bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-01-26: Procoagulant biomarkers may direct axillary nodal surgery
Authors: Shaker H , Bundred NJ , Glassey E , Kirwan CC 
Published: August 2014

Abstract
Background: Preoperative accurate staging of the axilla (through identifying invasive breast cancers with subclinical nodal metastases) will reduce the need for repeat axillary surgery.
Tissue factor (TF) is overexpressed in cancer and is shed into the circulation leading to activation of the thrombin (extrinsic clotting) pathway. D-dimer is a fibrin degradation product and reliable systemic marker of thrombin pathway activation. TF and d-dimer are raised in breast cancer and may act as biomarkers to identify invasive cancer patients with undiagnosed lymph node (LN) metastases requiring axillary nodal clearance.
Methods: Plasma d-dimer and TF were measured pre-operatively using ELISA in patients undergoing curative surgery and sentinel node biopsy (SNB) for invasive breast cancer (n = 125). D-dimer was considered to be raised if it was above the clinically used upper limit of normal of 500ng/ml and if TF was above 200pg/ml. D-dimer and TF were correlated with the presence or absence of axillary metastases at sentinel node biopsy.
Results: Median age was 61 years (range 24–84). Mean invasive tumour size was 16.7 mm (range 1.6–70). One hundred and eleven (79%) invasive cancers were oestrogen receptor positive, 93 (67%) were progesterone receptor positive and 17(12%) were HER2 receptor positive.
Pre-operative d-dimer was higher in LN positive (mean 599 ng/ml, 95% CI 415–864, n=32) versus LN negative (454ng/ml, 95% CI 400–514, n=93, p = 0.068) invasive cancer. TF was not significantly higher in LN positive cancer (vs LN negative), although TF did show weak correlation with d-dimer (r = 0.2, p = 0.03).
Sixty eight patients (54%) had raised TF and 59 (47%) had raised d-dimer. On multivariate analysis (age, tumour size, invasive grade, ER status and presence of lymphovascular invasion as covariates) a raised pre-operative d-dimer combined with a raised pre-operative TF was a significant independent predictor of node positivity (odds ratio 6.43, CI 1.70–24.27, p = 0.006). Markers of systemic thrombin pathway activity (i.e. a combination of plasma d-dimer and TF) had a sensitivity of 91%, specificity of 32%, positive predictive value of 32% and negative predictive value of 92%.

Conclusion: High levels of clotting activation are seen in breast cancer patients.
Over 90% of patients with no axillary lymph node metastases had normal pre-operative levels of plasma TF and d-dimer. Combination of systemic markers of thrombin pathway activation may help predict axillary nodal involvement.
The role of thrombin pathway activation in breast cancer metastasis is under ongoing investigation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-26.
Abstract P1-04-01: Loss of Notch4 reduces mammary tumorigenesis by MYC and activated KRAS
Authors: Rodriguez EM , Bishop JM 
Published: August 2014

Abstract
Over-expression of Notch receptors and aberrant Notch signaling have been reported in both preinvasive ductal carcinoma in situ and invasive breast cancer. The Notch 4 receptor, in particular, is preferentially activated in human breast cancer stem cell-enriched populations, and inhibition of Notch 4 reduces tumor formation of human breast cancer cells in xenograft models (Harrison, 2010). Myc gene amplification has also been found in about 15% of breast tumors, and 22%–35% of tumors exhibit overexpression of Myc at the transcriptional level. Transgenic mice over-expressing MYC develop invasive adenocarcinomas and preferentially harbor secondary activating mutations in KRas. We examined whether Notch receptors were activated in mouse mammary tumors over-expressing MYC and activated KRAS (KRASV12) and found Notch 4 to be significantly activated in these tumors compared to normal mammary tissue. Furthermore, Notch 4 was localized to the nucleus in the tumors over-expressing MYC and KRASV12, but not in mammary glands over-expressing MYC or activated KRASV12 alone. To examine the requirement of Notch4 in mammary tumorigenesis by MYC and KRASV12, we transplanted mammary epithelial cells isolated from Notch4 knockout mice and wild-type mice that have been transduced with MYC and KRASV12 into the mammary glands of syngeneic mice. There was a significant reduction in the onset of tumorigenesis in mammary glands that had been transplanted with mammary epithelial cells lacking Notch4. These findings suggest that Notch4 is important in mammary tumorigenesis induced by cooperation of MYC and activated RAS. We are currently examining the relevance of Nocth4 activation in human breast cancers that over-express MYC and the mechanism by which Notch4 promotes tumorigenesis by Myc and activated RAS.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-01.
Abstract P1-04-08: Evidence for anti-apoptosis function of GNB1 in human breast cancer
Authors: Wazir U , Kasem A , Sharma AK , Jiang W , Mokbel K 
Published: August 2014

Abstract
INTRODUCTION: Guanine nucleotide binding protein beta polypeptide 1 (GNB1) integrates signals between receptors and effector proteins and regulates certain signal transduction receptors and effectors. We have hypothesised that GNB1 is involved in the anti-apoptosis pathway mediated by mTor. Therefore, this protein may play role in human carcinogenesis, however, there has been no investigations of this potential role published in the literature. The aim of the study was to investigate the mRNA expression of GNB1 in human breast cancer and examine the relationship between its expression and the tumour characteristics and disease outcome. Furthermore, the correlation between GNB1 and mTORC1 was also investigated.
METHODS: Specimens of breast cancer (BC) tissues (N = 136) and normal tissues (N = 30) underwent RNA extraction and reverse transcription. GNB1 transcript levels were determined using real-time quantitative PCR. Expression levels were analysed against clinicopathological data accrued over a 10 year follow-up period.
RESULTS: Significantly higher mRNA transcript levels were found in the breast cancer specimens compared to normal glandular tissue in paired samples (p = 0.0029). The expression of GNB1 mRNA was demonstrated to increase with increasing TNM stage (from 0.01 to 15.9) and this reached statistical significance when comparing TNM1 vs. TNM2/3/4 (p = 0.036). Furthermore, the expression levels increased with increasing tumour grade and this reached statistical significance when comparing grade 2 vs. grade 3 (p = 0.006). GNB1 expression was found to be higher in ductal tumours compared with non-ductal tumours (p = 0.0081). The patients who developed recurrent disease or died from breast cancer had higher expression levels than those who had been disease-free after a median follow-up period of 10 years (p = 0.017). Those who died from breast cancer had significantly higher levels than those who have remained disease-free (33.9 vs. 0.01, p = 0.0009). GNB1 showed a significantly positive correlation with mTORC1 mRNA levels (r = 0.57, p &lt; 0.000001).
CONCLUSION: GNB1 expression was found to be significantly higher in BC specimens compared to normal breast tissue. Higher transcript levels were significantly associated with unfavourable pathological parameters and adverse clinical outcomes. These observations in addition to the positive correlation with mTORC1 levels support the hypothesis that GNB1 is an important upstream component of the anti-apoptosis pathway and, therefore, can be a potential target for therapeutic intervention in human breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-08.
Abstract P1-05-03: A requirement for neural precursor cell-expressed developmentally downregulated gene 9 during the initiation of mammary tumorigenesis in MMTV-neu mice
Authors: Serzhanova VA , Little JL , Izumchenko E , Seo S , Kurokawa M , Egleston B , Klein-Szanto AA , Golemis EA 
Published: August 2014

Abstract
The Neural precursor cell-Expressed Developmentally Downregulated gene 9 (NEDD9; also HEF1, CAS-L) scaffolding protein regulates many signaling pathways associated with mitosis, survival, migration, and ciliary integrity. Within the last few years, elevated NEDD9 expression has been implicated in progression and metastasis of several types of cancer, including those of the lung, skin, and brain. We have investigated the consequences of introducing a Nedd9 genotype into the MMTV-neu mouse mammary tumor model, which in many respects recapitulates features of human HER2+ breast cancer. 80% of wild-type MMTV-Neu; Nedd9+/+ animals developed tumors with an average latency of 339 days, but only 18% of MMTV-Neu;Nedd9−/− animals developed tumors with an average latency of 416 days. This highly significant difference indicates that the Nedd9−/− genotype significantly prevents neu-dependent mammary tumor formation.
HER2-positive human breast tumors and MMTV-neu-induced tumors originate from mammary luminal epithelial progenitor cells. We evaluated mammary progenitor cell populations from non-tumor bearing MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ 4-month old mice (2 months prior to appearance of tumors). Flow cytometry analysis indicated a significantly reduced CD24high;CD49flow luminal progenitor subpopulation in MMTV-neu;Nedd9−/− and Nedd9−/− mammary glands, that could be contributed to the tumorigenesis resistance in the MMTV-neu;Nedd9−/− model. The MMTV-neu;Nedd9−/−genotype negatively affected the Matrigel mammosphere colony-forming potential of luminal progenitor cells compared to MMTV-neu; Nedd9+/+cells, causing formation of fewer colonies with aberrant size and morphology. Quantification of mitotic division planes of MMTV-neu;Nedd9−/− mammospheres revealed no contribution to the observed defects. However, MMTV-neu;Nedd9−/− mammospheres had defective expression of signaling proteins governing cell attachment, with reduced levels of FAK and more cytoplasmic localization of SRC.
The results reported above, together with other data, support three main conclusions. First, they revealed a very substantial requirement for Nedd9 during early stages of HER2/neu-dependent tumor formation. Second, these results are the first to demonstrate a role for Nedd9 in supporting the abundance and colony-forming potential of mammary luminal progenitor cells. Third, they indicate that the defects in mammosphere growth likely involve perturbation of crucial cellular attachment signaling pathways involving FAK and SRC. In sum, these data provide a strong justification for future analysis of NEDD9 in the defective signaling of transformed mammary epithelial progenitor cell populations that initiate human breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-03.
Abstract P1-05-20: Fluorescent Hyaluronan Probes Distinguish Heterogeneous Breast Cancer Cell Subsets and Predict their Invasive Behavior
Authors: Veiseh M , Kwon DH , Borowsky AD , Toelg C , Leong H , Lewis J , Turley EA , Bissell MJ 
Published: August 2014

Abstract
Background: Tumor heterogeneity is a determining factor in diagnosis and therapy of breast cancer (Bca). We investigated Bca cellular heterogeneity by a functional fluorescent hyaluronan (HA) probe, and monitored its binding characteristics in relation to the degree of Bca aggression. HA is a polysaccharide ligand for CD44 and RHAMM receptors, which are linked to cell plasticity and predict poor clinical outcome in Bca.
Methods: Fluorescent HA probes, multiplexed profiling, and cell sorting strategies were developed and used to detect/capture tumor cell subpopulations with differences in HA binding (HA−/low vs. HAhigh) and HA receptors surface display. Whereas we concentrated on the most metastatic cell line, MDA-MB-231, we also monitored the presence of subpopulations in other Bca lines and showed heterogeneity in all.
Results: The HA probe binding was highly heterogeneous, and the highest binding level was detected in highly invasive triple-negative basal subtypes such as MDA-MB-231. HA probes bound to the cell surface but also accumulated in cytoplasm and nucleus. Binding levels were dramatically reduced upon ‘reversion’ of highly malignant cells to a non-malignant phenotype in three-dimensional cultures, suggesting that the level of cellular binding to fluorescent HA probe provides a measure of malignant behavior. Comparison between HAhigh and HA−/low subpopulations revealed surprising differences in morphology, proliferation and invasion in culture, which were retained in two in vivo models. HAhigh subpopulations exhibited higher levels of invasion but surprisingly lower levels of proliferation compared to either unsorted parental cells or the HA−/low subpopulation.
Conclusions: Querying HA binding in Bca lines reveals an unexpected heterogeneity with respect to tumor phenotype in vivo, morphology in 3D, invasion and proliferation. These results may aid in diagnosis and therapy of invasive Bca subpopulations and early sorting of cancer patients needing intensive chemotherapy.
Keywords: Heterogeneity, 3D cultures, Hyaluronan, CD44, RHAMM/HMMR, Tumor phenotype, Breast cancer, Invasion.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-20.
Abstract P1-09-03: Chemoprevention in patients with newly diagnosed breast cancers
Authors: Refinetti AP , Chun J , Schnabel F , Guth A , Axelrod D 
Published: August 2014

Abstract
Background: Chemoprevention (including tamoxifen, raloxifene, and exemestane) is a strategy to reduce breast cancer incidence in high risk women. Studies have shown at least a 50% decrease in the incidence of breast cancer in users of these drugs. Despite this benefit, the majority of high risk, unaffected women who are offered chemoprevention decline the therapy. However, there is a growing population of women who have used these agents for primary prevention, and a larger population of survivors who have used these drugs as part of their systemic treatment. The purpose of this study was to identify a cohort of women with newly diagnosed breast cancers who had utilized chemoprevention and describe their patterns of disease.
Methods: The Breast Cancer Database of NYU Langone Medical Center was queried for patients who used chemopreventive drugs and developed breast cancer between 1/2010-1/2012. Patients were divided into primary and secondary chemoprevention groups (no previous history of breast cancer and previous history of breast cancer, respectively). Descriptive statistics were utilized.
Results: In the study period, 24 (2%) of 996 patients had used a chemopreventive agent. For 16 of the 24 (67%), the drug was part of systemic therapy for prior breast cancer, with a median of 12 years from the initial diagnosis to the diagnosis of a second breast cancer. The primary chemoprevention group included women with risk based on family history and atypical hyperplasias. The majority of patients were diagnosed with early stage disease (88% DCIS and stage I). This likely reflects their screening behaviors. In both groups, the majority of cancers were ductal in origin. Five of the 8 patients in the primary chemoprevention group were on treatment at the time of their cancer diagnosis, while 63% of patients in the secondary group were prior users. In the secondary group, the majority of cases were contralateral second primary breast cancers, with 31% ipsilateral recurrences. Interestingly, the majority of cancers in both groups were ER/PR positive.

Conclusions: Our cohort of women who used chemoprevention drugs were overwhelmingly diagnosed with early stage breast cancer, likely reflecting their commitment to screening. The majority of cancers were ER/PR positive. In this group, the choice of cancer treatment will need to be modified in light of prior hormonal treatment. Many of the patients in the secondary group were past users of prevention agents and further work is needed to clarify the duration of benefit of these drugs. In a similar vein, we look forward to research efforts to define the optimal age to initiate primary chemoprevention in high risk women.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-03.
Abstract P1-09-06: Biological Effects of Green Tea Capsule Supplementation in Pre-surgery Breast Cancer Patients
Authors: Yu S , Spicer D , Hawes D , Wu A 
Published: August 2014

Abstract
Green tea is rich in antioxidant polyphenols consisting primarily of epicatechins, epigallocatechin, epicatechin gallate, and epigallocatechin gallate (EGCG). There are suggestive evidence from observational epidemiologic studies that regular green tea consumers may have lower risk of breast cancer development and mortality. Inhibition of cell proliferation and angiogenesis and enhancement of apoptosis are some of the mechanisms that have been proposed to explain the anti-cancer actions of the bioactive extracts of green tea. We conducted a randomized pre-surgical pilot study of green tea capsules in women diagnosed with breast cancer at the Los Angeles County-University Southern California Medical Center. Women in both the green tea and control arms were non-green tea drinkers at baseline (i.e. less than 1 cup of green tea per week at the time of breast cancer diagnosis). Women (n = 17) who participated in the green tea arm took 3 green tea capsules daily (Pro Health Green Tea Mega EGCG, 3 capsules contained ∼ 870 mg EGCG; equivalent to ∼ 8 cups of green tea) between their breast cancer diagnosis until their scheduled surgery date. The average duration of green tea intake was 35 days. Women in the control arm did not drink green tea between diagnosis and surgery date. Participants in the green tea and control groups donated blood and urine specimens at enrollment and before surgery which were tested for urinary tea catechin levels as a measure of compliance. Baseline urinary tea catechin concentrations were low in both green tea and control arms. Tea catechin concentrations remained low for women in the control arm but increased significantly (2–10 folds for different catechins) for women in the green tea arm. The differences in pre-surgery urinary green tea levels were significantly different between these groups of participants We conducted standard immunohistochemical analysis of the formalin-fixed paraffin-embedded respective markers of cell proliferation (Ki67), apoptosis (BAX), and angiogenesis (CD34). Separate analysis was performed on benign and malignant breast cancer tissue. The changes in these three biomarkers pre- and post-treatment in the two groups will be presented.
Supported by the WHH Foundation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-06.
Abstract P1-12-02: Results of a phase 2, multicenter, single-arm study of eribulin mesylate as first-line therapy for locally recurrent or metastatic HER2-negative breast cancer
Authors: Vahdat L , Schwartzberg L , Glück S , Rege J , Liao J , Cox D , O'Shaughnessy J 
Published: August 2014

Abstract
Background: Eribulin mesylate is a novel nontaxane microtubule dynamics inhibitor that is approved in patients (pts) with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for MBC. We are reporting a preliminary planned analysis (first 6 cycles of treatment) of a phase 2 study that evaluates efficacy and safety of eribulin as first-line therapy for HER2-negative MBC.
Methods: Pts with measureable HER2-negative locally recurrent or MBC with at least 12 months since prior neoadjuvant or adjuvant chemotherapy received eribulin mesylate at 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints include objective response rate (ORR) (primary), safety, progression free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments were evaluated every 6 weeks for the first 6 cycles and every 6–12 weeks thereafter per RECIST 1.1.
Results: 54 of 56 enrolled pts had at least 1 post-baseline assessment. The median number of cycles delivered was 7 (range 1,21). Pt characteristics: median age, 56 yrs (range 31–85); ECOG of 0, 32 (57%); 29% had de novo stage IV; 38/56 (68%) had prior neo/adjuvant (45% had anthracycline and 45% taxane, the majority of which were given together). Seventy percent have visceral disease (45% liver, 38% lung); 41 (73%) have estrogen receptor-positive (ER) disease and 12 (21%) have triple negative (TN) (ER−/PR−/HER2−) disease. Objective response data are found in Table 1.

The most common treatment-related AEs are reported in Table 2.

Treatment-related serious AEs occurred in 5 (9%) pts, neutropenia (4%), and febrile neutropenia (5%). Five pts stopped study therapy due to adverse events. Fourteen pts remain on study treatment.
Conclusions: The preliminary results of this first-line study suggest that eribulin has antitumor activity in ER+/HER2− and TN MBC with an acceptable safety profile. Further exploration of this treatment as part of neo/adjuvant therapy is warranted.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-02.
Abstract P1-13-02: Analysis of the NNBC 3-Europe trial: Addition of docetaxel to anthracycline containing adjuvant chemotherapy in high risk node-negative breast cancer patients.
Authors: Thomssen Christoph , Kantelhardt Eva-Johanna , Meisner Christoph , Vetter Martina , Schmidt Marcus , Martin Pierre-Marie , Veyret Corinne , Augustin Doris , Hanf Volker , Paepke Daniela , Sweep Fred CGJ , Schmitt Manfred , von Minchwitz Gunter , Jaenicke Fritz , Harbeck Nadia 
Published: August 2014

Abstract
Withdrawn by Author
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-02.