bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD01-05: Histone Deacetylase Inhibitor LBH589 (Panobinostat) Suppresses the Activated-NFκB Pathway in Acquired Aromatase Inhibitor Resistant Breast Cancer Cells.
Authors: Kubo M , Kanaya N , Liu Z , Chen S 
Published: June 2012

Abstract
Background: Aromatase inhibitors (AIs) are effective in treating postmenopausal patients with estrogen receptor (ER)-positive breast cancer. However, resistance to endocrine therapies remains a major problem in the management of ER-positive breast cancer. Recently, histone deacetylase inhibitors (HDACis) show promise as cancer therapeutics, but the full scope of their utility remains unknown.
Experimental Design: In order to search for critical genes in developing resistance to AI, a microarray study was performed on AI resistant cells derived from MCF-7aro cells that overexpress aromatase and on AI resistant tumors from our mouse experiments. Moreover, using MCF-7aro cells that are resistant to anastrozole (Ana-R), letrozole (Let-R), and exemestane (Exe-R), as well as LTEDaro, we evaluated the significance of NFKB1 and several regulatory genes in AI resistance, and the anti-NFκB1 activity of HDACi LBH589 in vitro and in vivo.
Results: Significant changes (Fold change cutoff &gt; 1.5, false discovery rate &lt; 0.05) in the expression levels of 22 genes among three networks were identified from microarray analysis of our in vitro and in vivo models of acquired AI resistance. NFKB1 is a key player in one of three networks, including 11 genes, and is functionally up-regulated in all AI resistant cells. NFκB1 knockdown suppresses the proliferation of AI resistant cells more than that of MCF-7aro cells. Moreover, AI resistant cell lines are highly sensitive to LBH589 treatment and apoptosis is induced in these cell lines. LBH589 suppressed NFκB1 as demonstrated at both the mRNA and protein levels in LTEDaro and other AI resistant cell lines. Furthermore, the LBH589 treatment abrogated tumor growth in mice, and was associated with significant decreased levels of NFKB1 in tumors.
Conclusions: Our findings provide new insights into how the NFκB1-mediated networks play roles in AI resistance, and strongly support that LBH589 offers a novel therapeutic strategy for patients with AI resistant breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-05.
PD07-04: Lapatinib vs Trastuzumab in Combination with Standard EC-D Chemotherapy in the Neaodjuvant Treatment of HER2+ Patients. Results from the GEICAM 2006–14 Phase II Randomized Trial.
Authors: Alba E , Albanell J , de la Haba J , Barnadas A , Calvo L , Sánchez P , Ramos M , Rojo F , Burgués O , Porras I , Tibau A , Carrasco E , Cámara MC , Lluch A 
Published: June 2012

Abstract
Background: The addition of trastuzumab (T) to neoadjuvant chemotherapy increases pCR rate in patients with HER2 + breast cancer. Lapatinib (L) in combination with chemotherapy is also an active drug in breast cancer patients. This study investigates the efficacy of trastuzumab or lapatinib added to chemotherapy in the neoadjuvant setting.
Methods: Patients (Pt) with tumors greater than 2 cm (or less with positive axilla) and HER2+ (Herceptest 3+ or 2+ with FISH+) that have not received any prior treatment for breast cancer were recruited. Pts were randomized to receive epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles (cy) followed by docetaxel 100 mg/m2 (with growth colony stimulating factor support) plus either T 8 mg/kg loading dose and then 6 mg/Kg intravenous (EC-DT) or L 1250 mg orally (EC-DL). Patients were stratified according to tumor size (T1-2 vs T3-4), and estrogen receptor status (positive vs negative). The primary end-point was pathological complete response (pCR) in the breast measured by Miller and Payne criteria. Secondary end-points were clinical response (by imaging test), toxicity and correlation between pCR and tumor biomarkers.
Results: From February-09 to October-10, 102 pts were randomized (50 EC-DT, 52 EC-DL). Pts characteristics were well balanced between arms. Median age was 48 years (30-79), 56% of pts were premenopausal, 7% grade I, 45% grade III. 14/59/12/15% were T1/T2/T3/T4 and 69% N+. 58% were estrogen receptor positive and 44% progesterone receptor positive. Three patients were FISH negative after central assessment and were not considered evaluable for efficacy. pCR rate in the breast was 52% (95% CI: 38–66) for EC-DT and 25% (95% CI: 13.5−37.5) for EC-DL (p-value=0.0065). pCR—pN0 was 48% (95% CI: 34–62) for EC-DT and 24% (95% CI: 12 - 35) for EC-DL (p-value=0.01). Clinical response was 77% with EC-DT and 65% with EC-DL (p-value=0.176). Grade III-IV toxicity was similar between arms except for diarrhea that was more frequent in EC-DL 14% than in EC-DT 2% (p-value=0.03); more patients discontinue treatment due to toxicity with EC-DL (1 vs 6; p-value=0.055).
Conclusions: Our study shows that EC-DT was more efficacious and less toxic than EC-DL in the neoadjuvant treatment of HER2+ pts. Biomarker profiling in the tumors, including activation levels of tyrosine-kinase receptors, signaling pathways and surrogate markers (proliferation and apoptosis) is ongoing; their correlation with pCR will be presented at the meeting.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-04.
PD08-03: Inhibition of MEK/ERK- and JNK-Dependent Expression of Interleukin-6 and Interleukin-8 Targets Basal-Like Breast Cancer Stem Cells.
Authors: Balko JM , Cook RS , Kuba MG , Miller TW , Bhola NE , Sanders ME , Meszoely IM , Dowsett M , Gomez H , Arteaga CL 
Published: June 2012

Abstract
Background: Neoadjuvant chemotherapy (NAC) induces a pathological complete response in approximately 30% of triple-negative or basal-like breast cancers (BLBC). However, patients with residual disease often recur after surgery, presumably due to persistent drug-resistant subpopulations with cancer stem cell (CSC)-like properties. Thus, elimination of this CSC compartment in BLBC has the potential to improve survival by reducing post-surgical metastatic recurrences.
Methods: We sampled 49 post-NAC breast cancer samples including 22 BLBCs and quantified RNA for 355 cancer-related transcripts using Nanostring technology. Transcripts associated with a high Ki67 in the residual disease (a biomarker of early recurrence) were identified and bioinformatically examined for an association with drug resistance and a CSC phenotype. Loss of DUSP4, a negative feedback regulator of ERK1/2 and JNK1/2, was highly associated with a high post-NAC Ki67. We examined the role of loss of DUSP4 in promoting a drug-resistant, CSC phenotype.
Results: Low DUSP4 expression in post-NAC tumors was associated with high ERK1/2 activation and BLBC gene expression. siRNA knockdown of DUSP4 enhanced resistance to anti-cancer chemotherapy (docetaxel, camptothecin). Alternatively, forced DUSP4 expression in breast cancer cell lines abrogated the activation of transcription factors downstream of ERK and JNK and sensitized cells to docetaxel-induced apoptosis. In highly metastastic BLBC cell lines, MEK inhibition with AZD6244 and JNK inhibition with SP600125 significantly reduced mammosphere formation and self-renewal. Inhibition of JNK and MEK reduced IL6 and IL8 expression, two cytokines known to expand the CSC compartment. Reconstitution of exogenous IL6 and IL8 after MEK inhibition restored mammosphere formation potential. Chromatin immunoprecipitation demonstrated that the oncogenic transcription factor ETS-1, an ERK1/2 substrate, binds the IL8 promoter in a MEK1/2-dependent manner. We are currently confirming the association of DUSP4 loss with Ki67, ERK activation, and IL6/IL8 expression in a cohort of 113 post-NAC triple negative breast cancers. Conclusions: Our data demonstrate that loss of DUSP4 in BLBC promotes ERK and JNK activation by impairing negative feedback of these pathways. Activation of ERK and JNK drives expression of IL6 and IL8 expression, possibly through ETS-1 activation. Thus, targeting these signaling pathways may eliminate residual cancer stem cells after neoadjuvant chemotherapy and improve cure rates in BLBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-03.
PD09-03: Phase I/II Study of BKM120 in Combination with Trastuzumab in Patients with HER2 Overexpressing Metastatic Breast Cancer Resistant to Trastuzumab-Containing Therapy.
Authors: Saura C , Bendell J , Jerusalem G , Graña-Suárez B , Su S , Ru Q , De Buck S , Devisme C , Bosch A , Urruticoechea A , Beck JT , DiTomaso E , Rouyrre N , Sternberg DW , Massacesi C , Hirawat S , Dirix L , Baselga J 
Published: June 2012

Abstract
Introduction: HER2 amplification can activate the phosphatidylinositol-3-kinase (PI3K) pathway in breast cancer. Furthermore, trastuzumab (T) resistance can be associated with loss/deregulation of PTEN, which also causes activation of PI3K pathway signaling. BKM120, a potent orally bioavailable pan-class I PI3K inhibitor, could reverse resistance to T in vitro. Furthermore, administration of BKM120 with T demonstrated synergistic activity in preclinical models. The potential for combining BKM120 with T in heavily pretreated HER2+ metastatic breast cancer (MBC) patients (pts) will be determined in this study to substantiate the hypothesis for future development.
Methods: HER2+ MBC pts resistant to T-containing therapy (progression on or within 4 weeks since last T administration) received treatment in the dose-escalation portion of this multicenter trial. Prior anti-HER2−directed therapies were allowed. The primary objective was to determine the maximum tolerated dose (MTD) of BKM120 in combination with the standard dose of weekly T. A Bayesian logistic regression model with overdose control guided the dose escalation.
Results: Seventeen pts with MBC have been enrolled: 5 at 50 mg/day and 12 at 100 mg/day dose of BKM120. Escalation was conducted up to the MTD level of single agent BKM120, 100 mg/day. Patient characteristics: median age 46 years (range 34–70); most pts were heavily pretreated (reported range of prior chemotherapy lines 1–4). In preliminary results (cut-off date 1st June 2011), 7 pts discontinued treatment. BKM120 in combination with T showed a mean peak drug concentration and half-life similar to single-agent BKM120. T trough levels remained above the single agent efficacy threshold. Only one dose-limiting toxicity (G3 asthenia) was reported at the BKM120 dose of 100 mg/day. The MTD was determined to be 100 mg/day. Reported G3 adverse events were asthenia, altered mood, rash, GGT increase, hypokalemia, and hypersensitivity in 1pt each. No G4 toxicity has been observed so far. With regards to activity, 2 partial responses (1 confirmed) and 3 occurrences of disease stabilization have been observed.
Conclusions: BKM120 in combination with T in heavily pretreated HER2+ MBC pts with T-resistance has an acceptable safety profile and has shown encouraging preliminary activity. The Phase II portion of the study is ongoing. An updated analysis of efficacy, the potential correlation with PI3K pathway alteration status overlaying HER2 activation, and pharmacodynamics study will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-03.
PL1-1: How To Use Endocrine Therapy for Breast Cancer: Beyond the Basics.
Authors: Winer EP 
Published: June 2012

Abstract
Over two thirds of all breast cancers are hormone receptor positive. The majority of these tumors have some degree of sensitivity to endocrine treatments. The approach to endocrine therapy has become more complex over the past decade, and there are more treatment choices than before. Not only are there choices about which endocrine therapy to use, but also important decisions about how long to continue treatment and how to sequence agents. It has become clear that the benefits and risks of endocrine therapy vary both from tumor to tumor and from person to person. The landscape will soon become even more complicated as targeted therapies are combined with endocrine therapy to prevent or reverse drug resistance. This lecture will focus on a number of key issues: 1) Can we improve upon a 5 year course of tamoxifen in premenopausal women? 2) Given the high risk of late recurrence in many patients with hormone receptor positive disease, which patients will benefit from extended adjuvant therapy and what should this therapy be? 3) Is the use of an aromatase inhibitor alone in postmenopausal women sufficient therapy for all breast cancer patients and how should we select individuals who should be considered for other approaches? 4) In 2011, are there patients with hormone receptor positive disease who should not receive adjuvant endocrine therapy? 5) What approaches can be used to circumvent resistance to hormonal therapy, and how quickly will they be incorporated into clinical practice? The talk will address the dilemmas that are most vexing for clinicians and have immediate relevance for clinical practice.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PL1-1.
S2-6: ErbB3 Expression Is Required for Maintenance of Normal and Transformed Luminal Breast Epithelial Cells.
Authors: Cook RS , Balko JM , Rinehart C , Miller TW , Polyak K , Prat A , Perou CM , Arteaga CL 
Published: June 2012

Abstract
The ErbB receptor tyrosine kinase family regulates breast development and cancer. ErbB2/HER2 expression correlates with HER2-enriched breast cancers, while epidermal growth factor receptor (EGFR) expression often correlates with triple negative breast cancers. Less is known regarding ErbB3, which harbors only weak kinase activity, but strongly activates phosphatidylinositol-3 kinase (PI3K)/Akt signaling upon heterodimerization with EGFR or ErbB2. We report herein that ERBB3 mRNA expression strongly correlates with Luminal A/B breast cancers, which express lower levels of EGFR and ErbB2. Mammary-specific loss of ErbB3 in mice reduced Akt phosphorylation and caused cell death in the luminal epithelium. A decreased luminal population in ErbB3-deficient epithelium correlated with expansion of the mammary stem/progenitor fraction. In normal breast samples, ERBB3 mRNA expression was highest in mature/progenitor luminal populations, and lowest in the stem/basal population. Loss of ErbB3 shifted gene expression in mammary epithelial cells to resemble a mammary stem cell signature. The genes most greatly impacted by ErbB3 loss produced a signature that correlated with decreased overall survival in tamoxifen-treated patients. Knock-down of ErbB3 in human luminal breast cancer cells caused decreased cell growth under conditions of estrogen deprivation, decreased expression of the gene encoding aromatase, and impaired expression of estrogen receptor-induced genes, including those that encode progesterone receptor and TFF1. Treatment of MCF7 luminal breast cancer xenografts with AMG-888, a humanized monoclonal antibody directed against ErbB3, decreased tumor growth. Combination of AMG-888 with the estrogen receptor inhibitor fulvestrant caused MCF7 tumor regression. Taken together, these results suggest that ErbB3 is required to sustain normal and transformed luminal epithelial cells of the breast, and suggest that targeting ErbB3 may improve the clinical outcome of breast cancers treated with endocrine therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-6.
SR1-2: Breast Cancer and the Environment: A Life Course Approach - Report Release from an IOM Committee.
Authors: Hiatt RA 
Published: June 2012

Abstract
In response to a request from Susan G. Komen for the Cure®, an Institute of Medicine (IOM) committee was convened to review and assess the strength of the science base regarding the relationship between breast cancer and the environment. As part of their charge, the committee members reviewed the evidentiary standards for identifying and measuring cancer risk factors and the methodological challenges involved in conducting research on breast cancer and the environment. They also considered the potential interaction between genetic and environmental risk factors. The committee's report notes evidence-based actions that women could take to reduce their risk of breast cancer and offers recommendations for future research on breast cancer and the environment. The results of this IOM committee's work will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR1-2.
SR2-1: The Genomic Mutation Landscape of Breast Cancer: A TCGA Report.
Authors: Mardis ER 
Published: June 2012

Abstract
An important goal, that of characterizing the breadth and complexity of mutations in breast cancer, is being approached by The Cancer Genome Atlas in its next-generation sequencing and analysis of the exome and whole genome content of breast cancer samples. At present, we have produced, analyzed, and validated mutations by exome capture of matched tumor and normal genomic DNA across all breast cancer subtypes, using over 500 samples as our primary discovery set. The resulting information has been further analyzed by integration with other data types being generated in the project, including RNA-seq, methylation and SNP array data. We have further initiated a study using whole genome sequencing of 21 basal subtype cases. My presentation will provide an overview of the methods of data generation, analysis and integration. I will further provide information about our discoveries to-date and future plans.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR2-1.
Abstract A105: Application of national guidelines diminishes racial disparities in end-of-life cancer care
Authors: Austin Laura K. , Pendleton Delinda , Zhu Fang , Engstrom Paul , Levy Michael , Swaby Ramona F. 
Published: June 2012

Abstract
Introduction: There are known racial disparities in cancer mortality among African American (AA) patients with shorter median survival rates compared to white patients. Utilizing evidence based clinical guidelines allows for equitable treatment of all patients and may eliminate disparities. The goal of this study was to determine whether AA patients were referred to hospice earlier in their treatment course at a tertiary academic cancer center that routinely utilizes nationally recognized treatment guidelines (i.e. – National Comprehensive Cancer Center Network, NCCN).
Methods: We retrospectively analyzed 315 charts of patients referred for hospice during 2008–2009. Subjects identified as either AA or Caucasian were analyzed by race, age and socioeconomic category. Subjects residing in geographic neighborhoods corresponding to postal zip codes with median incomes of either &gt; or ≤ $50,000 were used as a surrogate for socioeconomic status. Charts were reviewed to determine how many lines of chemotherapy were administered before hospice referral. Patients were excluded if they were referred to hospice without receiving chemotherapy. Age, number of chemotherapy regimens and socioeconomic status were compared using Wilcoxon rank-sum test within each race. The overall number of lines of chemotherapy stratified by race was compared using Van Elteren's Test. All categorical variables were summarized by year and race and compared using Fisher's exact test.
Results: Patient characteristics and outcomes are as listed in the table below. There was no significant difference between the average number of lines of chemotherapy administered to AA or Caucasian patients, respectively (2.92 vs 2.62; p=0.026), and no racial difference in the percentage of patients referred for hospice discussion prior to hospice transfer [AA (92.2%) Caucasian (83.3%); p=0.36). Similarly, adherence to NCCN treatment guidelines was similar between races [AA (89.1%) Caucasian (93.1%); p=0.36]. AA patients were more likely to reside in a zip code with a lower median income (p&lt;0.001). Interestingly, lower income Caucasian patients were statistically found to have been treated with more lines of chemotherapy prior to hospice, (2.81 compared to 2.39; p=0.04).
Conclusions: In this retrospective single institution analysis, there was no evidence that AA patients or patients from lower median incomes were referred to hospice earlier than white patients or patients with higher median incomes. These results are encouraging and may be partially attributable to the use of evidence based NCCN treatment guidelines, suggesting that applying such guidelines to all patients help to eliminate racial bias and disparities in cancer care.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A105.
Abstract A2: Region 4 NCI CRCHD BMaP: A team science approach towards a multistate network to reduce cancer health disparities
Authors: O'Connell Mary A. , Vilchis Leticia O. , Oushy Mai H. , Ramirez Amelie G. , Gallion Kipling J. , Holden Alan 
Published: June 2012

Abstract
Background/Objectives: NCI CRCHD Region 4 BMaP (Arizona, Colorado, Oklahoma, New Mexico and Texas) was initiated in 2009. The overall goal is achieving measureable reductions in racial cancer health disparities through developing regional networks where resources can be pooled to facilitate team science approaches to cancer health disparity reduction.
Methods: We established a regional hub infrastructure with specific cores: administration, training, bioinformatics, biospecimen/biobanking, clinical trials, community translation, emerging technologies, and ethical-legal-policy issues. Three methods, a group meeting and two survey tools were employed to identify regional resources. The NCI-developed Readiness Assessment Tool (RAT) collected data on cores; the “Face-to-Face” gathering provided for a SWOT analysis in cancer health disparities among Region 4 stakeholders. The online Comprehensive Needs Assessment (CNA) survey identified institutional-level characteristics necessary to develop a regional implementation plan.
Results: 100% complete response for RAT and CNA surveys. Few reported significant needs although many reported significant institutional deficiencies in bioinformatics, biospecimen/biobanking, clinical trials, and emerging technologies. Primary diseases of interest include breast and colorectal cancers. In Region 4, few CRCHD funded investigators collected biospecimens in their research programs; and all members reported strong training programs. The Face-to-Face meeting strengthened existing partnerships and increased collaboration while providing attendees a regional overview of strengths, weaknesses, opportunities, and threats.
Implications/Next Steps: Regional networks of health disparities researchers are already leverging resources to reduce cancer health disparities among minorities in the region. The GMaP/BmaP network provided contacts to leverage CHEs in the region. The program is investigating methods to create a region-wide virtual biorepository, with descriptions of biospecimens collected in research program by Region 4 PIs. Such a virtual biorepository database would be linked with other regioanl BMaP databases that are developed. In addition, Region 4 implementation plan includes creating bioethics training tools for biomedical research on US minority populations. Training materials to be developed would address missing bioethical topics on health disparities issues with an emphasis on Native Americans and Hispanic Populations, and within the topics of biospecimen collection and clinical trial participation. This aims at creating career opportunities in bioethics for students and junior investigators at minority serving institutions.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A2.