bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-06-16: Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers
Authors: Park Jun Hyoung , Jung Kwang Hwa , Jia Dongya , Kaipparettu Benny A 
Published: March 2020

Abstract
Triple negative breast cancer (TNBC) is one of non-targetable cancers which are still poorly understood for the driver pathways and therapeutic targets. Over the past decade, cancer metabolism researches have a huge advance. Thus, it has enhanced our understanding on metabolic reprogramming in cancer therapy. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a key energy metabolic pathway in TNBC. Moreover, we reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC via autophosphorylation of Src at Y419. However, single treatment by FAO inhibitor alone cannot effectively control the tumor progression in TNBC because of metabolic reprogramming and flexibility of tumors. Therefore, proper combination therapies with other metabolic targets are necessary.
Recently increasing studies demonstrate that anti-diabetic biguanides have attractive anti-cancer effect in various cancer types including breast cancer (BC). However, its significance as an anti-cancer drug is not well established due to parallel metabolic pathways that support tumor growth. Biguanide like metformin is the most widely administered anti-diabetic agent worldwide. Phenformin, a biguanide derivative similar to metformin, has a greater potency than metformin. Like metformin, phenformin also inhibits mitochondrial electron transport chain (ETC) through complex I inhibition. In addition, biguanides lead to the activation of AMPK, which plays a important role in insulin signaling and energy sensing. Importantly, AMPK is an upstream regulator of FAO pathway because it can phosphorylate ACC to activate FAO. Considering the dependency of TNBC to FAO, we evaluated the therapeutic significance of the combination of biguanides (ETC inhibitors) and FAO inhibitors in TNBC progression and metastasis. And we investigated that targeting both ‘arms’ of the pathway can provide more effective and durable responses in TNBC treatments. Our various in vitro and in vivo studies using TNBC cell lines and PDX models suggest that the combination of both inhibitors can provide better therapeutic benefits in TNBCs. This is a rationale and cost-effective metabolic approach to overcome the currently non-targetable TNBCs. Further study toward the clinical effectiveness of this combination may offer better treatment opportunities for TNBC patients.
Citation Format: Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Benny A Kaipparettu. Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-16.
Abstract P3-08-51: Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis
Authors: Liu Miao , Wang Shu 
Published: March 2020

Abstract
Background: BRCA mutated breast cancer is associated with an aggressive phenotype with marked differences in histological grade and distant metastases and sensitive to PARPi and platinum therapy. Studies evaluating role of BRCA mutations on the survival outcomes in breast cancer (BC) patients have given confounding results due to the differences in clinical and pathological status among study population. Therefore, we assessed the impact of BRCA mutations on survival of BC patients, based on their baseline characteristics and follow-up durations. Methods: Using PICO framework, articles comparing survival outcomes of BC patients having BRCA mutations against sporadic BRCA phenotype were retrieved from PubMed, EMBASE and Cochrane Library. Overall survival (OS) was the primary outcome, with disease free survival (DFS), distant metastasis free survival (DMFS) and breast cancer specific survival (BCCS) as the secondary outcomes. Hazard ratio (HR) with 95% confidence interval (CI) was used for analysis. Sub-group analysis was performed for survival based on age, tumor stage, estrogen receptor status, triple negative breast cancer (TNBC) status, tumor stage (Stage I-III vs I-IV) and follow-up durations. Results: Altogether, 30 articles with 35,972 patients (mean age 45.6 years) were included in the analysis. In BRCA1/2+ group, no significant difference in OS and DFS than BRCA- group were observed (HR: 0.98, 1.36, respectively),have a better DMFS in BRCA- patients than that in BRCA1/2+ patients (HR: 1.32; 95% CI: 0.71, 2.44). However, the difference observed between the groups was insignificant (P = 0.3825). BRCA1+ patients had significantly lower OS (HR [95%CI]: 1.2 [1.08, 1.33]; P&lt;0.001),poor BCSS at 10 years follow-up. DMFS was significantly poor in BRCA1+ patients compared with BRCA- patients both at 5 years follow-up (HR [95%CI]: 1.07 [1.04, 1.10]; P&lt;0.0001) and 10 years follow-up (HR [95%CI]: 1.21 [1.13, 1.29]; P&lt;0.0001).BRCA2+ patients had significantly lower DFS (HR [95%CI]: 1.35 [1.1, 1.67]; P = 0.0049) and BCSS (HR [95%CI]: 1.46 [1.26, 1.7]; P&lt;0.0001) than BRCA2- patients. Among TNBC patients, OS was non-significantly better in BRCA1/2+ patients (HR 0.96, P = 0.803) than in BRCA- patients. However, DFS was significantly poor in BRCA1+ TNBC patients than BRCA1-/TNBC patients (HR [95% CI]:1.65 [1.08, 2.54]; P = 0.0216).Conclusion: BRCA1/2 mutation is associated with poor prognosis in patient with breast cancer. Hence, BRCA testing might help assess patient prognosis and treatment such as PARPi and platinum.
Citation Format: Miao Liu, Shu Wang. Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-51.
Abstract P3-08-58: Ratio of CD8 +/ FOXP3, number of FOXP3 + cells and the presence of PTEN labeling in tumor cells and association with survival in triple negative breast cancer
Authors: Tavares Monique C , Lima Geraldine E , Sampaio Cristina D , Andrande Victor P , Gonçalves Daniel G , Macedo Mariana P , Lima Vladmir C 
Published: March 2020

Abstract
Introduction: Triple-negative mammary carcinomas (CMTN) correspond to about 15 to 20%, the subtype being more aggressive when compared to the others. The interaction between immune system cells and cancer plays a crucial role in tumor development and progression. However, it is still unclear whether the presence of CD8 cytotoxic lymphocytes provides any prognostic information in breast cancer. Objective: To evaluate the prognostic significance of tumor-associated FOXP3 regulatory T cells (Tregs) and CD8 cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas Method: This is an observational, descriptive retrospective cohort study were evaluated 76 patients diagnosed with non metastatic (stages I, II and III) TNBC. A tissue microarray (TMA) was constructed containing two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phosphoSTAT1 was determined by immunohistochemistry in the TMA. Results: We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+ and FOXP3+). In our sample, we observed better survival associated with a higher CD8 + (p = 0.054) and CD4 + (p = 0.082) cell counts, but with no statistical significance in both situations. However, when we analyzed the association of overal survival (OS) with the ratio between the number of CD8 + cells and FOXP3 + (p = 0.007) and CD4 + and FOXP3 + (p = 0.034) and CD4 (p = 0.058) cells, we found that a higher relative proportion of CD8 + or CD4 + lymphocytes in relation to lymphocytes FOXP3 + was associated with an increase in OS. Together, these data suggest that infiltration by T lymphocytes into the tumor microenvironment should exhibit antirumor activity and promote growth control and tumor progression, as opposed to events favoring immunosuppression (regulatory lymphocyte infiltration). The number of FOXP3+ cells and the presence of PTEN staining in tumor cells were associated with OS. Conclusion: We did not observe improvement in survival, with an increase in CD8 and CD4 alone, so we found an improvement in survival, the higher the ratio between CD8 / FOXP3 being statistically significant. The number of FOXP3+ cells and the presence of PTEN staining in tumor cells were associated with OS.
Citation Format: Monique C Tavares, Geraldine E Lima, Cristina D Sampaio, Victor P Andrande, Daniel G Gonçalves, Mariana P Macedo, Vladmir C Lima. Ratio of CD8 +/ FOXP3, number of FOXP3 + cells and the presence of PTEN labeling in tumor cells and association with survival in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-58.
Abstract P3-08-59: High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive breast cancer patients
Authors: Tokumaru Yoshihisa , Oshi Masanori , Asaoka Mariko , Takeshita Takashi , Katsuta Eriko , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki 
Published: March 2020

Abstract
Background: MicroRNA-143(miR-143) is known to function as the tumor suppressor in various cancers, including breast cancer. The tumor immune microenvironment such as the balance between the T helper cell type 1 (Th1) and Th2 is reported to associate with the survival of the breast cancer patients. In this study, we hypothesized that the miR-143 has favorable effect to the tumor immune microenvironment.
Material and Methods: We obtained the clinicopathological data and survival information of 755 breast cancer patients from The Cancer Genome Atlas (TCGA) database. Survival analysis, Overall survival (OS) and Disease free survival (DFS) was conducted comparing the high and low expression groups. CYT score, CIBERSORT, and other immunological factors were used to evaluate intratumoral immune cell composition within estrogen receptor (ER) positive breast cancer patients. Also, gene set enrichment analysis (GSEA) was performed between miR-143 high and low expression groups within the ER positive group.
Results: High expression of miR-143 was significantly associated with prolonged OS only in ER positive breast cancer patients (p=0.014). Expression of miR-143 was not associated with DFS, stage, TNM factors of breast cancer patients. Within ER positive patients, the result of CIBERSORT revealed that high expression of miR-143 was associated with higher percentage of macrophage M1 (p&lt;0.03) and lower percentage of macrophage M2 (p&lt;0.001). There was more Th1 cells in miR-143 high group (p&lt;0.001) whereas Th2 cells were less (p&lt;0.001). This result was strikingly echoed by GSEA, where miR-143 high significantly enriched the genes related to Th1 cells compared with that of Th2 cells. Regulatory T cell, Lymphocyte infiltration signature score, and T cell receptor diversity were higher in the patients with high miR-143 expression (p&lt;0.03, p&lt;0.001, and p&lt;0.001 respectively). CYT score that reflect cytolytic activity was higher in the high miR-143 expression group (p&lt;0.04).
Conclusion: High expression of miR-143 was associated with improved OS in ER positive breast cancer patients. Also, miR-143 was found to associate with high Th1 and low Th2 cells as well as enriching the genes relating to Th1 cells, which may explain the favorable role of miR-143 in ER positive breast cancer.
Citation Format: Yoshihisa Tokumaru, Masanori Oshi, Mariko Asaoka, Takashi Takeshita, Eriko Katsuta, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe. High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-59.
Abstract P3-08-72: Poor prognosis in elderly patients with breast cancer resulted from under-treatment in patients with triple negative breast cancer and mortality from other than breast cancer
Authors: Moon Gilseong , Ko Ji wool , Noh Hany , Cho In-Jeong , Lee Jong-in , Han Airi 
Published: March 2020

Abstract
Background: Breast cancer is the leading cause of malignant disease in Korean women nest to thyroid cancer. Age is one of the significant risk factor and Korean population is aging rapidly, almost 1.5 times older than a half century ago, from 52.4 years in 1960 to 78.5years at 2005. While it is uncertain the proportional incidence is also increasing, absolute number of elderly patients is increasing and unmet clinical needs and unanswered questions are remained in the clinical practice for elderly patients. The aim of this study is to outline breast cancer in elderly patients and examine survivals by clinicopathologic factors such as age, stage and disease subtype.
Material and Methods: Patients who were diagnosed and completed their primary treatment for breast cancer from 2000 to 2013 were included. Clinicopathologic data was collected with retrospective data review and survival data and risk factors, if the survival was statistically significant, were obtained.
Results: 1103 patients with invasive breast cancer were included. Mean age was 52.71±11.478(22-89). Subjects were divided into three group, &lt;40 (n=147, 35.9±3.704), 40-60 (n=680,49±5.131), &gt;60(n=276,68.6±5.62). Patients over 60 had statistically worse overall survival(p=0.011) and distant disease free survival(p=0.012) with Kaplan-Meier method with log rank test and hazard ratio(HR) of elderly was 2.206 with 1.046-4.658 96% Confidence Interval(CI). For the worse prognosis of elderly, triple negative breast cancer who got less than standard systemic treatment (HR=4.836, 95% CI, 1.514-15.452) and mortality from other than breast(HR=2.395, 95% CI,1.106-5.188) cancer were significantly correlated with higher mortality in elderly patients.
Conclusion: Elderly patients with breast cancer experience significant worse survival when they got less than standard systemic treatment or second primary disease other than breast cancer in their follow up period.
Citation Format: Gilseong Moon, Ji wool Ko, Hany Noh, In-Jeong Cho, Jong-in Lee, Airi Han. Poor prognosis in elderly patients with breast cancer resulted from under-treatment in patients with triple negative breast cancer and mortality from other than breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-72.
Abstract P3-10-13: Rac inhibition as an alternative approach to treating hormone dependent breast cancer
Authors: Goka Erik T , Sun Jun , Lopez Dayrelis T Mesa , Lippman Marc E 
Published: March 2020

Abstract
Hormone positive breast cancer remains one of the leading causes of cancer mortality in women. Despite the advancement in endocrine therapy and the addition of cyclin dependent kinase (CDK) 4/6 inhibitors, patients eventually become refractory to treatment creating a desperate need for the development of alternative therapies. Previously, we discovered HACE1, the E3 ubiquitin ligase that targets the small GTPase Rac1 for proteasomal mediated degradation. HACE1 is commonly lost in estrogen receptor (ER) positive and HER2 positive breast cancers and results in the hyperactivation of the Rac signaling pathway. Here, we show that Rac1 resides in the estrogen receptor transcriptional complex and acts as a critical estrogen receptor transcriptional co-activator. The dependency of Rac on ER transcription is further exemplified by the treating ER+ breast cancer cells with a Rac inhibitor where transcriptional profiling identified ER target genes were preferentially down-regulated. Thus, we confirm the dependency of Rac1 in ER+ breast cancers and show that Rac1 is necessary for estrogen receptor transcriptional activity. Importantly, we show that a novel Rac1 inhibitor is capable of reducing estrogen receptor transcriptional activity as well as impairing cellular proliferation and migration. Moreover, Rac inhibition is shown to enhance the anti-tumor effects of fulvestrant both in vitro and in vivo, including in a patient-derived-xenograft (PDX) model of ER+ disease. Lastly, we demonstrate that the administration of a novel Rac inhibitor is well-tolerated after chronic dosing in both small and large animal species. Together these data suggest a new potential pathway for treating hormone dependent breast cancer.
Citation Format: Erik T Goka, Jun Sun, Dayrelis T Mesa Lopez, Marc E Lippman. Rac inhibition as an alternative approach to treating hormone dependent breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-13.
Abstract P3-11-21: Identification and characterization of novel splice variants in triple-negative breast cancer
Authors: Arun Gayatri , Dhingra Priyanka , Munch Robin , Fredrick Vanessa , Akerman Martin 
Published: March 2020

Abstract
Splicing deregulation is a major hallmark of cancer, affecting progression, metastasis and therapy resistance. Multiple studies have demonstrated the oncogenic activity of specific splicing events and splicing factors, including SRSF1, SRSF2, ESRP1, and RBFOX1, in human and animal models. As such, cancer-associated splicing deregulation may be a novel source of clinically-applicable biomarkers and therapeutic targets, particularly for treatment-insensitive cancers such as TNBC. Here, we identified and experimentally characterized novel splicing changes in triple negative breast cancer by analyzing TCGA breast cancer RNA-seq data using our software platform SpliceCore. SpliceCore integrates machine learning (ML) algorithms with high-performance computing to analyze large RNA-Seq datasets to predict biologically relevant splicing events. Our analysis of TCGA BRCA datasets has revealed several previously unknown splicing events specific to TNBC patient cohorts, that is subsequently experimentally validated in TNBC cell lines. We provide biological evidence for such TNBC specific splice-switch both at the RNA and protein level. We provide evidence for SpliceCore predicted splice-switching oligonucleotides (SSO) and verify their biological activity in TNBC cell lines. Further, functional studies using potent and specific SSOs against the top candidates reveal a critical role for some of these novel isoforms in TNBC. Together, we provide a proof of concept study using SpliceCore to identify, design, and target novel splicing changes for subsequent clinical translation and therapeutic development.
Citation Format: Gayatri Arun, Priyanka Dhingra, Robin Munch, Vanessa Fredrick, Martin Akerman. Identification and characterization of novel splice variants in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-21.
Abstract P4-01-09: Phenotypic profiling of circulating tumor cells (CTCs) in patients with metastatic breast cancer reveals clinically-relevant heterogeneity in CTC morphology and marker expression
Authors: Pramparo Tiziano , Jendrisak Adam , Ontiveros Priscilla , Kearney Megan , Chu Lincy , Ebrahim Nadia , Schonhoft Joseph , Wenstrup Rick , Wang Yipeng 
Published: March 2020

Abstract
Background: The choice between hormonal therapies and chemotherapy is a frequent decision in the standard of care of metastatic breast cancer (mBCa) patients. We previously developed quantitative measures of phenotypic CTC heterogeneity in metastatic prostate cancer and found that higher heterogeneity was associated with better survival on chemotherapy vs. targeted hormonal therapies in a risk adjusted analysis (Scher et al. 2017 Cancer Research). Here we sought to test the feasibility of measuring CTC heterogeneity in mBCa patients.
Methods: 295 blood samples from 165 pts (84 HR+, 19 Her2+, 8 HR+/Her2+, 54 TNBC) from mBCa patients were processed for CTC analysis utilizing the Epic Sciences Functional Cell Profiling platform. Following enumeration, multi-dimensional phenotypic characterization analysis was performed utilizing protein expression and digital pathology features. Features from each CTC (3994 CTCs from 165 pts, were compared by unsupervised clustering to assess intra-patient CTC heterogeneity among mBCa CTC phenotypes.
Results: CTCs were detected in 76.9% (227/295) of mBCa patients (med=2.4 CTC/mL, Range 0 - 747). Phenotypic profiling identified distinct CTC subtypes characterized by morphological and protein expression features that correlated with mBCa subtypes. Prevalent CTC features that associated with mBCa were either high cytokeratin (CK) expression or lower nuclear to cytoplasmic (N/C) ratio with lower CK expression. Analysis of mBCa subtypes showed that TNBC pts were characterized by CTCs with a large nuclear area and high CK expression. We observed marked differences in CTC heterogeneity across patients, with some patients having more uniform CTC profiles, and others having higher phenotypic diversity. mBCa subtypes had similar intra-patient heterogeneity level.
Conclusions: Distinct CTC phenotypes can be visualized and quantified across patients and associated with specific mBCa subtypes. Our analysis revealed significant heterogeneity between individual CTCs both between and within patients. Identification of patients with high heterogeneity may help to identify patients unlikely to respond to targeted therapies. Studies to link heterogeneity to efficacy of specific therapies and patient outcome are ongoing.
Citation Format: Tiziano Pramparo, Adam Jendrisak, Priscilla Ontiveros, Megan Kearney, Lincy Chu, Nadia Ebrahim, Joseph Schonhoft, Rick Wenstrup, Yipeng Wang. Phenotypic profiling of circulating tumor cells (CTCs) in patients with metastatic breast cancer reveals clinically-relevant heterogeneity in CTC morphology and marker expression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-09.