bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-03-02: Chronic CXCL12 exposure induces a metastatic phenotype in ER-positive breast cancer cells through transcriptional reprogramming
Authors: Sun J , Slingerland JM , Lippman ME 
Published: March 2017

Abstract
The chemokine CXCL12 is transcriptionally activated by estrogen in estrogen receptor (ER)-positive breast cancer cells. We have found that CXCL12 signaling is essential to maintain the long-term growth of ER-positive breast cancer cells and promotes cancer cell growth in the absence of estrogen. Chronic blockade of CXCL12 signaling with AMD3100, an inhibitor of CXCL12 receptor CXCR4, causes cell death in these cells. Chronic exposure to CXCL12 reprograms ER-positive breast cancer cells through genome-wide transcriptional changes and activates numerous signaling pathways including EMT and the inflammatory response. Many ER target genes are activated in CXCL12-reprogrammed cells even in the absence of estrogen which leads to the diminished estrogen modulated transcription in these cells. These cells also show enhanced signaling via TGFb, EGFR and Rac1 pathways, rendering these cells more sensitive to the CDK7 inhibitor, THZ1, and to drug combinations of THZ1 with the EGFR inhibitor Gefitinib or the RAC1 inhibitor EHT 1864. Furthermore, CXCL12-reprogrammed ER-positive breast cancer cells become more motile in vitro and display a metastatic phenotype in a mouse model. The lung-tropic phenotype of CXCL12-reprogramed MCF-7 cells could be explained by increased expression of integrins and pro-inflammatory signaling molecules. Our novel finding of chronic CXCL12 action on ER-positive breast cancer cells suggests a mechanism by which the interaction between stromal and tumor cells leads to increased breast tumor metastatic potential.
Citation Format: Sun J, Slingerland JM, Lippman ME. Chronic CXCL12 exposure induces a metastatic phenotype in ER-positive breast cancer cells through transcriptional reprogramming [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-03-02.
Abstract P6-05-04: Relationship between obesity and breast tumor pathology in a contemporary set of patients
Authors: Ellsworth RE , Lovejoy L , Costantino N , Sheiver CD 
Published: March 2017

Abstract
Background: Obesity is a risk factor for breast cancer in postmenopausal women, and is associated with decreased survival regardless of menopausal status. This outcome disparity has been attributed to clinical factors such as delayed diagnosis, inadequate dosing with chemotherapeutic agents, and co-morbid conditions. Here, we evaluated the association between pathological characteristics and BMI in a cohort of patients enrolled in the Clinical Breast Care Project (CBCP) 2001-2013.
Methods: All female patients with invasive breast cancer who had height and weight recorded at the time of diagnosis were identified from the CBCP database. BMI was calculated and patients categorized as normal/lean (&lt;24.9 kg/m2), overweight (25-29.9 kg/m2), or obese (&gt;30.0 kg/m2). Chi-square univariate analysis was performed to determine statistical significance followed by multivariate logistic regression. Statistical significance was defined as p &lt;0.05. Survival analysis was done using Cox proportional hazard regression models.
Results: Of the 1,705 patients, 32.4% were normal/lean, 31.6% were overweight and 36.0% were obese. Univariate analysis revealed that obese women were significantly more likely to be older at age at diagnosis, African American, menopausal and treated at Joyce Murtha Breast Care Center, a rural civilian hospital in western-central PA. These factors were thus include in multivariate analysis which showed that obese patients were at an increased risk relative to normal/lean patients of having a higher tumor stage (OR = 1.32, 95% CI [1.043-1.681], p = 0.021), size (OR = 1.42, 95% CI [1.091-1.857], p = 0.009), and grade (OR = 1.37, 95% CI [1.085-1.718], p = 0.008) but at decreased risk of PR- tumors (OR=0.57, 95% CI [0.394-0.837], p = 0.004). Overweight patients did not differ significantly from either normal weight or obese patients. Neither breast cancer-specific nor overall survival differed significantly between groups.
Discussion: Higher tumor stage and size may reflect delayed detection in obese women. In contrast, tumor grade and PR status likely reflect underlying biological differences driven by increased adiposity in the breasts of obese women. Despite these differences in pathology, survival did not differ by BMI status, suggesting that factors such as suboptimal dosing may not be relevant in current patient care.
Citation Format: Ellsworth RE, Lovejoy L, Costantino N, Sheiver CD. Relationship between obesity and breast tumor pathology in a contemporary set of patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-05-04.
Abstract P6-07-20: Allele-specific PCR assay for estrogen receptor (ESR1) mutation detection
Authors: Litterst CM , Tran HB , Chien S , Chen X , Wen W , Begovich A 
Published: March 2017

Abstract
Seventy percent of breast cancers are estrogen receptor (ER) positive and, while the majority of these patients initially respond to hormone therapy, approximately 20-30% will become therapy refractory. Recent data suggest activating-mutations in the estrogen receptor gene (ESR1) ligand binding domain (LBD), which are acquired during anti-estrogen treatment and rarely found in primary untreated ER+ breast cancer, are associated with resistance. Some researchers propose that ESR1 mutations are a prognostic and predictive marker, but more studies are needed to assess the clinical utility of the ESR1 mutations. However, current ESR1 mutation detection methods, that is, next generation sequencing and digital PCR, are very labor-intensive, lengthy, and expensive and require special training.
To aid research on the diagnostic potential of ESR1 mutations, we developed a prototype allele-specific qPCR assay for the detection of 18 recurrent mutations in the ESR1 LBD. The test is suitable for DNA obtained from FFPE tissue as well cfDNA from plasma. It is sensitive, yet simple, robust and results can be obtained in less than 8 hours. Herein, we demonstrate the analytical performance of our ESR1 mutation detection assay using contrived samples. We are also planning to test clinical FFPET and plasma samples in the future.
Citation Format: Litterst CM, Tran HB, Chien S, Chen X, Wen W, Begovich A. Allele-specific PCR assay for estrogen receptor (ESR1) mutation detection [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-20.
Abstract P6-07-27: Characterization of neuroendocrine breast carcinomas for biomarkers of therapeutic options
Authors: Gatalica Z , Feldman R , Ghazalpour A , Vranic S 
Published: March 2017

Abstract
Introduction: Neuroendocrine breast carcinoma (NBC) is an extremely rare type of cancer, constituting less than 0.1% of all breast tumors, without specific treatment options. We investigated a biomarker database for frequency of molecular markers that may guide personalized treatment choices for these patients.
Materials and Methods: Molecular profiles of 40 breast carcinomas with neuroendocrine features [ER/PR+ (n=20), HER2+ (n=1) and TNBC (n=14)] were assessed (all female patients, mean age: 60.3 years, range: 39-83 years). Gene expression (Illumina DASL microarray platform), protein expression (IHC), gene amplification (ISH) and next-generation sequencing (NGS; TruSeq Illumina platform) were performed.
Results: 57% of NBCs were positive for hormone receptors (ER/PR), 40% were triple negative TNBC and 3% HER2+ subtypes. Therapeutic biomarkers (IHC) that may guide chemotherapies (and used in other primary sites neuroendocrine tumors) included: high TOP2A (85%) for etoposide or doxorubicin, low TS (57%) for 5-fluorouracil and low ERCC1 (45%) for cisplatin. Additional biomarkers for chemotherapy included: high TOPO1 (60%) for irinotecan, low RRM1 (48%) for gemcitabine and low MGMT (57%) for temozolomide. Biomarkers associated with available targeted therapies included: PTEN loss (39%), positive ALK (33%), cKit (30%), EGFR (29%), AR (26%) and PDGFRA (17%). No gene amplifications were detected in cMET, EGFR, or TOP2A. Targeted sequencing analysis of 47 genes detected variants in TP53, PIK3CA, ERBB4 and APC genes. Gene expression data (included somatostatin receptor gene family- SSTR1/2/3/4/5) was available for 5 patients, for which 3/5 patients exhibited overexpression of at least one SSTR gene.
Conclusions: Molecular profiling by a multiplatform approach reveals potential personalized therapy options for this very rare breast cancer subtype. With recent success of somatostatin analogs for other neuroendocrine tumors, the overexpression of SSTR gene family in NBC is worthy of further investigation.
Citation Format: Gatalica Z, Feldman R, Ghazalpour A, Vranic S. Characterization of neuroendocrine breast carcinomas for biomarkers of therapeutic options [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-27.
Abstract P6-07-28: The 21-gene assay in the decision impact assessment of ER+, HER2- Breast cancer: A French real life prospective study
Authors: Gligorov J , Dohollou N , Mouysset JL , Laplaige P , Fignon A , Lafuma A , Michaud P 
Published: March 2017

Abstract
BACKGROUND: Tumour gene expression analysis is useful in predicting adjuvant chemotherapy benefit in breast cancer (BC). The 21-gene assay test is used to estimate the risk of recurrence and to predict the benefit of adjuvant chemotherapy (ACT) at an early stage of hormone-receptor-positive (ER+) BC. This study aims to examine the implications of RecurrenceScore (RS) testing within the routine clinical practices in France.
METHODS: We conducted a prospective multicentert study, with voluntary participation, involving women with ER+, HER2-, BC. Performing the assay was left at the discretionof the physicians. The final treatment decision was discussed pre and post assay among tumor board (TB). The therapeutic changes after knowledge of RS were collected. RS and classical BC prognostic markers were investigated in parallel including an estimate of the budget impact of the assay.
RESULTS: 603 patients were included in this analysis (tumor size ≤ 20 mm: 70.6%; node-negative patients: 61.2%; SBR 2: 74.9%). After the first TB, ACT was recommended for 529 patients (88.0%) and hormonotherapy (HT) alone for 74 patients (12.0%). The RS was low for 59.7% of the cases, intermediate for 34.0% and high for 6.3%. Based on RS results, second TB changed treatment decision for 70.48% of patients, avoiding CT in 64 % of cases. Only 24% received ACT while 76% received HT alone. The calculated budget impact as a minimal estimate according to the French healthcare payer perspective is estimated at a savings of € 570 per patient, corresponding to a global cost-saving of € 221,730.
CONCLUSION: The results of this “real life” study confirm that the 21-gene assay had a significant impact on therapeutic decision. These findings warrant further consideration for the use of this genomic assay in patients with early stage BC in France.
Citation Format: Gligorov J, Dohollou N, Mouysset JL, Laplaige P, Fignon A, Lafuma A, Michaud P. The 21-gene assay in the decision impact assessment of ER+, HER2- Breast cancer: A French real life prospective study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-28.
Abstract P6-08-05: Genome-wide identification of transcripts regulated by estrogen in MCF-7 cells using BrU-seq
Authors: Sun J , Capobianco E , Tsinoremas N , Lippman M 
Published: March 2017

Abstract
Estrogen promotes estrogen receptor (ER)-positive breast cancer cell growth by modulating transcription through ligand activated ER. The spectrum of early ER target genes has been identified through gene expression microarray and more recently with RNA-seq analyses. These methods, although comprehensive, fall short in identifying many ER-regulated transcripts which are either not present in microarray; too abundant to determine estrogen regulated changes among steady-state pools of RNAs; or have very short half-lives and low abundance such as some non-coding RNAs, including RNAs generated by enhancers bound by ER (eRNAs). Global run-on sequencing (GRO-seq) has been used to identify ER target genes and eRNAs in breast cancer cells. It is technically cumbersome and is performed under non-physiological condition.
We have applied BrU-seq technique to identify global transcripts regulated by estrogen in MCF-7 breast cancer cells. The newly synthesized RNAs in MCF-7 cells treated with or without estrogen for various time points, were labeled with 5'-bromo-uridine (BrU). The labeled RNAs were purified by immunoprecipitation using an anti-BrdU antibody and then subjected to RNA sequencing analysis, which provides greater sensitivity than regular RNA-seq analysis from steady-state total RNA samples. Robust estrogen-regulated transcripts can be detected within 30 min of treatment. Significantly more transcripts (both coding and non-coding RNAs) were identified as estrogen targets using BrU-seq analysis than RNA-seq analysis from total RNA pools. Many of these estrogen-regulated transcripts are located close to ER binding sites identified from ER ChIP-seq analysis, indicating a functional role for these ER binding sites in regulating RNA transcription. For estrogen targets identified through both analyses, the magnitude of expression changes (both up- and down-regulation) is usually greater from BrU-seq than from the regular RNA-seq analysis. The dynamics of RNA synthesis and degradation for some unstable RNAs (such as eRNAs) can be interrogated through our data set. Also, RNA pol II elongation rate can be deduced from some long ER target genes (&gt;100 kb) such as GREB1. In addition to identifying estrogen targets, BrU-seq should be a very useful technique in assessing transcriptional changes triggered by various signal transduction pathways.
Citation Format: Sun J, Capobianco E, Tsinoremas N, Lippman M. Genome-wide identification of transcripts regulated by estrogen in MCF-7 cells using BrU-seq [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-05.
Abstract P6-08-06: A positive feedback loop couples CD44s and HAS2 for sustained Akt activation and tumor cell survival
Authors: Liu S , Cheng C 
Published: March 2017

Abstract
Breast cancer is the second leading cause of cancer death in women worldwide. Despite recent advances in breast cancer treatment, tumor metastasis and recurrence remain the most significant clinical obstacles, largely due to the resistance of residual breast tumor cells to existing therapies. RNA alternative splicing is a fundamental mechanism for gene regulation and protein diversity. Despite the fact that nearly all human genes are regulated by alternative splicing, very limited studies have addressed the role of alternative splicing in tumorigenesis. Our lab uses the cell adhesion molecule CD44 as a model to investigate the role of alternative splicing in breast cancer metastasis. CD44 undergoes extensive alternative splicing, giving rise to the standard (CD44s) and variant (CD44v) isoforms. Previous work from our lab demonstrated that the CD44s isoform is required for Epithelial to Mesenchymal transition (EMT) and breast tumor metastasis. Mechanistically, we have shown that CD44s, but not CD44v, potentiates Akt signaling, promoting cell survival and chemoresistance in breast cancer cells.
To better understand CD44s-mediated downstream pathways critical for breast tumor metastasis, we analyzed CD44s-dependent gene signature and identified Hyaluronan Synthase 2 (HAS2), an enzyme that produces hyaluronan (HA), as one of the most significantly upregulated genes in response to CD44s expression. Interestingly, HA is the major ligand for CD44, and HA/CD44 interaction promotes Akt activation. These results led us to test a hypothesis that a positive feedback loop, involving CD44s and HAS2, sustains Akt signaling and promotes tumor cell survival. Indeed, our results show that CD44s-mediated Akt activation stimulates HAS2 transcription. This increase in HAS2 transcription is mediated by Akt phosphorylation of FOXO1, a transcription repressor inactivated by phosphorylation. We further show that HAS2 and HA activate Akt signaling in a CD44s-dependent manner. Importantly, disruption of this feed-forward loop inhibits EMT and triggers cell death.
PI3K/Akt signaling is hyperactive in more than 70% of breast tumors. Hence, the proteins involved in this positive feedback loop represent very attractive and promising drug targets for breast cancer therapy. Our work has demonstrated how aberrant expression of alternative spliced isoform in breast cancer, through a positive feedback loop, leads to sustained Akt signaling, enhanced cell survival, and a metastatic phenotype. Disrupting this positive feedback loop may provide a foundation for an innovative approach to treat metastatic breast cancer patients.
Citation Format: Liu S, Cheng C. A positive feedback loop couples CD44s and HAS2 for sustained Akt activation and tumor cell survival [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-06.
Abstract P6-09-04: Nuclear grade has a limited role in predicting recurrence in DCIS following breast conserving surgery: A population-based study
Authors: Nofech-Mozes S , Hanna W , Baehner FL , Saskin R , Tuck A , Sengupta S , Elavathil L , Jani PA , Bonin M , Chang MC , Slodkowska E , Paszat L , Rakovitch E 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P6-09-36: Tamoxifen resistance: EGFR expression in hormone receptor-positive and HER2 negative breast cancer
Authors: Bae SY , Nam SJ , Lee SK , Kim SW , Lee JE , Yu JH 
Published: March 2017

Abstract
Purpose: Crosstalk between growth factor receptor tyrosine kinases (RTKs) and the estrogen receptor (ER) represents one of the most important mechanisms of endocrine resistance. EGFR and HER2 have been recognized as prominent factors associated with endocrine resistance. Most previous studies did not identify subgroups by HER2 overexpression and/or included breast cancer with HER2 overexpression. Accordingly, we analyzed HR positive (HR+) tumors without HER2 overexpression (HER2-).
Methods: We analyzed the clinical data of 2,166 patients with HR+HER2- breast tumors, between January 2007 and July 2013.We included only patients who had endocrine therapy with tamoxifen. Immunostaining for EGFR was interpreted as positive when at least 10% of the tumor cells showed moderate to strong membrane staining.
Results: EGFR expression (EGFR+) was present in 109 patients (5%). EGFR expression was significantly associated with more advanced stage and higher grades. In the univariate analyses, EGFR+ tumors were associated with poorer prognosis than EGFR- tumors (5-year DFS, EGFR+ vs. EGFR-, 91.2% vs. 96.6%, P &lt;0.001; 5-year OS, EFGR+ vs EGFR-, 93.1 % vs. 99.4%, P &lt; 0.001). In the multivariate analysis, EGFR+ tumors had a hazard ratio of 2.63 (95% CI 1.14 -6.05) for DFS. EGFR+ tumors had a hazard ratio of 8.8 (95% CI 2.68-132.25) for OS.
Conclusion: EGFR expression could be prognostic factor in hormone receptor-positive and HER2 negative breast cancer, for tamoxifen resistance.
Citation Format: Bae SY, Nam SJ, Lee SK, Kim SW, Lee JE, Yu JH. Tamoxifen resistance: EGFR expression in hormone receptor-positive and HER2 negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-36.
Abstract P6-09-41: Factors predicting treatment outcomes of angiosarcoma of breast: A 25 year single institution experience
Authors: Ammannagari N , Attwood K , Cheney R , Young JS , Kane JM , Salerno KE , Opyrchal M 
Published: March 2017

Abstract
Background: Primary (PAS) and secondary angiosarcoma (SAS) of breast account for &lt; 1% of all breast neoplasms. SAS develops following radiation therapy (RT) to the breast or chest wall for treatment of breast cancer. The rarity of this tumor type makes it challenging to determine prognostic factors and develop optimal treatment strategies. Historically, large NCI cancer centers have reported a median overall survival ranging from 28 – 100 months with recurrence rate of 55%. Methods: We reviewed demographic, tumor, and treatment characteristics of breast AS patients diagnosed and treated at our institution between 1990 and 2015. Overall (OS) and recurrence free (RFS) survival were compared using standard statistical methods at a significance level of 0.05. Results: Of 12155 breast cancers, 22 patients (0.008%) with AS (PAS in 34%, SAS in 66%) were identified. Median age of PAS patients was significantly lower than SAS – 45 vs 71 years (p &lt; 0.001). Median tumor size was 6.9 cm (7.3 cm vs 6.9 cm, p = 0.93) with multifocal disease seen in 22.7%. Tumor was high grade in 14 (50% vs 83.3%, p = 0.34). Median time from RT to SAS diagnosis was 7.8 years. Treatment included: mastectomy in 17 (77.3%), wide excision in 4 (18.2%), adjuvant RT in 4 (18.2%), taxane based chemotherapy in 11 (50%) and chemo-RT in 1 (4.5%). No significant differences were noted in tumor (p = 0.9) or treatment characteristics (p = 0.4) between PAS and SAS. Recurrence rate (mainly distant) was 36% (8 pts). The 5-year OS and RFS rates were 51% (95% CI 27–72%) and 36% (95% CI 14–58%) with estimated medians of 64.2 and 55.5 months, respectively with no significant difference between the two groups. Black ethnicity (11.6 vs 64.2 months, p = 0.015), multifocal disease (15.5 vs 64.2 months, p = 0.004) and tumor size of &gt; 6.9 cm (8.3 vs 64.2 months, p = 0.03) were associated with poorer outcomes. Tumor grade was not related to OS. Adjuvant treatment (RT p = 0.49, chemotherapy p = 0.36) conferred no RFS or OS benefit. Conclusions: Patients with PAS were younger than SAS. Black race, multifocal presentation and larger tumor size predict worse clinical outcomes. Our institutional experience confirms the poor prognosis of angiosarcoma, and highlights the need for further research.
Citation Format: Ammannagari N, Attwood K, Cheney R, Young JS, Kane JM, Salerno KE, Opyrchal M. Factors predicting treatment outcomes of angiosarcoma of breast: A 25 year single institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-41.