bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany
Authors: De Laurentiis Michelino , Harbeck Nadia , Law Ernest , Ajmera Mayank , Mitra Debanjali , Davis Keith , Brucker Sara , De Placido Sabino 
Published: March 2020

Abstract
Background: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that, when combined with an aromatase inhibitor (AI) or fulvestrant, has been shown in clinical trials to prolong progression-free survival (PFS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/MBC). This study sought to describe real-world treatment patterns and clinical outcomes among patients with HR+/HER2- ABC/MBC treated with palbociclib in clinical practice settings in Italy and Germany. Methods: MARIA is an ongoing non-interventional, prospective multi-center study that includes women in Italy and Germany initiating their first or second therapy in the HR+/HER2- ABC/mBC setting. Data from 67 sites were used to assess patient and treatment characteristics and progression-free survival (PFS) among patients receiving palbociclib in combination with AI or fulvestrant. Landmark PFS estimates at 6-, 12-, and 18-months were reported by line of therapy (first- and second-line). Results: Overall, 72 patients formed the interim analytic cohort. Among these, 63 (47%) and 9 (7%) received palbociclib + AI as first- and second-line therapy, respectively. Twenty-six (20%) and 37 (27%) of patients received palbociclib + fulvestrant as first- and second-line therapy, respectively. Approximately 96%, 78%, and 64% of patients receiving palbociclib + AI as first-line therapy were progression free at 6-, 12-, and 18-months, respectively. Among patients receiving palbociclib + fulvestrant as first-line therapy, 6-, 12-, and 18-month PFS was 91%, 64%, and 39%, respectively. For second-line therapy, 6-, 12-, and 18-month PFS was 75%, 38%, 38% among palbociclib + AI users and 71%, 54%, and 45% for palbociclib + fulvestrant. Conclusions: This interim analysis indicates that PFS among women with ABC/mBC HR+/HER2-negative breast cancer in Italy and Germany receiving palbociclib, in combination with letrozole or fulvestrant is comparable to published randomized clinical trial results and other real-world observational studies. Further follow-up is required for longitudinal analysis and to estimate overall survival. Funding: Pfizer
Citation Format: Michelino De Laurentiis, Nadia Harbeck, Ernest Law, Mayank Ajmera, Debanjali Mitra, Keith Davis, Sara Brucker, Sabino De Placido. Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany [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 P3-11-25.
Abstract P4-01-06: Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations
Authors: Dubash Taronish Dorab , Bardia Aditya , Reeves Brittany A , Chirn Brian , Szabolcs Annamaria , Wittner Ben S , Iafrate John , Ting David , Patel Hitisha K , Bihani Teeru , Toner Mehmet , Haber Daniel A , Maheswaran Shyamala 
Published: March 2020

Abstract
Women with metastatic hormone receptor positive (HR+) breast cancer benefit from therapies targeting the Estrogen Receptor (ER), but the tumors eventually acquire resistance leading to disease progression. Endocrine resistance involves multiple mechanisms, including deregulation of ER signaling due to activating mutations in the ligand-binding domain of the ESR1 gene. In addition, recent reports describe specific contexts of ESR1 mutations in the preclinical setting where tamoxifen and fulvestrant have demonstrated limited activity. These data together with the frequency of ESR1 mutations (~20-60%) observed in mBC patients in the clinic suggest a need for more effective agents. The activity of elacestrant (RAD1901), an oral selective estrogen receptor degrader (SERD) with demonstrated activity against tumors harboring ESR1 mutations, both in preclinical models and in patients with previously treated advanced breast cancer, was assessed in ex vivo cultures of circulating tumor cells (CTCs) derived from women with metastatic HR+ breast cancer who had received multiple prior hormone therapies. Cultured breast CTCs underwent apoptosis following exposure to elacestrant, and CTCs harboring mutant ESR1 were significantly growth inhibited (IC50: 17.65 ± 3.32 nM) by elacestrant compared to the standard-of-care (SOC) agent fulvestrant. Furthermore, elacestrant eliminated the fulvestrant-resistant CTC populations in vitro. Elacestrant treatment led to significant suppression of ER target genes, PGR and GREB1. Elacestrant is currently being investigated versus standard of care endocrine monotherapy in a Phase 3 clinical trial (EMERALD) in patients with ER+/HER2- advanced/metastatic breast cancer. A co-primary endpoint of the EMERALD trial is evaluation of progression-free survival in patients whose tumors harbor ESR1 mutations.
Citation Format: Taronish Dorab Dubash, Aditya Bardia, Brittany A Reeves, Brian Chirn, Annamaria Szabolcs, Ben S Wittner, John Iafrate, David Ting, Hitisha K Patel, Teeru Bihani, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran. Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations [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 P4-01-06.
Abstract P4-01-15: CTC with EMT phenotype are associated with PD-L1 expression in tumor associated stroma in primary breast cancer patients
Authors: Mego Michal , Kalavska Katarina , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Manasova Denisa , Pindak Daniel , Mardiak Jozef , Cierna Zuzana 
Published: March 2020

Abstract
Background: Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. PD-L1 is prognostic factor in BC and PD-L1 inhibitors prolonged survival in metastatic triple-negative breast cancer. The aim of this study was to assess correlation between CTCs and tumor PD-L1 in BC. Methods: This study included 299 primary BC patients treated by surgery from March 2012 to February 2015. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSepTM negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n=60) were considered as CTC positive. Expression of PD-L1 in surgical specimens was evaluated by immunohistochemistry and quantified by multiplicative score (proportion of cells with staining x intensity of staining). Results: CTCs were detected in 75 (25.1%) of patients. CTCs exhibiting only epithelial markers were present in 28 (9.4%) of patients, whereas CTCs with only EMT markers were observed in 53 (17.7%) of patients. In 6 patients, CTCs exhibit both epithelial and EMT markers. Patients with EMT_CTCs had significantly higher mean ± SEM score of PD-L1 expression in tumor associated stroma than those of patients without EMT_CTCs (2.66 ± 0.62 vs. 0.88 ± 0.29, p=0.048). There was no association between CTCs and PD-L1 expression in cancer cells including CTCs subtypes. Tumors without PD-L1 expression had significantly better disease-free survival compared to patients with PD-L1 expression (HR = 0.50, 95%CI 0.29 - 0.86, P = 0.001), however, this prognostic value was restricted to CTC positive subpopulation (HR = 0.24, 95%CI 0.10 - 0.56, P = 0.002), while, in CTC negative patients PD-L1 lack prognostic value (HR = 0.77, 95%CI 0.39 - 1.54, P = 0.45) Conclusion: Our data suggest link between PD-L1 expression in tumor associated stroma and CTCs with EMT phenotype and thus further support connection between immunosuppression and EMT. PD-L1 expression is prognostic only in patients with detectable CTC in peripheral blood suggesting different biology of tumors with detectable CTCs.
Citation Format: Michal Mego, Katarina Kalavska, Marian Karaba, Gabriel Minarik, Juraj Benca, Tatiana Sedlackova, Denisa Manasova, Daniel Pindak, Jozef Mardiak, Zuzana Cierna. CTC with EMT phenotype are associated with PD-L1 expression in tumor associated stroma in primary 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 P4-01-15.
Abstract P4-04-02: Epigenomic analysis of cancer stem cells (CSCs) from triple-negative breast cancer (TNBC) reveals p63 and p73 as core metastasis drivers
Authors: Lambert Arthur , Fiore Christopher , Chutake Yogesh , Verhaar Elisha , Chen Mei Wei , Donaher Joana , Reinhardt Ferenc , Engstrom Ian , Yuan Bingbing , Bierie Brian , Farouq Daneyal , Carulli John , Olson Eric , Guenther Matthew , Weinberg Robert 
Published: March 2020

Abstract
Cancer stem cells (CSCs) are key drivers of cancer metastasis, drug resistance, and disease recurrence. While the transcriptional regulatory circuitry that underlies the generation and propagation of the breast CSC state is not completely understood, defining the core regulators of the CSC state has the potential to reveal how these cells arise and point to potential targetable pathways for therapeutic intervention.
We isolated CSCs by selecting for surface expression of integrin β4 (ITGB4). ITGB4-hi cells are highly enriched for CSCs and display cellular and molecular features indicative of their residence in an intermediate EMT state, including the ability to seed metastasis in vivo. Using ITGB4-hi CSCs isolated from the SUM159 breast cancer cell line, we deployed epigenome mapping by H3K27ac ChIP-seq, nucleosome occupancy by ATAC-seq, and transcriptome analysis by RNA-seq. Using comparative analysis of enhancer usage and DNA accessibility, we identified the transcriptional regulatory circuitry of breast cancer CSCs and pinpointed the master transcription factors that control the CSC state.
We find that p63/p73 proteins function as master transcriptional regulators in breast CSCs and establish super-enhancers at critical CSC state genes. Loss of p63 and p73 disrupts the transcriptional circuitry of CSCs and leads to a highly mesenchymal state that is incompatible with metastatic colonization. Re-introduction of p63/p73 expression into non-CSCs leads to reactivation of the CSC transcriptional program and enables metastasis. These findings reveal the unique transcriptional circuitry of CSCs and suggest potential dependencies and pathways for therapeutic targeting of cells in the CSC state.
Citation Format: Arthur Lambert, Christopher Fiore, Yogesh Chutake, Elisha Verhaar, Mei Wei Chen, Joana Donaher, Ferenc Reinhardt, Ian Engstrom, Bingbing Yuan, Brian Bierie, Daneyal Farouq, John Carulli, Eric Olson, Matthew Guenther, Robert Weinberg. Epigenomic analysis of cancer stem cells (CSCs) from triple-negative breast cancer (TNBC) reveals p63 and p73 as core metastasis drivers [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 P4-04-02.
Abstract P4-05-17: ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer
Authors: Lin Chun-Lin 
Published: March 2020

Abstract
Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Although studies have proposed models to explain its initiation, few discussed how transcription factors (TFs) influence chromothripsis for tumor progression. Frequent long-range chromatin interactions between TFs and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Herein we surveyed genomic alterations of chromosome 17 in 1,014 breast tumors in the Cancer Genome Atlas (TCGA) cohort and found five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the rearrangement sites were often mapped within or close to dense estrogen receptor 1 (ESR1) sites localized on the regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ESR1 transcription hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. Collectively, we identified a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.
Citation Format: Chun-Lin Lin. ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal 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 P4-05-17.
Abstract P4-13-05: The oncological safety of autologous fat grafting after breast conserving surgery for breast cancer: A systematic review, meta- analysis and meta regression analysis of observational studies
Authors: Tayeh Salim , Carmichael Amtul R , Darr Humaa , Al-Fardan Zuhair , Kasem Abdul , Hamdi Moustapha , Mokbel Kefah 
Published: March 2020

Abstract
Background: Autologous fat grafting (AFG) has been widely adopted to correct deformities resulting from breast conserving surgery (BCS) for breast cancer. However, clinical and animal studies and in vitro experiments have revealed conflicting results regarding the oncological safety of AFG.
Aim: The aim of this study was to systematically evaluate the current literature regarding the oncological safety of AFG in patients who underwent BCS for breast cancer by performing a meta-analysis of observational studies.
Methods: A literature research was performed using the PubMed and Embase search engines from conception until May 2019 to identify all studies of patients who underwent AFG following BCS for breast cancer. Reference lists of retrieved articles and relevant previous reviews were also searched. The primary outcome was the locoregional recurrence rate. For case-control studies a standard meta-analysis was performed to calculate a pooled relative risk (RR). For case series studies, subgroup analysis and meta-regression techniques were used with historical control data to increase reliability.
Results: 26 studies reporting on 1640 BCS patients who had undergone AFG met the inclusion criteria for analysis. There were 11 case-control studies and 15 case series. For the case-controlled studies, meta-analysis using the random effects model revealed no significant difference in the locoregional recurrence rates between the AFG and control groups [RR=0.82(95% CI= 0.41-1.66)]. The mean follow up duration from surgery for the AFG group and the control group was 39 and 49 months, respectively. For the case series and historical controls, the locoregional recurrence rates were 1.85% and 2.53% respectively (p=0.33) according to subgroup and meta regression analysis. There was no strong evidence of publication bias however selection bias could not be excluded.
Conclusions: Our study suggests that AFG does not increase the risk of locoregional recurrence after BCS for breast cancer. However further prospective research is needed to confirm the oncological safety of this technique particularly in patients with high risk disease.
Citation Format: Salim Tayeh, Amtul R Carmichael, Humaa Darr, Zuhair Al-Fardan, Abdul Kasem, Moustapha Hamdi, Kefah Mokbel. The oncological safety of autologous fat grafting after breast conserving surgery for breast cancer: A systematic review, meta- analysis and meta regression analysis of observational studies [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 P4-13-05.
Abstract P5-05-05: Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
Authors: Katzenellenbogen Benita S. , Ziegler Yvonne , Laws Mary J , Guillen Valeria S. , Kim SungHoon , Dey Parama , Smith Brandi P. , Gong Ping , Bindman Noah , Zhao Yuechao , Carlson Kathryn , Yasuda Mayuri A. , Singh Divya , Li Zhong , El-Ashry Dorraya , Madak-Erdogan Zeynep , Katzenellenbogen John A. 
Published: March 2020

Abstract
The transcription factor FOXM1 is up-regulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome-dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.
(Supported by Breast Cancer Research Foundation grant (BCRF-083 to BSK), The Julius and Mary Landfield Cancer Research Fund (to BSK), NIH grant R01 DK015556 (to JAK), NIH T32 GM070421 Fellowship (to VSG), Bankhead-Coley Foundation grant 09BW04 (to DEA), USDA award ILLU-698-909 and National Center for Supercomputing Applications Faculty Fellowship (to ZME), and UIUC Environmental Toxicology Scholarship (to BPS)).
Citation Format: Benita S. Katzenellenbogen, Yvonne Ziegler, Mary J Laws, Valeria S. Guillen, SungHoon Kim, Parama Dey, Brandi P. Smith, Ping Gong, Noah Bindman, Yuechao Zhao, Kathryn Carlson, Mayuri A. Yasuda, Divya Singh, Zhong Li, Dorraya El-Ashry, Zeynep Madak-Erdogan, John A. Katzenellenbogen. Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds [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 P5-05-05.
Abstract P5-05-15: Activation of osteocytes connexin43 hemichannels suppresses breast cancer bone metastasis, a potential therapeutic target
Authors: Riquelme Manuel A. , Gu Sumin , Chavez Jeffery B. , An Zhiqiang , Jiang Jean X. 
Published: March 2020

Abstract
Bone is a fertile place for metastasized breast cancer cell (BCC), however, mechanical loading is reported to inhibit BCC growth. Osteocytes, representing over 95% of bone cells, are mechanosensitive; they coordinate bone remodeling and modulate the extracellular environment. Mechanical loading activates osteocityc connexin 43 (Cx43) hemichannels, which mediates communication between the intracellular and extracellular space with message of molecules below 1 kDa. We have shown that ATP released by osteocytic hemichannels through the activation of BCC P2X7 receptor, inhibits BCC growth and migration. Here, we evaluate if activation of Cx43 hemichannels in osteocytes plays a critical role in inhibiting breast cancer bone metastasis. Our lab develops a monoclonal antibody, MHC2, which binds to extracellular domain of Cx43 and increases the activity of osteocytic hemichannels. This antibody was immune-reactive in HeLa cells transfected with Cx43 and osteocytes cell line MLO-Y4. It also labeled mouse osteocytes in situ. MHC2 antibody enhanced the activity of Cx43 hemichannels in cells and in vivo osteocytes and promoted the ATP release from osteocytic MLO-Y4 cells. Moreover, conditioned media collected from MHC2-treated osteocytes reduced BCC migration in vitro. The weekly injection of MHC2 reduced the breast cancer growth in bone in WT mice, but not in specific osteocyte Cx43 knockout mice. MHC2 antibody increase levels of lymphocytes T cytotoxic (CD3+/CD8+) and helper (CD3+/CD4+) in tumor and draining lymph nodes. Moreover, the weekly injection of MHC2, in intracardiac injected tumor cells model, in both immunocompetent and immune-compromised mice increased survival rate and reduced tumor spreading. As is known, osteocytic Cx43 hemichannels are permeable to ATP. We showed that P2X7 specific agonist benzoyl ATP reduced in vitro breast cancer cell migration, increased cytoplasmic free Ca2+ and induced formation of tubulin bundles, an indicator of cytoskeleton reorganization. The effect of benzoyl ATP required activation of CamKII in breast cancer cells. Our results suggest that Cx43 hemichannels are likely a potential therapeutic target in treating breast cancer growth and metastasizing to the bone, probably through the enhancement of the extracellular ATP level and the activation of P2X7/CamKII axis.
Citation Format: Manuel A. Riquelme, Sumin Gu, Jeffery B. Chavez, Zhiqiang An, Jean X. Jiang. Activation of osteocytes connexin43 hemichannels suppresses breast cancer bone metastasis, a potential therapeutic target [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 P5-05-15.