bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4-05-03: Mechanism Underlying Metabolic Heterogeneity in Breast Cancer Subtypes.
Authors: Molina JR , Dennison JB , Zhang F , Mills GB 
Published: June 2012

Abstract
Background: Several distinct subtypes of breast cancer (Luminal, Basal-like and Her-2+) have been identified by gene expression profiling of breast cancers and cell lines. Although much is known about the regulation of cell signaling in each breast cancer subtype, little is known about subtype-specific energy metabolism and its regulation. The majority of cancers, including breast cancer, acquire an accelerated metabolic index as part of the transformation process. One of the most studied metabolic changes in cancer, referred to as the Warburg effect, is the increased uptake of glucose and its conversion to lactate; which is released from the cell, thus creating an astringent tumor microenvironment with high lactate and low pH. Accumulation of lactate in the tumor microenvironment presents cancer cells with a potential rich carbon source that could be exploited when the preferred nutrient sources, glucose and glutamine, are not abundant or available. Thus uptake and conversion of lactate to pyruvate and then entry into the TCA cycle and oxidative phosphorylation could generate energy that could potentially allow cancer cells to survive until other nutrients become available or until the cancer cells can invade and migrate toward nutrient rich environments, in other words, until they spread locally and metastasize.
Methods and Results: Examination of 59 breast cancer cell lines shows differences in expression of numerous proteins and enzymes involved in cellular metabolism, including the lactate transporters (MCT), the enzyme lactate dehydrogenase (LDH), and glucose transporter proteins (GLUT). We found that MCT1 expression is lost in the Luminal subtype and correlates with loss of LDHB and the regulator and chaperone of MCT1, CD147 (Basigin). Conversely, MCT1 is highly expressed in Basal-like and normal cell lines, along with CD147 and LDHB. While monocarboxylate transporter proteins can transport bi-directionally, MCT1 preferentially transports lactate into the cell, while MCT4 transports lactate out of the cell. The loss of MCT1 in luminal cells suggests a distinct energy metabolism in this subtype versus basal-like cells. The basal-like subtype has been further categorized into Basal and Claudin-low subtypes. Claudin-low cells express stem-like markers such as CD44+/CD24-, EMT markers such as vimentin, and are low expressers of the Claudin proteins. We found that MCT1 and CD147 are highly expressed and differentially regulated in Claudin-low cell lines as compared to normal cells. We have evidence that high lactate (10mM) as a sole energy source delays ATP loss and apoptosis in MCT1 expressing cells, but not in luminal cell lines that lack MCT1. Thus, claudin-low tumors may benefit from local lactate production providing an unexpected energy source.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-05-03.
P4-07-17: Isolation of Highly Pure Circulating Tumor Cells (CTCs) from Metastatic Breast Cancer (MBC) Patients for Gene Expression Analysis.
Authors: Magbanua MJ , Hauranieh L , Pendyala P , Sosa E , Scott J , Rugo H , Park J 
Published: June 2012

Abstract
Background: The paucity of information regarding the molecular nature of CTCs can be largely attributed to the difficulty of isolating these rare cells. As such, efforts on RNA profiling of CTCs have been limited to studies using immuno-enriched samples containing a high background of leukocytes.
Methods: We developed a two-step process: immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS) to isolate CTCs away from leukocytes and performed expression analysis on a limited panel of genes. Magnetic beads coated with EpCAM mAb were used to enrich for tumor cells. Enriched samples were then subjected to FACS using fluorescently labeled mAbs to distinguish tumor cells (EpCAM+) from leukocytes (CD45+) during sorting. CTCs and matched leukocytes were isolated from 67 sequential patients with MBC. Total RNA from isolated 20–50 cells was reverse-transcribed into cDNA. Sixty four (64) CTC-related genes from previous published reports were chosen for expression analysis. cDNA of these genes were pre-amplified and analyzed in triplicate via Taqman®-based RT-PCR in a low density array format. Statistical analysis of gene expression data was performed using Realtime Statminer®.
Results: Unsupervised hierarchical clustering analysis showed that CTCs clustered away from the leukocytes. Differential gene expression analysis revealed the up-regulation of several genes including EPCAM, MUC1, and KRT19 in CTCs (adjusted p &lt;0.05). In addition, CTCs showed a significant down-regulation of the leukocyte-specific marker PTPRC (CD45) as well as CD44 and VIM, markers associated with stem cellness and epithelial to mesenchymal transition, respectively.
Discussion: We demonstrate the feasibility of isolation and gene expression analysis of CTCs. Molecular profiling confirmed that isolated CTCs were highly pure with little or no evidence of leukocyte contamination. This approach can serve as a non-invasive source of tumor tissue for further molecular characterization of CTCs and for monitoring of therapeutic efficacy of targeted therapies in clinical trials. This study was supported by CALGB and BCRF.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-17.
P4-08-01: Predictive Value of HER2 Serum Levels in Patients Treated with Lapatinib or Trastuzumab – A Translational Project in the Neoadjuvant “Geparquinto” Trial.
Authors: Witzel ID , Loibl S , von Minckwitz G , Abdallah A , Kühn T , Overkamp F , Fehm T , Schrader I , Uleer C , Kohls A , Stirnberg S , zu Eulenburg C , Untch M , Müller V 
Published: June 2012

Abstract
Background
Neoadjuvant chemotherapy (NT) has become an important approach to assess therapeutic efficacy of new treatment strategies. We observed a predictive role of of serum HER2 (sHER2) with neoadjuvant trastuzumab treatment in the previous trial “Geparquattro”. Predictive markers for response to new HER2−targeted therapies are still lacking. Therefore, we investigated the role of sHER2 in the context of trastuzumab and lapatinib treatment.
Methods: The clinical trial Geparquinto incorporated either trastuzumab or lapatinib treatment combined with chemotherapy for HER2−positive breast cancer patients. Serum samples were taken at three different time points: before initiation of NT, after 4 cycles of chemotherapy with epirubicin and cyclophophamide and after finalization of NT with 4 cycles of docetaxel (pre-surgery). Only those patients were included in the analysis with serum available at all three time points. sHER2 levels were measured by a commercially available ELISA in 159 patients with a HER2−positive primary tumor, 77 (48%) patients were treated with trastuzumab, 82 (52%) with lapatinib. Pathological complete remission (pCR) was defined as no microscopic evidence of invasive residual tumor cells in the breast and lymph nodes.
Results: Overall pCR rate in this cohort was 28%. sHER2 levels were higher in patients with larger tumors (&gt; 5cm, p=0.012) and positive nodal status (p=0.001). Higher pre-chemotherapy sHER2 levels were associated with higher pCR rates in the entire study cohort (OR 2.9, 95% CI 1.3−6.7, p=0.012). Additionally, in the lapatinib treated patient group, a decrease of serum levels of more than 20% after 4 cycles of chemotherapy showed a tendency to be associated with higher pCR rates (OR 7.7, 95% CI 0.8- 70, p=0.071). In contrast to the finding of the previous trial Geparquattro, this was not the case in the trastuzumab-treated patient group (p=n.s.).
Conclusion: Results of this study demonstrate pre-chemotherapy sHER2 levels to be an independent predictor of response to NT with both trastuzumab and lapatinib treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-08-01.
P4-09-16: Factors Affecting the Development of Axillary Lymph Node Metastases in T1a-T1b Breast Cancers.
Authors: Khair TA , Boolbol SK , Boachi-Adjei K , Klein P 
Published: June 2012

Abstract
Background: The presence of axillary nodal metastases is a poor prognostic indicator in patients with breast cancer. In the majority of patients, axillary nodal involvement correlates with tumor size and most commonly in tumors greater that 1 cm. Many series report an incidence of axillary nodal metastases in 3–37% of patients with tumors less than or equal to 2 cm. The presence of axillary nodal metastases will often change the stage of the cancer and role of adjuvant systemic treatment; therefore, it is important to understand what features are associated with these small lymph node positive tumors. The purpose of this study is to identify characteristics of T1a and T1b breast cancers that present with axillary nodal metastasis. Methods: A retrospective review of a prospective database identified 878 patients with T1a and T1b breast cancer. Pathologic features including tumor grade, hormone receptor status, lymphatic and vascular invasion, Her-2 neu status, and tumor histology were examined in patients with and without axillary nodal metastases. Pearson's χ2 test along with stepwise linear regression analysis were used to determine which factors were associated with the development of axillary nodal metastases.
Results: There were 289 T1a lesions and 589 T1b lesions studied. Four independent variables were found to be associated with axillary nodal metastases in T1a-T1b breast cancer. As illustrated in Table 1, a significant difference was seen in nodal positivity among patients with ER negative tumors compared to those with ER positive tumors (p=.0000). An increased incidence of nodal positivity was also observed among patients with LVI compared with those without LVI (p= .0000). A significant difference was observed in nodal positivity among patients with perineural invasion compared to those without (p=.0006). An increased incidence of nodal positivity was also observed among T1a and T1b tumors with a higher histologic grade (p= 0409, p= .0001). Of note, when comparing T1a to T1b breast cancers, there was no significant difference found among the identified exposure variables of interest.

Conclusion: In this series, the overall prevalence of nodal positivity in T1a and T1b breast cancer is 12%. An absence of a relationship between T1a and T1b cancers with nodal positivity was observed. However, the presence of nodal positivity showed a significant correlation with ER negativity, LVI, perineural invasion, and higher histologic grades.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-16.
P4-09-17: Leptin and Adiponectin Expression in Breast Cancer.
Authors: Jeong Y-J , Jeong H-Y , Bong J-G , Park S-H , Choi J-H , Oh H-K 
Published: June 2012

Abstract
Background: Several adipocytokines, such as leptin, resistin, and adiponectin, are associated with obesity and breast cancer. Multiple studies have indicated that adipocytokines may significantly influence the growth and proliferation of tumors. However, the relationship between adipocytokines and breast cancer invasiveness has not been investigated in human tissue. The aims of this study were to determine the expression of leptin, leptin receptor (ObR), adiponectin and adiponectin receptor (AdipoR) in human breast cancer, to evaluate their prognostic significance in the breast cancer.
Material and Methods: Specimens from 198 patients with primary breast cancer were enrolled, and representative paraffin tumor blocks were selected for constructing tissue microarrarys (TMA). Immunohistochemical staining for leptin, ObR, adiponectin, and AdipoR was performed using TMA, and the clinicopathologic characteristics were evaluated from the patient's medical records. Results: Stage 0 breast cancer accounted for 41 cases, and 157 cases were invasive cancer. A univariate analysis showed that positive rates of leptin and ObR expression in the ductal carcinoma in situ (DCIS) group were significantly higher than those of the invasive cancer group (97.4% vs. 34.0%, p&lt;0.001; 74.4% vs. 29.8%, p&lt;0.001). However, positive rates of adiponectin and AdipoR expression in the invasive cancer group were significantly higher than those in the DCIS group (53.7% vs. 33.3%, p=0.024; 59.9% vs. 26.3%, p&lt;0.001). High leptin expression was significantly associated with high Ki-67 expression (p=0.016). High adiponectin expression was significantly correlated with smaller tumor size (p=0.001). The disease-free survival (DFS) and overall survival (OS) rate at 5 years were 89.3% and 96.7%, respectively. No difference in DFS and OS was observed based on leptin, ObR, adiponectin, AdipoR expression.
Discussion: Previous studies, using serum of breast cancer patients or breast cancer cell line, revealed that leptin and ObR may affect processes related to cancer initiation and progression, and adiponectin has protective effect on tumor progression. However, the precise effects of leptin, ObR, adiponectin and AdipoR in breast cancer are still unclear. Our results suggest that losses of leptin and ObR expression could be associated with invasive cancer, whereas high adiponectin and AdipoR expression may be associated with breast cancer invasiveness.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-17.
P4-09-21: A Novel Prognostic Marker for Triple-Negative Breast Cancers.
Authors: Wallon UM , Sabol JL , Zemba-Palko V , Carp NZ , Ciocca RM , Wojciechowski BS , Prendergast GC 
Published: June 2012

Abstract
BACKGROUND: Triple-negative breast cancers (TNBC) represent a highly aggressive form of this disease with few treatment options available. Currently, even the smallest node negative cancers are considered by many to warrant treatment with chemotherapy (CTX). While many recur early (within 2–3 years), there is a subset of long-term survivors illustrating the heterogeneity within this group. Here we report our ongoing effort to establish tissue inhibitor of metalloproteinase-4 (TIMP-4) as a prognostic marker in all early breast cancers a. While the canonical function of TIMPs is to inhibit tissue degradation, numerous reports have established that TIMPs exert tumor promoting activity. In our prospective study, we evaluated TIMP-4 as prognostic marker for TNBC and its role in disease progression.
METHODS: Specimens from our retrospective and prospective cohorts were assessed by immunohistochemical staining using standard techniques and a monoclonal antibody for TIMP-4b in accordance with the IRB approved protocol. Staining intensity was documented on a scale of 0–3. No data was released to the treating physicians at the time of collection. Outcome data from a total of 240 pts was obtained through tumor registry and clinician practices. Staining intensity was then correlated with outcome to calculate sensitivity and specificity of the marker. To determine the role of TIMP-4 in TNBC cell behavior we have performed microarray analyses. The effects of TIMP-4-induced signaling were tested using invasion and clonogenic survival assays under normal growth conditions and after exposure to gamma radiation.
RESULTS: Elevated TIMP-4 expression identified a high risk of relapse and short survival time with 75% sensitivity and 80% specificity. No discernable differences were noted between retrospective and prospective cohorts. Array analyses revealed activation of the PI3K/AKT pathway in the presence of TIMP-4. Furthermore, elevated TIMP-4 increased the invasive behavior of breast cancer cells in Matrigel™-coated invasion chambers and reduced sensitivity to gamma irradiation. These effects were reversible by addition of either a PI3K inhibitor or an anti-TIMP-4 antibody, suggesting their use as potential therapeutic strategies.
CONCLUSIONS: On the basis of these clinical data we suggest that TIMP-4 may offer a simple prognostic marker for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly despite standard CTX treatment. Our research suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be explored. Therefore, TIMP-4 testing of TNBC patients could aid in the selection of a treatment regimen to improve survival outcome.
a Liss, M et.al. Am. J. Pathol. 2009
b Donover, P et.al. J. Cell. Biochem. 2010
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-21.
P4-10-11: Genetic and Environmental Predictors, Endogenous Hormones and Growth Factors and Risk of Estrogen Receptor-Positive Breast Cancer in Japanese Women.
Authors: Yoshimoto N , Nishiyama T , Toyama T , Takahashi S , Shiraki N , Sugiura H , Endo Y , Iwasa M , Fujii Y , Yamashita H 
Published: June 2012

Abstract
The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We have recently demonstrated that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype. It is necessary to establish risk factors capable of predicting the risk of ER-positive breast cancer which will enable the efficient selection of candidates for preventive chemotherapy. We analyzed genetic factors, including 14 single nucleotide polymorphisms (SNPs), environmental risk factors (body-mass index (BMI), age at menarche, pregnancy, age at first birth, breastfeeding, family history of breast cancer, age at menopause, use of hormone replacement therapy, alcohol intake and smoking), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3)) and mammographic density in 913 women with breast cancer and 278 disease-free controls. To identify important risk factors, risk prediction models for ER-positive breast cancer in both pre- and postmenopausal women were created by logistic regression analysis. In premenopausal women, 1 SNP (CYP19A1-rs10046), age, pregnancy, breastfeeding, alcohol intake, serum levels of prolactin, testosterone and IGFBP3 were considered to be risk predictors. In postmenopausal women, 1 SNP (TP53-rs1042522), age, BMI, age at menopause, serum levels of testosterone and IGF1 were identified as risk predictors. Risk factors may differ between women of different menopausal status, and inclusion of common genetic variants and serum hormone measurements as well as environmental factors might improve risk assessment models. Further validation studies will clarify appropriate risk groups for preventive chemotherapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-11.
P4-13-03: Retrospective Analysis of Palonosetron Compared with Older 5-HT3 Receptor Antagonists (Ondansetron, Dolasetron, and Granisetron) in Preventing Anthracycline-Induced Nausea and Vomiting in Breast Cancer Patients from Four Phase 3 Trials.
Authors: Rugo HS , Schwartzberg L , Morrow GR , Barbour SY , Ballinari G , Thorn MD , Cox D 
Published: June 2012

Abstract
In patients with breast cancer, the risk of developing chemotherapy-induced nausea and vomiting (CINV) is particularly high due to the common use of highly emetogenic chemotherapy coupled with pt-related risk factors including female gender and young age. Despite prophylactic antiemetics, controlling CINV is difficult in this high risk population, particularly in the delayed phase following CT. Palonosetron, a potent 5-HT3 receptor antagonist (RA) with a distinctly different pharmacokinetic and receptor binding profile, has demonstrated improved CINV protection compared to older 5-HT3 RAs in phase 3 and 4 clinical trials in a variety of settings and tumor types.
We conducted a retrospective subset analysis of pts with breast cancer, the majority of whom (89%) received anthracycline combination chemotherapy (doxorubicin or epirubicin and cyclophosphamide, AC/EC) from four phase 3, randomized, double-blind, parallel group studies to assess the comparative effectiveness and safety of single IV doses of palonosetron (0.25 or 0.75 mg) versus older 5HT3-RAs (ondansetron 32 mg, dolasetron 100 mg, and granisetron 3 mg) in preventing CINV in pts receiving this highly emetogenic chemotherapy. The primary efficacy evaluation was for complete response (CR), defined as the proportion of patients with no emetic episodes & no use of rescue medication during 0–24hrs (acute), &gt;24-120hrs (delayed), & 0–120hrs (overall) using a logistic regression model. A comparative descriptive safety assessment was also performed.
A total of 1197 patients with breast cancer were included in this analysis (palonosetron n=714; older 5HT3-RAs n=483). Higher CR rates were seen for palonosetron vs. older 5HT3-RAs during the acute (63.4% vs 59.4%, p= 0.08), delayed (59.2% vs. 44.9%, p&lt;0.0001) and overall (50.7% vs.38.5%, p&lt;0.0001) phases. Rates for CR were similarly higher for palonosetron-treated patients in the large subgroup of patients receiving AC/EC based chemotherapy. Consistent improvements associated with palonosetron were seen for secondary endpoints of complete control (CR + no more than mild nausea), no emesis, and severity of nausea. The adverse event (AE) profile for palonosetron was similar to older 5HT3-RAs, with headache and constipation being the most commonly reported treatment-related AEs with similar incidences for all 5-HT3 RAs.
This retrospective analysis of patients with breast cancer, including a large subgroup receiving anthracycline-based highly emetogenic chemotherapy, demonstrated significantly improved CINV prevention with palonosetron compared to older 5HT3-RAs, particularly in the delayed phase. Safety was comparable. This data has important implications for current CINV prevention guidelines.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-13-03.