bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-09-05: Preventive efficacy of the Chinese nutritional herb epimedium grandiflorum in a preclinical cell culture model for luminal A molecular subtype of breast cancer
Authors: Telang NT , Li G , Katdare M , Sepkovic DW , Bradlow LH , Wong GYC , Telang N 
Published: August 2014

Abstract
Background: The Luminal A molecular sub-type of clinical breast cancer expresses estrogen receptor (ER) and progesterone receptor (PR), but lacks the expression of HER-2 oncogene. This cancer sub-type responds to endocrine therapy involving the use of selective estrogen receptor modulators or inhibitors of estrogen biosynthesis. Conventional therapeutic options are frequently associated with acquired tumor resistance and systemic toxicity, and therefore, emphasize a need for identification of promising new non-toxic agents for secondary prevention. Nutritional substances that do not incur long-term toxicity represent ideal candidates. Nutritional herbs have been used in traditional Chinese medicine for a variety of health related issues, including prevention of breast cancer.
Methods: The present study utilized the human mammary carcinoma derived ER+/PR+/HER-2- MCF-7 cells as a model for the Luminal A breast cancer to examine the preventive efficacy of non-fractionated aqueous extract from Epimedium grandiflorum (EG), a popular Chinese nutritional herb. Anchorage dependent growth, cell cycle progression, cellular metabolism of 17b-estradiol (E2), and anchorage independent colony formation represented the quantitative end point biomarkers for preventive efficacy.
Results: Maintenance of MCF-7 cells in a chemically defined serum depleted culture medium (serum 0.7%, E2&lt;1 nM) retained their cellular growth promoting response to the physiologically relevant concentration range of 1 nM to 20 nM E2, exhibiting a 10.3% to a 91.9% increase in the viable cell number, respectively. A 7 day treatment of MCF-7 cells with EG resulted in a dose dependent inhibition of E2 promoted growth (EG IC50: 0.49%). At its maximum cytostatic concentration, EG inhibited cell cycle progression via G1 arrest, resulting in a 1.6 fold increase in the G1:S+G2/M ratio, and modulated the cellular metabolism of E2 in favor of formation of anti-proliferative metabolites 2-hydroxyestrone (2-OHE1) and estriol (E3), exhibiting a 5.1 and a 7.6 fold increase, respectively. In addition, EG produced a favorable 3.9 fold increase in the
2-OHE1: 16α-OHE1 ratio, an endocrine biomarker of breast cancer risk. A 21 day treatment of MCF-7 cells with EG produced a dose dependent inhibition in anchorage independent growth (EG IC50: 0.49%; IC90: 1.03%).
Conclusions: These data demonstrate the growth inhibitory effects of EG and identify clinically relevant mechanistic leads for its preventive efficacy. The present approach promises to facilitate identification of new efficacious herbs for the secondary prevention of the Luminal A subtype of clinical breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-09-05.
Abstract P4-11-03: Effect of tamoxifen and raloxifene on proliferative activity of breast epithelium in premenopausal women
Authors: Freitas-Junior R , Lucato MT , Moreira MA , Bernardes-Junior JM , Pinto SA , Paulinelli RR , Soares LR 
Published: August 2014

Abstract
Background: Both Tamoxifen and raloxifene have been demonstrated to be effective to reduce the incidence of breast cancer among women. Objective: To compare the effects of raloxifene (60 mg/day) and tamoxifen (20 mg/day) on the proliferative activity of normal human breast epithelium, during the luteal phase of the menstrual cycle, by means of the immunoexpression of Ki-67/MIB-1. Patients and Methods: Forty-eight women presenting benign breast nodules with an indication for lesion excision took part in this study. These women were randomized to use tamoxifen or raloxifene for 22 days. They underwent surgery after using the medication, and a one-centimeter fragment of normal breast tissue was removed to study the immunoexpression of Ki-67. For this, the frequency of cells immunolabeled for Ki-67/MIB-1 per thousand epithelial cells was quantified. Results: The mean percentage ratios between immunolabeled and non-labeled cells were 2.02 (±1.09) and 3.13 (±3.23) for the tamoxifen and raloxifene groups, respectively. There was no statistically significant difference between the two groups, tamoxifen (n = 16) and raloxifene (n = 14), in relation to the immunoexpression of Ki-67 (p = 0.205). The mean of progesterone level was 19.62 (±17.67) for the tamoxifen group and 14.59 (±8.98) for the raloxefene group (p = 0.32). The plasma levels of estradiol, the values found were: 355.72 (± 337.98) and 171.02 (± 119.83) for groups of tamoxifen e raloxifene groups, respectively (p = 0.055). Conclusion: In this study, we observed that there was no difference in the potential for reducing the proliferative activity of normal breast epithelium between tamoxifen and raloxifene in premenopausal women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-03.
Abstract P4-12-12: Phase 2, multicenter, single-arm study of eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer
Authors: Wilks S , Puhalla S , O'Shaughnessy J , Schwartzberg L , Berrak E , Song J , Rege J , Cox D , Vahdat L 
Published: August 2014

Abstract
Background: Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received ≥2 chemotherapeutic regimens for MBC. We present final data from a phase 2 study that evaluated efficacy and safety of eribulin + trastuzumab as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2 positive (HER2+) BC.
Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and an initial trastuzumab dose of 8 mg/kg IV on day 1, followed by 6 mg/kg on day 1 of each subsequent cycle. Endpoints include objective response rate (ORR), safety, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 6-12 weeks thereafter per RECIST 1.1.
Results: Fifty-two patients with a median age of 60 years (range 31- 81) were treated; 96% had stage IV disease, 73% had visceral disease, and 48% had liver metastases. Thirty one patients had prior neo/adjuvant chemotherapy (11 had prior anthracycline, and 22 had prior taxane). Patients received a median of 10(0, 33) cycles of eribulin and 11(1, 31) cycles of trastuzumab. ORR was 67% with median TTR of 1.3 months and PFS of 11.5 months (Table). The most common (&gt;5%) Grade 3/4 treatment related treatment emergent (TRTE) AEs were neutropenia (n = 20; 38.5%), peripheral neuropathy (n = 14; 26.9%) and febrile neutropenia (n = 4; 7.7%). Serious TRTE AEs occurred in 14 patients and included neutropenia (n = 9; 17.3%), febrile neutropenia (n = 4; 7.7%), and peripheral neuropathy (n = 3; 5.8%). Reasons for discontinuation were AEs (n = 7) and PD (n = 22).
Table. Summary of Efficacy EndpointsEfficacy EndpointsEribulin/Trastuzumab N = 52Objective Response Rate, n (%)35 (67)- Complete Response (CR)2 (4)- Partial Response (PR)33 (64)Stable Disease (SD)15 (29)Progressive Disease (PD)1 (2)Not Evaluable1 (2)Overall Clinical Benefit Rate, n (%)42 (81)Time to First Objective Response, median months (95% CI)1.3 (1.2, 1.4)Duration of Objective Response, median months (95% CI)a11.1 (6.5, 17.8)Progression-Free Survival, median months (95% CI)11.5 (7.3, 13.5)Duration of Stable Disease, median months (95% CI)7.1 (5.2, 13.5)Clinical Benefit Rate = ORR+ ≥6 mo SD; an = 35
Conclusions: This study suggests that the combination of eribulin + trastuzumab first-line therapy for locally recurrent or metastatic HER2+ BC has an acceptable safety profile and results in considerable tumor response with a long DOR. Additional larger studies with this combination are warranted.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-12.
Abstract P4-12-23: Subcutaneous trastuzumab (Herceptin™) in patients with HER-2 positive early breast cancer: A UK time and motion study in comparison with intravenous formulation
Authors: Burcombe R , Chan S , Simcock R , Samanta K , Percival F , Barrett-Lee P 
Published: August 2014

Abstract
Aim:
To quantify active healthcare professional (HCP) time and costs associated with subcutaneous (SC) and intravenous (IV) infusion administration of trastuzumab (Herceptin) in the treatment of patients with HER2-positive early breast cancer within the adjuvant PrefHer trial; secondly, to measure patient time in the care unit and patient chair time for both routes of administration.
Methods:
A UK multi-centre prospective, observational time and motion study was conducted alongside the PrefHer trial (ClinicalTrials.gov id: NCT01401166). Trained observers measured the duration of each SC and IV related task HCPs undertook and recorded patient time in the chemotherapy unit and treatment chair. The type and quantity of medical consumables used with each route of administration were also collected. 24 patient episodes were recorded (12 SC, 12 IV). Mean total administration time was calculated as the mean sum of task times, for both IV and SC formulations. The mean cost of each route of administration was calculated as the mean cost of HCP time plus the mean cost of consumables used. HCP time was costed using data from the Personal Social Services Research Unit. Consumables were costed using hospital pharmacy data and online sources.
Results:
Mean active HCP time for IV preparation and administration was 92.6 minutes compared with 24.6 minutes for SC administration. The mean cost for IV preparation and administration was £144.96 (£132.05 of HCP time and £12.92 of consumables) versus £33.15 (£31.99 of HCP time and £1.17 of consumables) for SC administration. Mean time spent by patients in the care unit and treatment chair was 94.5 minutes and 75 minutes respectively for IV, and 30.3 minutes and 19.8 minutes for SC.
SC administration of trastuzumab could translate to a HCP time saving of 68 minutes (34.5 minutes of preparation time and 33.5 minutes of administration time) (versus IV) with a total cost saving of £111.81 per patient episode. This equates to a potential saving of £2012.58 over a full course of adjuvant trastuzumab treatment (18 cycles).
Conclusion:
Substituting IV infusion with SC administration of trastuzumab may lead to a substantial reduction in active HCP time, consumable use and overall cost. The reduced patient chair and unit time could provide increased capacity within existing resources.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-23.
Abstract P4-16-07: Mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT) are closely related to chemotherapy resistance of triple negative breast cancer
Authors: Deng X , He J , Chang HR 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) is among the most aggressive clinical phenotypes and the presence of residual resistant cancer cells of TNBC after chemotherapy is associated with tumor recurrence and metastasis. In recent years more and more evidence highlight a crucial role of CD44 (+)/CD24 (-/low) (stem/progenitor cell-phenotype) population in cancer drug resistance but the mechanism remains elusive. In the current study, we screened for CD44 and CD24 using Fluorescence-activated cell sorting (FACS) in 8 TNBC cell lines before and after Docetaxel and Doxorubicin treatment. Our data showed that after Docetaxel treatment, several CD44 (+)/CD24 (-/low) cell lines changed their phenotypes to CD44 (+)/CD24 (+) and most of the CD44 (+)/CD24 (+) cell lines kept their double positive phenotypes. In contrast, after Doxorubicin treatment, all the CD44 (+)/CD24 (-/low) cell lines kept their phenotypes and all the CD44 (+)/CD24 (+) cell lines changed their phenotypes to CD44 (+)/CD24 (-/low). Furthermore, among the studied 8 cell lines, CD44 (+)/CD24 (+) cell population is always more resistant to Docetaxel and CD44 (+)/CD24 (-/low) population is always more resistant to Doxorubicin. Our finding of EMT transition from CD44 (+)/CD24 (+) to CD44 (+)/CD24 (-/low) in breast cancer cell lines and its inducible by Doxorubicin is consistent with the literature. However, our results showed for the first time that both EMT and the inverse MET in TNBC could be induced by specific chemotherapy drugs based on the phenotypes of CD44 and CD24. Besides, our gene microarray data also showed that TGFb2, BCL2, KLF6 and TAF4 pathways were dramatically changed in both CD44 (+)/CD24 (+) to CD44 (+)/CD24 (-/low) transition and CD44 (+)/CD24 (-/low) to CD44 (+)/CD24 (+) transition. Further study of these pathways in the transitions may give us new clues to overcome the chemotherapy resistance and lead us to develop successful therapeutic strategies of different types of TNBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-07.
Abstract P4-17-02: Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the datecan project for breast group
Authors: Gourgou-Bourgade S , Dabakuyo-Yonli S , Cameron D , Cardoso F , Poortmans P , Asselain B , Azria D ,   For DATECAN Group
Published: August 2014

Abstract
Background: Surrogate endpoints of overall survival (OS) are increasingly being used in cancer RCTs with the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. The objective of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) initiative is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. Here, we presented results for BREAST cancer.
Methods: We relied on a validated formalized consensus process for the development of practice guidelines using a modified Delphi consensus method. International experts with various backgrounds and expertises were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints, events of interest and the existence of guidelines in metastatic and non metastatic settings. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee.
Results: The consensus process involved 2 rounds of scoring (31 experts) and finally one in-person meeting. Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death from breast cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 150 events had to be scored for the 11 selected endpoints. Consensus was reached for 57% of the events after the 2 rounds of scoring. After the in-person meeting, consensus was reached for all the remaining events but one.
Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect by disseminating the recommendations in major congress. (previously presented to ASCO’13)
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-17-02.
Abstract P5-04-06: Loss of the E3 ubiquitin ligase HACE1 plays a critical role in transformation of mammary cells and clinical progression of human breast cancer via accumulation of active Rac1
Authors: Goka ET , Lippman ME 
Published: August 2014

Abstract
Invasive ductal breast cancer arises when the immediate precursor, ductal carcinoma in situ (DCIS), breaches the basement membrane of the ductal lumen and invades into the surrounding tissue. Although this transition has been implicated as a crucial step in the progression of breast cancer, the specific alterations responsible for this transition have yet to be identified.
HER2/neu, a member of the epidermal growth family receptor (EGFR) family, is frequently overexpressed in non-invasive lesions (50-60%) but is significantly less common in invasive breast cancer (20-30%). This suggests that while HER2/neu may be partially transformative, additional alterations are required for mammary epithelial cells to achieve full malignant transformation.
To identify novel genes capable of cooperating with HER2, we performed an insertional mutagenesis screen for genes whose alteration induces anchorage-independent growth on primary mouse mammary epithelial cells isolated from MMTV-neu transgenic mice. We identified HECT domain and ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) as a putative breast tumor suppressor gene whose loss contributes to the transformative process.
Loss of HACE1 expression is commonly seen in publicly available breast cancer patient data sets as well as in established breast cancer cell lines supporting the role of HACE1 as a breast cancer tumor suppressor gene. Knockdown of HACE1 in HER2 overexpressing human mammary epithelial cells (HMECs) enhanced colony formation over HER2 overexpressing HMEC controls cells. Moreover, knockdown of HACE1 alone was sufficient to allow anchorage-independent growth in soft agar in the HMECs while the overexpression of HACE1 in breast cancer cell lines diminishes clonogenic capacity in soft agar.
We confirmed recent studies that have shown that HACE1 is capable of tagging the Rho GTPase Rac1 for ubiquitin-mediated proteasomal degradation. In mammary epithelial cells, the loss of HACE1 leads to enhanced levels of active Rac1 resulting in increased clonogenicity, migration and invasion. Importantly, we show that targeting Rac1 can rescue the effects of HACE1 loss in mammary epithelial cells. Our results establish HACE1 as a breast cancer tumor suppressor gene by attenuating active Rac1 signaling. Our work supports the role of Rac1 as a critical signaling node in breast cancer and that loss of HACE1 leads to enhanced Rac1 signaling resulting in driving cancer progression. Furthermore, our results suggest the role of HACE1 loss as a biomarker for tumor progression and may identify patients vulnerable to Rac1 or Rac effector targeted therapies.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-06.
Abstract P5-04-18: Identification of a novel combination therapy that prevents the metastatic outgrowth and reduces the viability of dormant breast cancer cells: implications for clinical translation
Authors: El Touny LH , Vieira A , Mendoza A , Khanna C , Hoenerhoff MJ , Green JE 
Published: August 2014

Abstract
Recurrent metastatic disease many years after initial therapy is a major cause of breast cancer (BC) mortality and strongly suggests that disseminated cells survive long periods in a growth-arrested state that is refractory to chemotherapy, known as “cellular dormancy.” Alterations in the components of the extracellular matrix (ECM), such as fibrotic foci and collagen-1 (Col-1) deposition, are associated with more aggressive breast cancer, increased metastasis and poor prognosis for BC patients. This suggests that ECM alterations may have a role in influencing the behavior of dormant BC cells. In fact, we have previously shown both in vitro (using 3-dimensional culture) and in vivo (preclinical model of fibrosis at the lung metastatic site) that alterations in the ECM surrounding disseminated, dormant BC cells can induce signaling pathways requiring Src and ERK1/2 activation that switch dormant cells into a proliferative state. We now demonstrate using the Src inhibitor AD0530 or Src shRNA, that the proliferative outbreak of dormant BC cells in Col-1-enriched microenvironments is prevented through the induction of a reversible G1-phase arrest and the upregulation of nuclear cyclin dependent kinase inhibitor p27Kip1, without affecting the viability of the dormant cells. Src inhibition, however, is not efficacious in regressing already established metastatic lesions, suggesting that Src signaling is crucial to engage the dormant-to-proliferative switch but is not necessary for survival once the cells have begun to proliferate. Since ERK1/2 activation is also required for the dormant-to-proliferative switch, we determined the effect of the MEK1/2 inhibitor AZD6244 that prevents ERK1/2 activation on the proliferative switch alone and in combination with the Src inhibitor. Importantly, we show that combination treatment with AZD0530 and the MEK1/2 inhibitor AZD6244 of dormant cells undergoing the dormant-to-proliferative switch induces apoptotic cell death in a significant fraction of the dormant cells, which is not seen with either inhibitor alone, and significantly delays metastatic outgrowth in the lung metastatic site. In conclusion, inhibition of Src alone prevents the proliferative response of dormant cells to external stimuli without affecting survival, but the addition of a MEK1/2 inhibitor suppresses survival of dormant cells, indicating that this combination may have clinical value in preventing breast cancer recurrence.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-18.