated aromatase expression and/or activity in the local mammary tissue.
To test our hypothesis, we investigated how ERa activity in mammary epithelial cells was influenced by adipose stromal cells (ASC) cultured under obesity-associated conditions, including high cell density and exposure to elevated levels of circulating growth factors and cytokines. For the latter condition, sera was obtained from postmenopausal women, pooled by BMI category (lean: 18.5−24.9; obese: ≥30), and applied to the ASC, which were originally derived from women undergoing reduction mammoplasty. High ASC density was achieved via the protocol previously published by Dr. Li. Preliminary data indicated that both elevated cell density and sera from obese postmenopausal women induces greater aromatase expression in ASC, indicating that multiple factors may be contributing to the increased local aromatase expression seen with obesity. We are currently exploring the signaling pathways responsible for obesity's upregulation of ASC aromatase expression and will present these results at the meeting. Intriguingly, exposure to conditioned media from both the high density and obese sera-exposed ASC enhanced ERa activity in MCF-7 mammary epithelial cells, independent from exogenous estradiol but dependent on the presence of androgens, suggesting an important role for the aromatase enzyme in this observation. To expand on this finding, we plan to investigate the effect of ASC conditioned media on different markers of cancer aggression, including proliferation and survival, and assess the degree to which these effects depend on estradiol. Through further examination of obesity's impact on signaling pathways in both the epithelial and stromal tumor compartments, we ultimately hope to identify more effective chemopreventive and therapeutic regimens for the high-risk obese postmenopausal population.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-08.
P4-05-01: Rab25 Alters Cellular Energetics and Growth Signaling during Breast Oncogenesis.
Authors: Mitra S , Cheng KW , Dennison JB , Mills GB 
Published: June 2012

Abstract
Background: Conservation and consumption of cellular energy is centrally regulated by growth and metabolism of the whole organism. The cancer cell gains autonomy from this regulation to become an organism with indeterminate growth potential. Plasma membrane receptors including growth factors and nutrient receptors are sensors for microenvironmental cues that dictate the intracellular energetic pathways to recalibrate ATP production based on available resources. So altercations in both growth and metabolic pathways are common features of cancers. A unifying component between receptor mediated growth signaling and metabolic pathways within a cell could be the vesicular trafficking system that imports, transports and exports a wide array of cargo from both these pathways.
In fact, derailed endocytosis is a hallmark of cancer. The endocytic pathway, as demonstrated by our laboratory, is a frequent target of genomic aberrations in cancer, and plays a critical role in maintenance of cellular polarity, stem cell fnction, bioenergetics, proliferation, motility, invasion, metastasis, apoptosis and autophagy. The Rab GTPases along with their effectors are critical regulators of this endocytic machinary and can have a huge impact on the cellular iterinary of growth and metabolism.
Methods and results: A broad spectrum analysis of distribution of all the Rab family members across 52 breast cancer cell lines reflected a dichotomous distribution of Rab25, with higher mRNA and protein expression in ER+ cell lines. Rab 25 is of immense interest to us because of its unique substitution of leucine for glutamine at position 71which typically decreases the intrinsic GTPase activity, resulting in a dominant, constitutively active protein, akin to a transforming RAS mutation.
Using high throughput mRNA data analysis, we report that Rab25 and its effector Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER +ve breast cancers. Specifically in the luminal B subtypes, they are significantly associated with a markedly worsened outcome. In vitro, in MCF7 cell line, we observe an increased EGFR stability and MAPK signaling in Rab25 overexpressing stable clones which could be reversed with shRNA knockdown of Rab25. Loss of either Rab25 or RCP inhibited survival and growth of MCF7 lines under serum free conditions suggesting that Rab25 can potentially facilitate growth factor independence in cancer cells. Most importantly, we report that Rab25 enhances mitochondrial ATP production in breast and ***ovarian cancer cells and significantly reduces acidification of the ECM. Our ongoing experiments are directed towards understanding the mechanistic link between Rab25 mediated effects on EGFR/pERK signaling and its effects on cellular metabolism.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-05-01.