bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-20-13: Preliminary report of a phase I/II study of entinostat (IND#NSC 706995, /M275) and lapatinib (IND#NSC 727989) in patients with HER2-positive metastatic breast cancer in whom trastuzumab has failed
Authors: Ueno NT , Jackson SA , Alvarez RH , Willey JS , Hortobagyi GN , Angulo-Gonzalez AM , Giordano SH , Booser DJ , Valero V 
Published: August 2014

Abstract
Background: Entinostat is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has shown that Entinostat can enhance the activity of Lapatinib in HER2+ metastatic inflammatory and non-inflammatory breast cancer. The primary objective of the phase I portion of this study is to determine the recommended phase II dose for Entinostat in combination with Lapatinib in patients who have received Trastuzumab for HER2+ metastatic breast cancer.
Methods: This is a single center, open-label study to evaluate the safety and tolerability of every other week entinostat in combination with a 28-day cycle of Lapatinib. Patients with metastatic breast cancer in whom trastuzumab has failed were included. The phase I portion of the study is a conventional 3+3 dose-escalation design. Dose levels include 0 (starting dose) Entinostat 10 mg orally every other week, I Entinostat 12 mg, and II Entinostat 15 mg. Lapatinib 1,250 mg orally is given every day without dose escalation. Toxicities are evaluated at the end of each cycle.
Results: Here we report the phase I portion of the study. To date, 9 patients were enrolled, 3 were in level 0, and 6 were in level I. In Level 0, 2 patients were taken off study due to disease progression (PD) at the end of cycle one and 1 patient was taken off study due to PD at the end of cycle two. In Level I, 1 patient was taken off study due to PD at the end of cycle one and 2 patients were taken off study due to PD at the end of cycle 2. 1 patient had stable disease. The median age is 41 (range, 26–69). Seven of the nine patients are evaluable for toxicity. Most common toxicities reported by the patients are nausea grade 3 (1), fatigue grade 3 (1), muscle aches/pain grade 2 (3), skin rash grade 3 (1), paresthesias grade 2 (2), heartburn grade 1 (4), and diarrhea Grade 2 (1). Lapatinib dose was reduced in 2 patients. The most common hematological toxicities were neutropenia grade 1 (3), anemia grade 2 (1), and thrombocytopenia grade 4 (1).
Conclusions: Overall, patients have tolerated the combination regimen relatively well. We have not reached the maximum tolerated dose, so patient enrollment will continue until the phase I portion of the study is complete, most likely in July 2012. We plan to proceed with phase II portion in two parallel cohorts (HER2+ inflammatory and non-inflammatory metastatic breast cancer).
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-13.
Abstract P6-04-10: Comprehensive gene and protein assessment of the role of Her2 in the response to neoadjuvant Letrozole suggests patients without amplification may also benefit from anti-Her2 treatment
Authors: Webber V , Turnbull AK , Larionov AA , Sims AH , Harrison D , Renshaw L , Dixon JM 
Published: August 2014

Abstract
Background: Older postmenopausal patients with large operable or locally advanced oestrogen receptor positive, invasive breast cancers are candidates for treatment with neoadjuvant letrozole. HER2 positivity is a potential marker for early endocrine therapy resistance. In this study we have evaluated the effects of HER2 amplification, gene and protein expression at diagnosis and following 14 and 90 days of treatment with neoadjuvant Letrozole.
Methods: 70 postmenopausal women with large operable and locally advanced oestrogen receptor (ER) positive invasive breast cancers were treated with neoadjuvant letrozole. Response was assessed by 3D ultrasound. Sequential core biopsies were taken at 0, 14 days and 3 months of treatment. 12 patients were HER2 positive (either 3+ or 2+ FISH positive), 20 were HER2 2+ FISH negative and 38 were HER2 negative (0 or +).
Results: 43 patients were responders to letrozole and 17 were non-responders. 7 of the 17 non-responders were HER2 positive. Analysing response in two groups (HER2 2+ and 3+ together versus 0 or +) there was a greater difference in response rate between these two groups than when splitting into conventional HER2 positive and negative groups (P &lt; 0.0001). In non-responding patients HER2 gene expression levels from the microarrays taken at baseline were significantly higher than the HER2 expression in responding patients (p = 0.01). There was also an increase in HER2 gene expression seen during the first 14 days of treatment in non-responding but not responding patients (p = 0.08). Rank product analysis of gene expression identified 34 down-regulated genes and 7 up-regulated genes which were shared between the HER2 2+ FISH negative samples and samples which were HER2 3+ or HER2 2+ FISH positive.
Conclusion: This large cohort of patients treated with neoadjuvant letrozole shows that:
HER2 expression correlates with response to letrozole.
A better cut off for prediction of response to letrozole is the split between 0 and + versus 2+ and 3+ rather than the traditional 3+.
Patients with increased MRNA expression at diagnosis for HER2 have a significantly lower response rate to neoadjuvant letrozole.
Endocrine therapy together with anti-HER2 therapies should be considered for patients having neoadjuvant endocrine therapy for cancers which over express HER2.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-10.
Abstract P6-04-25: Genomic Deregulation and Therapeutic Role of Nemo-like Kinase in Luminal B Breast Cancer
Authors: Cao X , Qin L , Kim J-A , Tan Y , Wang X , Schiff R 
Published: August 2014

Abstract
Luminal B breast tumors are notoriously known as high grade breast cancer prone to Tamoxifen resistance and early recurrence. Chromosomal abnormalities are a crucial class of drug targets in cancer which can be classified into numerical and structural rearrangements. Gene amplification is the result of numerical rearrangement that generates multiple copies of an otherwise normal human gene, such as Her2 amplification observed in breast cancer. Gene fusion is the result of structural rearrangement that fuses together pieces of two different genes, such as BCR-ABL gene fusion identified in leukemia.
Due to their critical role in causing human cancers and their presence exclusively in the tumor tissues, gene amplifications and fusions provide highly specific drug targets with only minimal side effects. In order to identify these chromosome aberrations that can serve as new therapeutic targets in breast cancer, we developed a novel bioinformatics analysis called “copy number signature analysis”. This is based on the observation that driving gene fusions and their original (wild-type) genes are often amplified in fusion-positive tumors, or tumors without the fusions respectively. This suggests that gene fusions and amplifications may synergize to activate important oncogenes; if directly druggable, these aberrations will provide substantial opportunities for new therapies.
Applying this analysis to the newly emerged genomic data from the Cancer Genome Atlas (TCGA) project nominated Nemo-like kinase (NLK) as a lead therapeutic target for invasive breast cancer. NLK encodes a serine-threonine mitogen activated protein kinase that plays a pivotal role in transforming growth factor beta pathway and embryo development. Genomic amplifications and rearrangements at NLK locus happen in 7%–9% of breast tumors, which may lead to deregulated serine-threonine kinase activity. Of note, these aberrations preferentially present in luminal B or Her2 positive breast tumors, suggesting their association with these high grade tumors. Most interestingly, transient inhibition of NLK through small RNA interference in multiple breast cancer cell lines harboring NLK deregulations, we observed potent inhibition of cell growth and capability of forming tumor-like colonies, as well as increased sensitivity to Tamoxifen treatment.
These data suggest that NLK might be deregulated by genetic events which may promote growth-factor signaling and Tamoxifen resistant phenotype. Molecular assays detecting NLK chromosomal aberrations may serve as a predictive biomarker for endocrine resistance in breast cancer as well as selection of patients for appropriate treatment.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-25.
Abstract P6-04-28: Changes in BAG-1 expression level affect the Tamoxifen-induced apoptosis and Gegitinb-induced apoptosis in breast cancer cells
Authors: Lu S , Zhuang X , Liu H 
Published: August 2014

Abstract
BAG-1 (bcl-2-associated athanogene-1) is a multifunctional protein which can interact with a number of molecules to regulate diverse biological processes including apoptosis, proliferation, signal transduction and transcription. BAG-1 protects cells from a wide range of apoptotic stimuli including radiation, hypoxia and chemotherapeutic agents and growth factor withdrawal. Therefore, BAG-1 may contribute to reduced cell death in cancer development, as well as to resistance to important therapeutic agents. Our study showed that the TAM sensitive cell line MCF-7 expressed lower levels of BAG-1 than the TAM resistant cell line MCF-7/TAMR, which was induced from MCF-7 cell line by culturing in medium containing 4-OH TAM (1×10-7M) for 6 months. Our study also found that down-regulation of BAG-1 significantly enhanced the sensitivity of the TAMR/MCF-7 cells to TAM treatment. Additionally, we used vectors carrying the individual BAG-1 isoforms to transfect the MCF-7 cells, and found that BAG-1 p50 was the only isoform that inhibited the TAM-induced apoptosis in the MCF-7 cells, while the other isoforms had little effect. Besides, we detected strong expression of BAG-1 in several breast cancer cell lines including T47D, MCF-7, MDA-MB231 and SK-BR-3. We even observed a 1.56 fold increase of EGFR in T47D cells transfected with BAG-1 siRNA when compared with the negative control. To further explore the association between BAG-1 expression and Gefitinb response in breast cancer cell lines, we used Gefitinb of different concentrations to treat cells for 24 hours, 48 hours and 72 hours respectively. The results of cell viability assay indicated that the down-regulation of BAG-1 in breast cancer cell line T47D significantly enhanced the T47D cells' sensitivity to Gefitinb-induced apoptosis.
In summary, our results indicated that BAG-1 may have influence in the development of TAM resistance and Gefitinb resistance in breast cancer. However, our study was conducted in breast cancer cells in vitro; further studies on the relationship between BAG-1 expression and response to TAM and Gefitinb in a large cohort of breast cancer patients may be needed to confirm our findings.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-28.
Abstract P6-05-01: Evaluation of the prognostic significance of androgen receptor (AR) expression in relation to ER expression in breast cancer (BC)
Authors: Gucalp A , Datko FM , Patil S , Hedvat CV , Kalinsky K , Hudis CA , Traina TA , Moynahan ME 
Published: August 2014

Abstract
Background: AR is expressed in 60–80% of invasive BC. Emerging data suggest that AR expression may have a prognostic role in BC irrespective of ER and that the androgen-signaling pathway may be involved in BC pathogenesis. We previously identified an AR-dependent subset of ER/PR(−) BC and reported clinical benefit from AR-inhibition (Gucalp, ASCO 2012). We now describe the prevalence, clinicopathologic characteristics, and survival outcomes of AR(+) BC in relation to expression of ER in a single-institution retrospective cohort.
Methods: We identified 590 patients (pts) with resectable BC (tumor &gt;1cm) who had surgery at MSKCC from 1992–1996. IRB approval was obtained. Tissue microarray (TMA) construction/scoring has been described (Kalinsky CCR 2009). TMAs were stained, scanned and digitally scored (Aperio ScanScope XT) for nuclear steroid receptors (ER, AR), HER2, p53, and MIB1 (Ki67). Using digital quantification of tumor cell nuclear staining, pts were categorized into the following 7 groups: ER dominant (ERD, both ER and AR &gt;10% with ER&gt;AR by &gt;5%), ER only (ER&gt;10%, AR &lt;10%), ER=AR (both &gt;10%, &lt;5% difference), AR dominant (ARD, both &gt;10%, AR&gt;ER by &gt;5%), AR only (AR&gt;10%, ER&lt;10%), hormone receptor negative (HRN, both &lt;10%) and unknown. Due to small pt numbers, ER=AR and ARD data were combined as were AR only and HRN. Associations between IHC expression and clinicopathologic features were assessed using the Chi-square/t-test. The Kaplan-Meier method, Cox proportional hazards models, and log-rank test were used to evaluate the association of IHC expression category on disease-free survival (DFS), distant (d)-DFS, and overall survival (OS).
Results: 528 pts had adequate tumor cores for image analysis/quantification of AR; 302 (57%) tested AR(+). Median followup 12.8 years (yr). A significant difference in DFS (P = .0145), d-DFS (P = .006) and OS (P = .0485) was observed among the following groups: ERD, ER only, ER=AR/ARD and HRN/AR only, with a more favorable outcome associated with ERD (Table 1).

In ER+ BC, ER=AR and ARD are associated with a high frequency of tumor MIB1, p53 and HER2 over-expression (Table 2).

Conclusions: The degree of AR expression relative to ER may be prognostic as survival appears attenuated when AR is the more highly expressed steroid transcription factor. Other poor prognostic factors, including p53, HER2 and higher proliferation indices associate with this finding. The biology associated with AR dominance in ER+ BC needs further study. The inferior clinical outcome of the ER only category is in agreement with recent reports. Further analysis of PIK3CA mutational status and PI3K signaling pathway activation in relation to AR is ongoing. Supported in part by Geoffrey Beene Cancer Research Center at MSKCC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-01.
Abstract P6-05-05: Triple receptor comparison between primary breast cancer and metachronous or synchronous liver metastasis
Authors: Tuyls S , Brouckaert O , Vanderstichele A , Vanderhaegen J , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Peeters S , Vanbeckevoort D , Floris G , Moerman P , Paridaens R , Wildiers H , Vergote I , Christiaens M-R , Neven P 
Published: August 2014

Abstract
Background: Decisions about systemic treatment in women with metastatic breast cancer are currently based on the presence of estrogen receptors (ER), progesterone receptors (PR) or Human Epidermal growth factor Receptor 2 (HER2 receptors) in the primary tumor. Recently, several studies have reported significant discordances in ER, PR and HER2 status between the primary tumor and metastatic lesions and this may vary by metastatic site. Prognostic implications remain unclear although alterations in ER, PR and/or HER2 can influence metastatic management. This study represents one of the largest studies evaluating how frequent receptor discordances occur in liver metastasis, whether this alters therapeutic options and impacts prognosis.
Patients and methods: 246 breast cancer patients with histological confirmed liver metastasis were analyzed in this retrospective study. Immunohistochemistry (IHC) and/or FISH were used to determine ER, PR and HER2 receptor status. We excluded patients when comparison between receptors of primary tumor and metastasis was impossible due to missing data (n = 85), when liver metastasis did not originate from breast cancer (n = 36) and when pathology was obtained from autopsy specimens (n = 38).
Results: 87 patients had matched tissue samples of primary tumor and liver metastasis with possible comparison of at least one of the receptors. Table 1 summarizes changes in ER, PR, HER2 between primary and metastatic lesion. Discordance in receptor status was associated with shorter time to death (63.3 months) compared to the concordant group (75.5 months).

Conclusions: A significant proportion of ER and PR show discordance between primary tumor and liver metastasis. However we could not establish the same level of discordance for the HER2 receptors as in other studies. In general, only about 1 in 5 patients gained new (endocrine or targeted) therapeutic options. Tissue confirmation remains important to evaluate whether metastatic disease has become endocrine insensitive (in approximately 1 in 5 patients), avoiding unnecessary delay in chemotherapy. Discordance in receptors may be associated with inferior prognosis.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-05.
Abstract P6-05-11: Leptin and Leptin receptor expression in human breast cancer
Authors: Wazir U , Al Sarakbi W , Jiang WG , Mokbel K 
Published: August 2014

Abstract
INTRODUCTION: Leptin is a protein that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones and has been suggested to act as a growth factor in neoplasms. Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of oestrogen has been regarded as the main cause for this association, but other factors affecting fat metabolism may be implicated. There is recent evidence that Leptin stimulates cancer cell proliferation in MCF-7 cancer cells. Both Cox2 and hTERT have been proposed as mediators of Leptin's carcinogenic role.
Our objective was to determine, using quantitative PCR, whether the mRNA expression levels of Leptin and Leptin receptor were consistent with a tumour proliferative function and whether levels from these genes were positively correlated with clinical outcome in breast cancer.
METHODS: A total of 153 samples were analysed. The levels of transcription of Leptin and its receptor were determined using quantitative PCR and normalised against (CK19). Transcript levels within breast cancer specimens were compared to normal background tissues and analysed against conventional pathological parameters and clinical outcome over a 10 year follow-up period.
RESULTS: The levels of Leptin and Leptin receptor mRNA were significantly higher in malignant samples (p = 0.0011 and 0.0014 respectively). This difference remained statistically significant when comparing levels between normal samples and all malignant subgroups according to their NPI, grade, stage, local recurrence, and distant metastasis in both ER receptor positive and negative samples. It was also present across all histological types for both Leptin and its receptor.
There was no significant change in mRNA transcription levels correlating with tumour grade, stage, disease free survival, or development of loco regional recurrence.
There was also no statistically significant difference in levels of expression of both Leptin and its receptor when comparing ER positive to negative patients (p = 0.74 and 0.27 respectively).
Leptin levels showed a significantly positive correlation with Leptin receptors (r = 0.504, 0.0000000222). We have observed no significant correlations between Leptin and hTERT or Cox2.
CONCLUSION: This study demonstrates compelling evidence that both Leptin and Leptin receptor mRNA transcription levels are more readily expressed in cancerous tissues providing further evidence that it plays a significant role in the process of breast carcinogenesis. However, Leptin levels did nor correlate with tumor's stage, clinical outcome, hTERT or Cox-2 levels.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-11.
Abstract P6-07-25: Annexin expression and survival outcomes in women with breast cancer
Authors: Dawood S , Gonzalez-Angulo AM , Liu S , Chen H , Li Y , Albarracin CT 
Published: August 2014

Abstract
Background: The annexin superfamily of proteins has been implicated in several cellular processes. In particular, annexin A1 is known to have anti-inflammatory, anti-proliferative and pro-apoptotic functions. The expression and precise role of annexin A1 in breast cancer have been conflicting. The goal of this retrospective study was to explore the association of annexin A1 expression and survival outcome among women with breast cancer.
Methods: 426 women with breast cancer whose tumor samples and associated data was available were identified. Annexin A1 expression was measured using RPPA and was considered as a categorical and continuous variable. Range of annexin A1 levels for the cohort was −1.90 to 2.36. Patients were divided into four groups according to the annexin A1 level: a) negative (annexin A1 &lt;-0.84), b) low (annexin A1 &gt; = −0.84 and &lt;0.23), c) medium (annexin A1 &gt;=0.23 and &lt; 1.29) and d) high (annexin A1 &gt;=1.29). Recurrence free survival (RFS) was estimated using the Kaplan-Meier product limit methods and compared across groups using log rank statistic. Cox proportional hazards models were used to determine the association of survival outcomes and annexin expression (continuous variable) adjusted by patient and tumor characteristics.
Results: Median age at diagnosis was 62 years. 41 (9.6%), 245 (57.5%), 25 (5.9) and 115 (27.0%) patients had Her2 positive, hormone receptor (HR) positive, metaplastic and triple negative (TNBC) disease respectively. For the whole cohort 44 (10%), 235 (55.2%), 119 (27.9%), 28 (6.6%) breast tumors were classified as having negative, low, medium and high annexin expression respectively. High annexin A1 levels were associated with hormone receptor positive disease, increased age, post-menopausal status, low grade and lower disease stage. Median annexin A1 level was −0.19, 0.0, −0.34, −0.2 among tumors that were HER2 positive, HR positive, metaplastic and TNBC disease respectively. 5-yearRFS was 65.8% and 84.9% respectively among women with negative/low and medium/high annexin A1 levels respectively (p &lt; 0.0001). Among women with Her2 positive, HR positive, metaplastic or TNBC disease 5-year RFS was significantly higher among tumors with medium/high annexin A1 levels. In the multivariable model an increase in annexin was associated with a 13% reduction in the risk of recurrence (HR = 0.87, 95% CI 0.60–1.26, p = 0.46).
Conclusion: In this large dataset with long follow up our results indicate that high annexin A1 expression among women with breast cancer was associated with favorable patient and tumor characteristics and an improved RFS. Annexin A1 should be explored further as a potential prognostic biomarker.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-25.