bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-13-18: The feasibility of nurse intervention to improve and maintain the BMI of breast cancer survivors over 25 to appropriate levels
Authors: Arakaki M , Tamaki K , Kamada Y , Uehara K , Gushikawa H
Published: March 2017

Background: Some studies have shown that women with breast cancer who have a BMI value gain of more than 2.0 kg/m2 after diagnosis have an elevated risk of dying of breast cancer, and likewise breast cancer patients who gained 5 or more kilogramshad a higher mortality rate than those who maintained their weight. Therefore it can be said that weight control is important for women with breast cancer.

In addition to the survival benefit, preliminary research suggests that exercise intervention for weight control may also be effective for enhancing the QOL of cancer survivors.

Purpose: We designed an exercise intervention study to assess the feasibility of the intervention in maintaining standard weight and also the effect of the excercise in breast cancer patients.

Patients and methods: Breast cancer patients aged 20 to 75 years, stage I to IIIA, with no metastases, who had completed chemotherapy, with BMI values greater than 25 kg/m2 are eligible for participation. The intervention will be to have the patients do aerobic exercise 150 minutes per week, and assess the BMI and health-related QOL using the care note questionnaire, at baseline, 6 months, and 12 months later for each participant. We are also planning dietary interventions for the patients. We will calculate the actual calorie consumption of each patient and give dietary advice for optimal calorie intake. Patients will be required to record their exercise in a formatted note so we can check the exercise adherenece.

Citation Format: Arakaki M, Tamaki K, Kamada Y, Uehara K, Gushikawa H. The feasibility of nurse intervention to improve and maintain the BMI of breast cancer survivors over 25 to appropriate levels [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 P5-13-18.
Abstract P5-16-07: Non-anthracycline-containing docetaxel plus cyclophosphomide was inferior to docetaxel, anthracycline and cyclophosphomide in neoadjuvant treatment of triple negative or HER2 positive breast cancer: Long term follow-up result from NATT study
Authors: Chen X , Ye G , Zhang C , Li X , Shen K
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-16-12: Pertuzumab and trastuzumab in combination with weekly paclitaxel delivers high pCR rates with favourable toxicity profile in neo-adjuvant treatment of Her-2 positive breast cancer
Authors: Gupta N , Giblin E , Leagre C , Longmire-Cook S , Tigges T , Compton J , Dugan T , liebross R , Givens S , Schmidt K , Paul R , Trivedi R , Smith B , Reeves D , Hanson J , Schmidt T
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-16-17: Population based long term outcomes of pathologic complete response after neoadjuvant chemotherapy in stage I-III breast cancer: The British Columbia experience
Authors: Sun J , Gondara L , Diocee R , Speers C , Lohrisch C , Chia S
Published: March 2017

Background:

Neoadjuvant chemotherapy is a treatment option for breast cancer patients (pts) with locally advanced disease and for pts with operable breast cancer who desire breast conservation. Neoadjuvant therapy also allows for early evaluation of the effectiveness of systemic therapy. Pathologic complete response (pCR) has been shown in clinical trials to be associated with improved survival. The objective of this study was to determine if the outcomes demonstrated in clinical trials can be applied in the population based setting by comparing the outcomes of breast cancer pts who achieved pCR (no invasive disease in breast and nodes) vs. those that did not achieve a pCR.

Methods:

This is a retrospective cohort study of stage I-III invasive breast cancer pts treated with neoadjuvant chemotherapy from 2005 to 2010 in British Columbia. Cases were identified from the Breast Cancer Outcomes Unit database. Data was collected on demographics, tumor pathology, and type of treatment (chemotherapy, endocrine therapy, trastuzumab) and linked to standard clinical outcomes.

Results:

267 pts who met inclusion criteria were identified, of whom 5% had stage I, 33% Stage II and 59% Stage III breast cancer. Median follow up was 7.4 years. Overall 74 pts (28%) demonstrated a pCR and 193 pts did not. pCR pts had better 5-yr overall survival (OS) vs. non-pCR pts: 88% vs. 73% (HR 0.43, 95% CI 0.23-0.82, p=0.01). 5-yr disease free survival (DFS) was 84% in pCR pts vs. 70% in non-pCR pts (HR 0.45, 95% CI 0.24-0.83, p=0.01). Similarly, 5-yr breast cancer specific survival (BCSS) and distant disease free survival (DDFS) were significantly better in favor of the pCR cohort: HR 0.39 (95% CI 0.18-0.82, p=0.01) and HR 0.45 (95% CI 0.24-0.83, p=0.02) respectively. pCR pts were more likely to be HER2-positive and/or ER negative.

Conclusions:

Our population based results showed that early stage breast cancer pts who achieved pCR after neoadjuvant chemotherapy had better outcomes on all survival parameters compared to pts who did not achieve a pCR. This finding is consistent with results from neoadjuvant clinical trials and the FDA meta-analysis. These 'real world' results demonstrate that pCR can be used as a surrogate endpoint for survival outcomes even among non-trial pts.

Citation Format: Sun J, Gondara L, Diocee R, Speers C, Lohrisch C, Chia S. Population based long term outcomes of pathologic complete response after neoadjuvant chemotherapy in stage I-III breast cancer: The British Columbia 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 P5-16-17.
Abstract P5-16-22: Survival after adjuvant and neoadjuvant chemotherapy in elderly patients with triple negative breast cancer: A Cleveland Clinic experience
Authors: Mohapatra S , Seepana J , Haddad A , Spiro T , Daw H
Published: March 2017

Background:

Triple negative breast cancer (TNBC) comprises of approximately 15% of the total breast cancers. There is limited data on treatment outcome of these patients in elderly population. We report our experience with elderly patients with TNBC treated at our tertiary care centers.

Objectives and rationale:

1. Percentage of TNBC patients who received neoadjuvant chemotherapy (NACT) vs. Adjuvant chemotherapy (ACT).

2. Chemotherapeutic agents used for NACT and ACT.

3. Progression free survival (PFS) and overall survival (OS) after neoadjuvant CT and adjuvant CT.

4. Outcomes between elderly patients 65-74 years vs. 75 years and above.

Methods:

With IRB approval, the Cleveland Clinic's database was used to identify TNBC patients treated between 2000 to 2013. OFS from the diagnosis of TNBC was the primary end point. Cox proportional hazard models with stepwise variable selections were used for data analysis.

Results:

A total of 223 patients, divided in to two groups, were prospectively followed. The age group from 65-74 years consisted of “Group A” (N=140, median 69) and 75 or older formed “Group B” (N= 83, median 80, maximum 92). Eighty eight percent had ductal carcinoma. Clinically majority had stage I (50%) and stage II (33%) disease; 17% had stage III disease and most tumors were poorly differentiated (74%, grade 3). Slightly more than half the patients had lumpectomies (55%); and in only 13% of cases (25/190) were margins positive. Patients who received neoadjuvant (NACT), aduvant chemotherapy (ACT) and radiation therapy (RT) were 65%, 53% and 38% respectively. For NACT primarily doxorubicin, cyclophosphamide and paclitaxel were used whereas for ACT it was docetaxel with cyclophosphamide. Group B had somewhat poorer performance status than younger patients (p=.05), received chemotherapy especially neoadjuvant therapy much less frequently (p<.0001). OS and PFS were significantly lower in Group B (p=0.001 and 0.007 respectively). This holds true even if one adjusts for performance status and use of chemotherapy (p=0.04 and 0.03 respectively).

Conclusion:

Among elderly patients with triple negative breast cancer, those above 75 years and older have poorer outcomes compared to those with age 65-74 years. However, this is a retrospective study and has limitations; prospective randomized studies are needed to confirm these findings.

Citation Format: Mohapatra S, Seepana J, Haddad A, Spiro T, Daw H. Survival after adjuvant and neoadjuvant chemotherapy in elderly patients with triple negative breast cancer: A Cleveland Clinic 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 P5-16-22.
Abstract P6-01-11: Distinct recruitment of tumor-associated immune cells correlates with increased pro-malignant chemokines in tumors expressing epithelial atypical chemokine receptor 1 (ACKR1/DARC), indicating a unique tumor microenvironment
Authors: Jenkins BD , Martini RN , Hire R , Monteil MA , Davis MB
Published: March 2017

The breast tumor microenvironment is a complex assortment of cancer and host immune cells that interact to produce a myriad of clinical outcomes for breast cancer (BrCa) patients.Chemokine receptors, such asthe Atypical Chemokine Receptor 1 (ACKR1), play an important role in maintaining the homeostasis of pro-inflammatory chemokines, as well as influencing the migration of host immune cells. ACKR1 has the ability to modify the breast tumor microenvironment in multiple ways, including sequestering chemokine activity and affecting leukocyte migration. The purpose of this study is to characterize the variation in immune cell signaling between ACKR1 positive and negative tumors, and determine any correlation between ACKR1 and CCL2 (MCP-1) and CXCL8 (IL-8) in various BrCa cell types.

Primary breast tumor samples were stained using immunohistochemistry for ACKR1, in addition to various immune cells including, T-cells, B-cells, dendritic cells, and macrophages. We determined levels of circulating chemokines using a Luminex assay kit on whole blood lysate. We also tested the localization of ACKR1-associated chemokines and the abundance of ACKR1 using immunofluorescence techniques. Pilot data collected from primary breast tumor tissue suggested that differential expression of ACKR1 from various tumor subtypes leads to the recruitment of a specific subset of host immune cells to the tumor microenvironment. In our cohort, ACKR1 positive tumors tended to recruit B cells and dendritic cells to the site of the tumor, whereas ACKR1 negative cells did not. We also detected a positive correlation between ACKR1 levels in tumor tissue with CCL2 and CXCL8 levels in the circulating blood of our study group. Finally, co-localization of ACKR1 with CCL2 and CXCL8 was observed in cultured mammalian breast cancer cells. Overall, our pilot data suggests that there is differential recruitment of immune cells within the ACKR1 positive and negative BrCa tumor microenvironments, and that circulating CCL2 and CXCL8 concentrations are positively correlated with ACKR1 levels in BrCa cells.

Citation Format: Jenkins BD, Martini RN, Hire R, Monteil MA, Davis MB. Distinct recruitment of tumor-associated immune cells correlates with increased pro-malignant chemokines in tumors expressing epithelial atypical chemokine receptor 1 (ACKR1/DARC), indicating a unique tumor microenvironment [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 P6-01-11.
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

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

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 (<24.9 kg/m2), overweight (25-29.9 kg/m2), or obese (>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 <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 P6-07-04: Comprehensive genomic profiling to assess tumor mutation burden in >8,000 breast cancer cases: Implications for immunotherapy
Authors: Frampton GM , Connelly C , Fabrizio D , Miller VA , Stephens PJ
Published: March 2017

This abstract was withdrawn by the authors.
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

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

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

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 P6-07-29: Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer
Authors: Li M , Li A , Zhou S , Xu Y , Xiao Y , Bi R , Yang W
Published: March 2017

This abstract was not presented at the symposium.
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

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 (>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

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

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

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 <0.001; 5-year OS, EFGR+ vs EGFR-, 93.1 % vs. 99.4%, P < 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

Background: Primary (PAS) and secondary angiosarcoma (SAS) of breast account for < 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 < 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 > 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.
Abstract P6-09-53: Targeting RB loss for the precision treatment of triple negative breast cancer
Authors: Knudsen E , Essf J , Balaji U , Witkiewicz A
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-09-56: Tissue microarray (TMA) based immunohistochemical studies of lymphocyte-specific markers yield inaccurate results
Authors: McIntire PJ , Ginter PS , Irshaid L , Cui X , Chen Z , Shin SJ
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-11-15: Pre-clinical investigation of estrogen receptor β agonists for the treatment of breast cancer
Authors: Samayoa C , Krishnegowda NK , Vadlamudi RK , Tekmal RR
Published: March 2017

Breast Cancer is the primary cause of cancer-associated mortality worldwide, and in United States alone, more than 250,000 women are diagnosed every year. Current breast cancer treatment strategies focus on Estrogen Receptor α signaling, given that the majority of cases diagnosed are ERα positive. These treatment strategies include endocrine therapies; such as anti-estrogens or aromatase inhibitors. Although, endocrine therapy has been demonstrated to be successful and effective, therapy resistance commonly arises and results in relapse. While current endocrine therapies focus on ERα signaling, emerging studies highlight the importance of Estrogen Receptor β.Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. Recent studies have identified, synthesized, and tested the clinical safety of ERβ-selective agonists. The objective of this study was to investigate the utility of using ERβ agonists in the treatment of breast cancer.

To investigate the utility of ERβ agonists in the treatment of breast cancer, we used in-vitro and in-vivo pre-clinical models systems. Our results demonstrated that treatment with ERβ agonists, S-Equol and LY500307, was able to inhibit the short-term and long-term growth of both endocrine therapy sensitive and resistant breast cancer cells. Progression through the cell cycle, cell migration and cell invasion was also abrogated upon treatment. In-vivo, our syngeneic tumor mouse model demonstrates a decline in tumor growth rate after treating with a combination of letrozole and ERβ agonist. Gene expression array analysis reveal that treatment with ERβ agonist elicits changes in key signaling molecules involved in cell death and cell cycle pathways. In Letrozole resistant cells, Letrozole treatment had not effect on gene expression, while LY500307 treatment resulted in the modulation of 780 genes. Interestingly, combining Letrozole with LY500307 resulted in the modulation of 966 genes, of which 417 were unique to the combination treatment. Our studies suggest that activation of ERβ signaling is a valuable strategy in the treatment of breast cancer, even in cases which have developed resistance to current endocrine therapies.

Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Pre-clinical investigation of estrogen receptor β agonists for the treatment of 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 P6-11-15.
Abstract P6-12-11: A randomized, double-blind, placebo-controlled window of opportunity trial evaluating clinical effects of high dose vitamin D in patients with breast cancer
Authors: Arnaout A , Robertson S , Addison C , Chang N , Pond G , Clemons M
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-12-16: Delivery and anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) in metastatic xenograft models of triple negative breast cancer
Authors: Lee H , Ventura M , Bernards N , Mohammad AS , Foltz W , Fitzgerald J , Jaffray DA , Lockman PR , Zheng J , Hendriks BS
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-16-07: Analysing the factors affecting survival of breast cancer patients with leptomeningeal metastasis
Authors: Niwinska A , Rudnicka H , Kunkiel M , Jagiello-Gruszfeld A , Nowecki Z
Published: March 2017

AIM: To assess those factors which affect survival in three groups of breast cancer patients with leptomieningeal metastasis (LM) treated at the Warsaw Cancer Center in Poland. Subject groups were: 187 patients consecutively referred during 2003-2015 (group A), 69 patients with LM as the first/only site of dissemination of the disease (group B) and 27 patients who survived for more than 1 year (group C).

Methods: Univariate and Cox multivariate analysis were performed using the following variables: age, Karnofsky Performance Status (KPS), biological subtype of breast cancer (ER/PR+HER2- vs. HER2+ vs. ER-PR-HER2-), systemic intravenous/oral treatment, intrathecal treatment, radiation therapy and the number of treatment methods.

Results. Median survival of patients in group A was 17 weeks, in group B 18 weeks (p=0.72) and in group C 19.2 months. In group A, factors positively affecting survival were: KPS => (p=0.01), older age (p=0.003), biological subtype ER/PR+HER2- (p=0.003), systemic intravenous/oral treatment (p=0.0001), intrathecal treatment (p=0.001) and radiation therapy (p=0.001). In the group B, the most important factors affecting survival were a KPS=> 70 (p=0.001), biological subtype ER/PR+HER2- (p=0.04), systemic therapy (p=0.001) and intrathecal therapy (p=0.001). For group C, older patients (p=0.01) with ER/PR+HER2- breast cancer (p=0.05, HR 0.18) and after systemic intravenous/oral treatment (p=0.02) had higher a probability of survival after 1 year.

Conclusions: Those breast cancer LM patients who were older, having high KPS, with luminal breast cancer and treated with systemic inravenous/oral therapy had a higher probability of survival than the rest of the group. Based on the presented data, the role of intrathecal therapy could not be exactly defined.

Citation Format: Niwinska A, Rudnicka H, Kunkiel M, Jagiello-Gruszfeld A, Nowecki Z. Analysing the factors affecting survival of breast cancer patients with leptomeningeal metastasis [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 P6-16-07.
Abstract PD7-06: SEER study of breast cancer-specific mortality in patients with poorly differentiated tumors treated based on recurrence score results
Authors: Petkov VI , Miller DP , Howlader N , Baehner FL , Penberthy L , Shak S
Published: March 2017

Introduction: The SEER Program of the NCI is an authoritative source of cancer incidence and survival statistics. Linking the 21-gene assay Recurrence Score® (RS) results to the SEER Registries (N=44,825) demonstrated very low 5-year breast cancer-specific mortality (BCSM) with RS <18 across many key clinical-pathological subgroups, such as age, nodal status, tumor grade, and size (npj Breast Cancer. 2016;2:16017). Given the large sample size and specific interest in outcomes as a function of tumor grade, further stratification of patients with poorly differentiated tumors was performed to determine BCSM when examined by both tumor grade and tumor size.

Methods: Patients were eligible if node negative (N0), HR+, HER2-negative (by RT-PCR), had no prior malignancy, had poorly differentiated (G3) tumors, and were diagnosed between Jan 2004 (test available in Jan 2004) and Dec 2011 (SEER survival updated through 2012). BCSM was defined according to pre-existing robust methodology (J Natl Cancer Inst. 2010;102:1584). RS was categorized according to the cutpoints of 18 and 31 established in the NSABP B-14 study. Five-year BCSM was estimated using actuarial methods.

Results: Among 6,666 eligible patients with G3 tumors, 4,683 had tumors ≤2 cm and 1,983 had tumors >2 cm. Median age was 57 years; 99.1% were female. Median follow-up was 39 months. The proportion of patients with RS <18 was 29% among those with tumors ≤2 cm and 25% among those with tumors >2 cm, somewhat lower than the overall population. For RS <18, 5-year BCSM was 0.3% (G3; ≤2 cm) and 1.4% (G3; >2 cm); reported chemotherapy use was 10% and 16%, respectively. 5-year BCSM for all groups are provided in Table. An additional year of BCSM follow-up in N0 G3 disease, as well as results for patients with node positive (micrometastases or 1-3 positive nodes) G3 disease, will be available for presentation.

N0, G3 tumor, RS <18N0, G3 tumor, RS 18-30N0, G3 tumor, RS ≥31Tumor sizeN5-y BCSM (95% CI)N5-y BCSM (95% CI)N5-y BCSM (95% CI)≤2 cm13620.3% (0.1%, 1.2%)21482.1% (1.3%, 3.3%)11732.9% (1.8%, 4.7%)>2 cm4861.4% (0.4%, 4.6%)8514.6% (2.7%, 7.8%)6469.0% (6.0%, 13.4%)

Conclusions: Although patients with poorly differentiated tumors have worse prognosis in general, the RS identifies a sizable proportion of patients who can expect good outcomes without chemotherapy and its associated toxicity.

Citation Format: Petkov VI, Miller DP, Howlader N, Baehner FL, Penberthy L, Shak S. SEER study of breast cancer-specific mortality in patients with poorly differentiated tumors treated based on recurrence score results [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 PD7-06.
Abstract A27: Evaluation of two HPV vaccination educational interventions for Hispanic parents
Authors: Fernandez Maria E. , Savas Lara , Angelica Roncancio , Khan Myrna , Fernandez-Espada Natalie , Rodriguez Serena , Vernon Sally
Published: March 2017

Background:

We examined effectiveness of two lay health worker-delivered educational interventions for parents to increase HPV vaccination among Hispanic girls.

Methods:

Twenty-nine clinics were randomized to standard care or one of two interventions: a print fotonovela or an tailored interactive multimedia intervention (TIMI). Lay health workers delivered the interventions to parents. Data collectors completed follow-up assessments at 6 and 12 months. We assessed vaccine initiation at first follow-up and series completion by end of the study. Data were analyze using hierarchical logistic regression.

Results:

Among all participants recruited at baseline (576= fotonovela intervention group; 389=TIMI intervention group; 433=control group) intent-to-treat analysis indicated significant differences in vaccine initiation between TIMI and control at 6-month follow-up (OR: 1.63, 95% CI: 1.13-2.35, p=0.01), and between fotonovela and control (OR: 1.67, 95% CI: 1.20-2.32, p=0.002). Per protocol analyses (including only parents who completed follow-up surveys or whose daughter's vaccination status was ascertained through medical records) showed significant differences in initiation at 6 month follow-up: between TIMI and control (OR: 1.79, 95% CI: 1.21-2.70, p=0.004) and between fotonovela and control (OR: 1.65, 95% CI: 1.17-2.34, p=0.004). There were no statistically significant differences between TIMI and fotonovela (OR: 1.08 CI: 0.76-1.55, p=0.66).

Conclusion:

Hispanic parents receiving education - either the fotonovela or the TIMI - were more likely to initiate HPV vaccination within 6 months than parents in the comparison group. We will determine education effectiveness on completion of the 3-dose HPV series at 12-month follow-up.

Citation Format: Maria E. Fernandez, Lara Savas, Roncancio Angelica, Myrna Khan, Natalie Fernandez-Espada, Serena Rodriguez, Sally Vernon. Evaluation of two HPV vaccination educational interventions for Hispanic parents. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr A27.