bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-08-39: Influence of lifestyle factors and tumor cell dissemination in 632 early breast cancer patients
Authors: Aktas Bahriye , Frackenpohl Anna , Hauch Siegfried , Kraus Johann , Kestler Hans Armin , Kimmig Rainer Klaus , Kasimir-Bauer Sabine 
Published: May 2015

Abstract
Introduction: Influence of lifestyle behaviour in risk of developing breast cancer is supported by several lines. Data from 632 early breast cancer (EBC) patients were collected to evaluate the influence of lifestyle factors in progression free survival (PFS) and overall survival (OS). Results of disseminated tumor cell (DTC) in bone marrow and circulating tumor cells (CTC) in blood were available as well. A complete pathological data set and medical history were obtained. It was the purpose of the present study to correlate these data to compare the findings.
Methods: We evaluated 629 bone marrow samples and 606 blood samples from EBC patients treatet between 2004 to 2010 at the time of first diagnosis. All samples underwent immunomagnetic enrichment using the AdnaTest BreastCancerSelect (AdnaGen AG, Germany) within 4 hours after blood withdrawal followed by RNA isolation and subsequent gene expression analysis by reverse transcription and Multiplex-PCR in separated tumor cells using the AdnaTest BreastCancerDetect. CTCs were analyzed for the three breast cancer associated markers: GA733-2, Muc-1, Her-2 and actin as an internal PCR control. BM aspirates were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Lifestyle data icluding menopausal status, BMI, usage of Metformin, hormone replacement drugs, beta blockers and Bisphosphonates were collected by accessing the patient files. Histological data of the primary tumor were available for each patient.
Results: The overall detection rate for CTCs was 15.41% (88/571 patients) and for DTC was 38.5% (242/628 patients), respectively. The mean BMI of 428 patients was 26.4 in 81/574 premenopausal, 426/574 postmenopausal and 67/574 perimenopausal patients. Medical history of smoking (128/394 patients), using hormone replacement therapy (92/354 patients), alcohol consumption (68/378 patients), having allergies (188/419), using Metformin (22/389 patients), taking beta blockers (83/392 patients) and Bisphosphonates (201/526 patients) were compared to PFS and OS as well as the histological data of the primary tumor.
Conclusion: Lifestyle factors seems to influence the outcome in our cohort of EBC patients as shown in previous studies. Final data and results regarding to tumor cell dissemination compared to lifestyle behaviour will be available for the SABCS 2014.
Citation Format: Bahriye Aktas, Anna Frackenpohl, Siegfried Hauch, Johann Kraus, Hans Armin Kestler, Rainer Klaus Kimmig, Sabine Kasimir-Bauer. Influence of lifestyle factors and tumor cell dissemination in 632 early breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-39.
Abstract P6-11-03: HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies
Authors: Goka Erik T , Senderoff Dana S , Munguba Gustavo , Lippman Marc E 
Published: May 2015

Abstract
HER2-targeted therapies have been instrumental in improving the treatment of HER2+ breast cancer. However, drug resistance usually emerges and remains a big challenge in using anti-HER2 therapies. Previous studies have implicated activation of the Rho GTPase Rac1 by PTEN loss or IGF-1R overexpression as a mechanism of resistance to HER2-targeted therapies. We identified HACE1, an E3 ubiquitin ligase for Rac1, as a tumor suppressor capable of cooperating with HER2 to transform normal mammary epithelial cells. While HACE1 loss alone resulted in enhanced Rac activation, HER2 activation of Rac1 combined with HACE1 loss resulted in even higher levels of activated Rac resulting in the ability to form tumors in immunocompromised mice. In this study, we show that loss of HACE1 confers resistance to the HER2 tyrosine kinase inhibitor (TKI) Lapatinib due to sustained Rac signaling irrespective of EGFR/HER2 signaling. While Lapatinib inhibition alone is capable of attenuating proliferation of HER2 overexpressing mammary epithelial cells, HACE1 loss continues to drive proliferation of in vitro tumor formation (clonogenicity) as well in vivo tumor growth. We demonstrate that Lapatinib sensitivity can be restored using a Rac inhibitor in HACE1 knockdown cells. Moreover, while the Rac inhibitor alone was capable of attenuating the effects of HER2 overexpression and HACE1 loss, simultaneous inhibition of both HER2 and Rac signaling was superior to either monotherapy alone. These results support Rac activation as a mechanism of resistance to HER2-targeted therapies and highlight the use of a Rac inhibitor to treat HER2+ refractory breast cancers.
Citation Format: Erik T Goka, Dana S Senderoff, Gustavo Munguba, Marc E Lippman. HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-03.
Abstract P6-11-08: Exploring the best therapeutic partner of triple negative breast cancers: Using different characteristics/dependent pathways of triple negative breast cancer cell lines based on subgroups
Authors: Lim Bora , Dicker David T , Kline Leah C , El-Deiry Wafik S 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC) still remains as a difficult disease given the abscence of effective treatment modality, despite some success in PARP inhibition in BRCA gene mutation patients. Recently, TNBC was elucidated to be a large group of heterogenic subgroups based on their genetic/proteomic characters. Two main subgroups that consists of greater than 90% of whole TNBC include mesenchymal like (TNMBC) and basal (TNBBC) subgroups. Mesenchymal like subgroup harbor myoepithelial, epithelial-to-mesenchymal transition related phenotype, and genetic dependency on growth hormone pathway, higher sensisitivy to death receptor inducing apoptosis pathway, as well as more dependency on PI3K-Akt-mTOR pathway. In contrast, basal like subgroup harbor the characteristics that is related to a defective DNA repair system, cell cycles regulation, and interestingly - dependency on RAS-MEK pathway for their survival and growth. Given explosive enrichment of understanding such pathways and enumeration of pathway targeting inhibitors, as well as the ability of timely recognition of biomarkers in patients sample which can differentiate subgroups of TNBC- offer an attractive strategy of novel therapeutics development in this difficult to treat disease. We tested targeting both dependent pathway and core characteristics of TNBC using representative panels of each subgroups: MDA-MB-468, BRCA1KD MCF10A, HCC1937 as in TNBBC panel showed effective killing when various combination of pAkt and PI3K, mTOR inhibitors, CDK1/2 inhibitors, death receptor mediated apoptosis inducing agents were introduced in combination. In contrast TNMBC MDA-MB-231, SUM159,BT549 showed effective killing when pERK and MEK inhibitors, in combination with BMI-1 inhibitors were given. Further elucidation of mechanisms of action in each combinations will further offer the ground of proper combination in subgroups of TNBC that could be further studied in animal model, and finally in clinical development.
Citation Format: Bora Lim, David T Dicker, Leah C Kline, Wafik S El-Deiry. Exploring the best therapeutic partner of triple negative breast cancers: Using different characteristics/dependent pathways of triple negative breast cancer cell lines based on subgroups [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-08.
Abstract S1-07: HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer
Authors: Junttila Teemu T , Li Ji , Johnston Jennifer , Hristopoulos Maria , Clark Robyn , Ellerman Diego , Wang Bu-Er , Li Yijin , Mathieu Mary , Li Guangmin , Young Judy , Luis Elizabeth , Lewis Phillips Gail , Stefanich Eric , Spiess Cristoph , Polson Andrew , Irving Bryan , Scheer Justin M , Junttila Melissa R , Dennis Mark S , Kelley Robert , Totpal Klara , Ebens Allen 
Published: May 2015

Abstract
Based on recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2-TDB) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2-TDB can eliminate cells refractory to currently approved HER2 therapies. The potent anti-tumor activity of HER2-TDB was demonstrated using four model systems including MMTV-huHER2 and huCD3 transgenic mice. We demonstrate inhibitory effect of PD-L1 expression on the activity of bispecific T cell recruiting antibodies. This resistance mechanism is reversed by anti-PD-L1 treatment and combination of HER2-TDB with anti-PD-L1 immune therapy resulted in enhanced inhibition of tumor growth, increased response rates and durable responses.
Significance:
This report presents a new immunotherapy for HER2+ breast cancer with an alternative, extremely potent mechanism of action that is effective in cells resistant to current HER2 targeted therapies. Several significant advances are provided to bispecific T cell recruiting antibodies: we characterize a critical resistance mechanism, a potential diagnostic marker, a novel transgenic efficacy model and significantly improve the drug-like properties by using technology based on full length antibodies with natural architecture. Finally we demonstrate the benefit of combining two immune therapies: direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 signaling results in enhanced and durable long term responses.
Citation Format: Teemu T Junttila, Ji Li, Jennifer Johnston, Maria Hristopoulos, Robyn Clark, Diego Ellerman, Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li, Judy Young, Elizabeth Luis, Gail Lewis Phillips, Eric Stefanich, Cristoph Spiess, Andrew Polson, Bryan Irving, Justin M Scheer, Melissa R Junttila, Mark S Dennis, Robert Kelley, Klara Totpal, Allen Ebens. HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-07.
Abstract S2-01: Theranostic multiparametric tests improve residual risk assessment in early luminal breast cancer
Authors: Bartlett John MS , Sabine Vicky S , Haider Syed , Drake Camilla , Crozier Cheryl , Yao Cindy Q , Brookes Cassandra L , van de Velde Cornelis JH , Hasenburg Annette , Kieback Dirk G , Markopoulos Christos , Dirix Luc Y , Seynaeve Caroline , Rea Daniel W , Boutros Paul C 
Published: May 2015

Abstract
Background: Despite rapidly expanding availability of multiparametric tests which inform residual risk following adjuvant therapy for early breast cancer current approaches provide minimal information on the appropriate targeted therapy to be selected for patients at high risk of recurrence. We hypothesised that inclusion of key signalling nodes from driver molecular pathways in early breast cancer in residual risk signatures would both improve risk stratification and identify candidate theranostic targets for the next generation of clinical trials.
Methods: RNA was extracted from FFPE luminal breast cancers from the TEAM pathology study (Exemestane versus Tamoxifen-Exemestane). Gene expression analyses were performed for 29 genes mapped across key signalling nodes within the PIK3CA pathway. mRNA assessment for IHC4 (ER, PgR, HER2 and Ki67) was included in the model. Quantitative gene expression was performed using the Nanostring platform. Novel signatures were trained in a randomly selected sub-set of the TEAM pathology cohort (n=˜1700) and validated using the remaining 50% of patients (n=˜1700). Results presented represent those from the validation cohort.
Results: The IHC4-protein and IHC4-mRNA risk scores were highly correlated (Rho=0.72, p=4.12x10-265), suggesting the mRNA abundance-based classifier is able to serve as a good substitute for the protein-based model.
A gene signature including IHC4 markers assessed by mRNA performed significantly better (AUC 0.70 vs 0.66) than conventional IHC4. A gene signature including 4 signalling modules from the PIK3CA pathway significantly outperformed both IHC4 and the 4 gene (ER, PgR, HER2, Ki67) classifier (AUC 0.75; p = 3.23x10-7 vs IHC4 and 1.39x10-3 vs "IHC4mRNA").
Conclusions: Inclusion of PIK3CA signalling modules identified key genes/nodes which are linked to early relapse in luminal breast cancer and provided a significantly improvement in risk classification when compared to a currently validated multiparameter test.
Citation Format: John MS Bartlett, Vicky S Sabine, Syed Haider, Camilla Drake, Cheryl Crozier, Cindy Q Yao, Cassandra L Brookes, Cornelis JH van de Velde, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Caroline Seynaeve, Daniel W Rea, Paul C Boutros. Theranostic multiparametric tests improve residual risk assessment in early luminal breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-01.
Abstract S6-01: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1
Authors: Hurvitz Sara A , Andre Fabrice , Jiang Zefei , Shao Zhimin , Neciosup Silvia P , Mano Max S , Tseng Ling-Min , Zhang Qingyuan , Shen Kunwei , Liu Donggeng , Dreosti Lydia M , Feng Jifeng , Burris Howard A , Toi Masakazu , Buyse Marc E , Cabaribere David , Lindsay Mary-Ann , Kunz Tiffany , Rao Shantha , Pacaud Lida B , Taran Tetiana , Slamon Dennis 
Published: May 2015

Abstract
Background: Everolimus (EVE), an inhibitor of mammalian target of rapamycin (mTOR), is a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. In early studies, EVE showed antitumor activity in breast cancer and synergy with both trastuzumab (TRAS) and paclitaxel. The international BOLERO-1 study is being conducted to evaluate the addition of EVE to TRAS plus paclitaxel as first-line therapy for HER2+ advanced breast cancer.
Methods: In this phase 3 randomized trial, 719 adult women with HER2+ advanced breast cancer who had not received prior TRAS or chemotherapy in the advanced setting were randomized 2:1 to receive either EVE or placebo (10 mg) in combination with weekly paclitaxel and TRAS. The two primary objectives were to compare the progression-free survivals (PFS) of everolimus/trastuzumab/paclitaxel and trastuzumab/paclitaxel/placebo in both the full population and in the Hormone Receptor negative (HR-) subpopulation. Secondary endpoints included survival, response rate, and safety. The final analysis was performed after 420 PFS events were observed in the full population.
Results: In the full population, the median age was 53 years, 70.4% had visceral metastases, 56.1% had ER and/or PgR +ve disease, and 43.3% had ≥ 3 metastatic sites. Previous adjuvant therapy included TRAS (11.4%) and taxane (24.7%).
Conclusions: The data from the final analysis will be available in October 2014. PFS, safety, and secondary efficacy endpoints will be presented at SABCS 2014. (Funded by Novartis; BOLERO-1 ClinicalTrials.gov number, NCT00876395.)
Citation Format: Sara A Hurvitz, Fabrice Andre, Zefei Jiang, Zhimin Shao, Silvia P Neciosup, Max S Mano, Ling-Min Tseng, Qingyuan Zhang, Kunwei Shen, Donggeng Liu, Lydia M Dreosti, Jifeng Feng, Howard A Burris, Masakazu Toi, Marc E Buyse, David Cabaribere, Mary-Ann Lindsay, Tiffany Kunz, Shantha Rao, Lida B Pacaud, Tetiana Taran, Dennis Slamon. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-01.
Abstract A023: Investigating differential expression of microRNAs in the luminal breast cancer subtype
Authors: Ehman Dylan A. , Pinnaduwage Dushanthi , Bull Shelley B. , Andrulis Irene L. 
Published: May 2015

Abstract
Breast Cancer is a heterogeneous disease, and tumors vary in pathological and clinical characteristics making it important that tumors be accurately characterized at diagnosis. Current methods reveal a number of breast cancer subtypes correlating with clinical factors; however, patients with the luminal subtype have a range of outcomes. Our hypothesis is that microRNA (miRNA) expression profiling may provide a method of discriminating tumors in this subtype into good and poor prognosis groups, as well as reveal potential biological factors affecting prognosis.
Expression profiling was performed on miRNAs from 39 primary ER+, HER2- luminal breast tumors from a prospective cohort of women with node negative breast cancer with a median follow-up time of 116 months. Of the 39 tumors, 19 were from patients who eventually experienced a recurrence and 20 were from matched patients who remained disease-free. Total RNA was extracted from the specimens and the miRNAs quantified using TaqMan Array MicroRNA Cards. Results analyzed using significance analysis of microarrays (SAM) revealed nine miRNAs with a standard t-test p-value less than 0.05 and ranked within the top 20, designated as significantly differentially expressed between the two groups. Four of these, miR-135a, miR-140-5p, miR-200a, and miR-218, were selected for validation on the same samples using singleplex quantitative real-time PCR conducted in triplicate, and confirmed to be significantly less expressed in tumors in patients who had experienced recurrence compared to tumors from patients without recurrence.
Functional analysis of miR-200a and miR-218 is being performed in MCF-7 breast cancer cells to determine the role they play in luminal breast cancer recurrence. Validated targets of these miRNAs suggest involvement in epithelial to mesenchymal transition and cellular migration, invasion, and proliferation. The activity of these miRNAs is being studied in vitro and altered expression of miRNA targets is being confirmed. Future studies to examine whether these modifications result in changes in tumorgenicity phenotypes will be addressed by assaying cell proliferation, migration, and invasion.
This project has the potential to aid in improving breast cancer prognostication in the clinical setting, improve our knowledge of the role if miRNAs in luminal breast cancer, and identify miRNAs suitable as possible diagnostic biomarkers or novel therapeutic targets.
Citation Format: Dylan A. Ehman, Dushanthi Pinnaduwage, Shelley B. Bull, Irene L. Andrulis. Investigating differential expression of microRNAs in the luminal breast cancer subtype. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A023.
Abstract A035: Role of the transcription factor Id4 in the developing mammary gland
Authors: Best Sarah A. , Fu NaiYang , Vaillant Francois , Lindeman Geoff J. , Visvader Jane E. 
Published: May 2015

Abstract
Transcription factors are essential for controlling cell fate decisions and differentiation during embryonic and adult development. Although transcription factors have been implicated in regulating development of the mammary gland, most of these have not been defined at a cellular level. Recent studies in the laboratory have identified the transcriptional regulator Inhibitor of Differentiation 4 (Id4) as a highly expressed gene in the mammary stem cell (MaSC)-enriched population of both mouse and human mammary glands. This population also contains progenitors and mature myoepithelial cells. Germ-line deletion of Id4 in mice has previously revealed a role for this gene in neuronal differentiation1, and more recently, as a regulator of mammary gland development through its suppression of p38MAPK2. Id4 has been identified as differentially regulated in breast cancers and plays a role in the negative regulation of BRCA13,4. We have developed a conditional knockout mouse model to investigate the function of Id4 specifically in the mammary epithelium. Id4 is expressed in myoepithelial cells of the terminal end buds and ducts, with expression reducing after puberty. Consistent with previous findings2, Id4-deficient mammary glands displayed a prominent reduction in ductal elongation and branching. We found that Id4-deficient mammary epithelial cells also have a diminished capacity to maintain the balance of luminal to myoepithelial cells, and that the MaSC/basal subset had significantly reduced repopulating capacity when assayed by transplantation. Understanding the mechanism and role of Id4 in the developing mammary gland may reveal important parallels with the role of Id4 in breast cancer.
1. Yun et al. Development, 2004. 131(21):5441-8
2. Dong et al. Development, 2011. 138(23):5247-56
3. Beger et al. PNAS, 2001. 98(1):130-5
4. Roldan et al. Cancer Biology and Therapy, 2006. 5(5):505-10
Citation Format: Sarah A. Best, NaiYang Fu, Francois Vaillant, Geoff J. Lindeman, Jane E. Visvader. Role of the transcription factor Id4 in the developing mammary gland. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A035.