bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
Authors: Abraham J , Vallier A-L , Qian W , Machin A , Grybowicz L , Thomas S , Weiss M , Harvey C , McAdam K , Hughes-Davies L , Roberts A , Roylance R , Copson E , Pinilla K , Armstrong A , Provenzano E , Tischkowitz M , McMurty E , Earl H 
Published: May 2019

Abstract
Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)).
Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy.
Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites.
Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-03.
Abstract P1-02-06: Breast cancer screening in the Republic of Belarus: Advantages and learning perspective
Authors: Trusova O , Osharin V , Smelov V , Wilkinson L , Given-Wilson R 
Published: May 2019

Abstract
Background:
Breast cancer (BC) is the most common cancer among women in the Republic of Belarus. To reduce BC-related mortality, the implementation of organized pilot BC screening programmes using digital mammography has been supported by the European Union as part of the BELMED project. During recent years Belarus has developed its own digital mammographs and software that allows storing and processing images in the DICOM format. To assure digital mammographic performance in the local context, the first external clinical image quality assessment (QA) of Belarus mammograms was performed by a leading UK radiologist.
Methods:
The reviewed mammograms from 88 (out of 2,267) Belarus women (mean age: 59.5 years; SD:5.7) attending the a breast screening pilot in Minsk were examined as 81 with positive and 7 with negative findings, according to Belarus readers. This included all 10 histologically confirmed BCs. Within the framework of BELMED project, a total of 400 mammographic images were selected for evaluation by a leading expert radiologist from the UK Public Health England Breast Screening Programme. Evaluated mammographic images were classified according to the Belarus (non-BIRADS) and BIRADS (the UK radiologist) categories, associtated with a follow-up plan. Gradings were compared across categories (the Cohen's Kappa) and according to the proportion of cases referred for further tests (the Wilcoxon signed rank test).
Results:
The reviewer concluded that approximately 50% of the positive mammograms didn't require futher assessment in screening according to the UK radiologist. All histologically confirmed BCs were not among those downgraded. Substantial agreement was found in the gradings for BC (Kappa: 0.66, p&lt;0.001). The study has resulted in adopting the BIRADS classification in the country and launching additional training of radiologists (e.d. in biopsy) and radiographers (in positioning).
Conclusions:
To minimize additional tests on women, comprehensive QA (audit and regular check of mammographic technique, the opinion of physicists, etc.) is essential. Applying the implementation research may result in further improvement of the national BC programme. Improved practice can be promoted by continous image review and training for individual staff (i.e., through BELMED, in collaboration with UK training centres) to further improve the skills of Belarus specialists and increase the quality of BC screening programme in Belarus.
Citation Format: Trusova O, Osharin V, Smelov V, Wilkinson L, Given-Wilson R. Breast cancer screening in the Republic of Belarus: Advantages and learning perspective [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-02-06.
Abstract P1-02-08: Withdrawn
Authors: Ellsworth Beaumont C , Nwankwo E 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Ellsworth Beaumont C, Nwankwo E. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-02-08.
Abstract P1-04-01: Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators
Authors: Ramasamy K , Samayoa C , Krishnegowda NK , Thurlapati A , Vadlamudi RK , Tekmal RR 
Published: May 2019

Abstract
Breast Cancer is the main cause of cancer-associated mortality in women worldwide. The estrogen receptors (ER's) play an important role in normal mammary gland development, as well as in breast cancer. Estrogen Receptor α is expressed in 70% of breast cancers, where it contributes to increased cell proliferation and decreased cell death. Endocrine therapies such as anti-estrogens and aromatase inhibitors target ERα signaling and improve outcomes of these patients. Syngeneic, immunocompetent mouse models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of breast cancer. In contrast to the tumor-inducing role of ERα, ERβ has been shown to have tumor suppressive activities in various cancer, including the breast cancer. Compounds that selectively activate ERβ hold promise because they could potentially avoid the unwanted effects of ERα activation, while exploiting the tumor-suppressive function of ERβ. In the present study, we assessed the antitumor effects of ERβ agonists using three different syngeneic mouse models; D2A1 (BALB/c) and MM51 (FVB) syngeneic models and ex-vivo culture of highly metastatic cell line E0771 (C57/B6). Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. Our results demonstrate that ERβ agonists LY500307 and S-Equol not only inhibited the growth of all three mouse mammary tumor cell lines, but also reduced the colony formation ability. ERβ agonists also induced the cell-cycle arrest in time and dose-dependent manner. In mechanistic studies, ERβ agonists LY500307 and S-Equol, modulated the protein levels of cyclin-dependent kinases (CDKs) (4, 6, and 2), cyclins (D1 and E), in a differential manner in these three cell lines. Our in vivo studies of D2A1 and MM51 cells demonstrates that ERβ agonist LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Ex-vivo model of E0771 cells showed that LY500307 has potential to dramatically reduce the proliferation of mouse mammary tumor growth.Together, these results identify potential molecular targets and anticancer effects of ERβ agonists in mouse mammary tumors.
Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Thurlapati A, Vadlamudi RK, Tekmal RR. Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-04-01.
Abstract P1-05-05: eEF1A2 facilitates PTEN-GSK3β mediated Aurora-A protein degradation during S-G2 phase inactivated in PTEN-deficient breast cancer
Authors: Treekitkarnmongkol W , Solis LM , Kai K , Thompson AM , Tian W , Wistuba II , Sasai K , Jltsumori Y , Sahin AA , Hawke DH , Lee JM , Qin L , Bawa-Khalfe T , Rad R , Wong KK , Abbott CM , Katayama H , Sen S 
Published: May 2019

Abstract
The AURKA gene, encoding Aurora kinase-A (Aurora-A), is frequently amplified and overexpressed across multiple cancer types correlating with poor prognosis. Although the AURKA gene is frequently amplified in human cancers, underlying mechanism(s) for Aurora-A protein stability through different phases of cell cycle are not well elucidated. Inhibiting the kinase activity and promoting protein degradation are two well-validated conceptual strategies for targeting protein kinases in cancers. Here, we demonstrate that Eukaryotic Elongation Factor 1 Alpha 2 (eEF1A2) facilitates PTEN-GSK3β mediated Aurora-A protein degradation through the SCF complex (SKP1-Cul1-FBXW7) during the S/G2 phase of proliferating cells. In contrast, this mechanism is inactivated in cancer cells accompanying PTEN-GSK3β pathway deficiency. Mechanistically, eEF1A2 interacts with Aurora-A, GSK3β, FBXW7 and Cul1-E3 ligase, as the SCF complex, to facilitate Aurora-A polyubiquitination for 26S proteasomal degradation. eEF1A2 promotes PTEN phosphorylation at T366 and stability, inactivates AKT and activates GSK3β which in turn phosphorylates Aurora-A at S283, S284 and S342. The phosphorylation of Aurora-A at S342 is detected during S/G2 phase of cell mitosis in parallel with eEF1A2-SCF complex formation with active form of GSK3β and neddylated Cul1. Conversely, genetic ablation of EEF1A2 and PTEN, activation of AKT, inhibition of GSK3β, expression of Aurora-A phosphodeficient-mutant attenuates the Aurora-A protein degradation which is corroborated in Aurora-A overexpressing mouse mammary carcinomas and human breast carcinomas. This study identifies a novel mechanism of Aurora-A protein degradation mediated eEF1A2-PTEN-GSK3β pathway and provides a framework for the discovery of Aurora-A therapeutic targets in breast cancer that harbors deficiency of PTEN tumor suppressor pathway.
Citation Format: Treekitkarnmongkol W, Solis LM, Kai K, Thompson AM, Tian W, Wistuba II, Sasai K, Jltsumori Y, Sahin AA, Hawke DH, Lee JM, Qin L, Bawa-Khalfe T, Rad R, Wong KK, Abbott CM, Katayama H, Sen S. eEF1A2 facilitates PTEN-GSK3β mediated Aurora-A protein degradation during S-G2 phase inactivated in PTEN-deficient breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-05-05.
Abstract P1-06-03: A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity
Authors: Quereda V , Bayle S , Francesca V , Andrii M , William R , Derek D 
Published: May 2019

Abstract
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are Ser/Thr protein kinase members of the CDK family. CDKs are regulated by cyclins and members of the family are key regulators of the cell cycle. Other members of this family—CDK7, CDK8, CDK9, CDK12 and CDK13—have been described as transcription-regulating kinases. CDK12 and CDK13 phosphorylate the C-terminal domain (CTD) of rpb1 the largest subunit of RNA polymerase II and interact with RNA processing factors, playing pivotal roles controlling transcription initiation and elongation, as well as posttranscriptional RNA processing. Specifically, CDK12 acts as the limiting factor for the transcription of a small subset of genes that are involved in the DNA damage response pathway and CDK13 affects expression of genes involved in growth signaling pathways. Importantly, like their cell cycle family members CDK12 and CDK13 have also been shown to be promising therapeutic targets for several cancer types. We have generated a novel, selective, and orally bioavailable, small molecule inhibitor of CDK12 and CDK13. Our lead molecule downregulates key DNA damage repair proteins including ATM, ATR, Brca1 and Rad51 leading to induction of apoptotic cell death in all triple negative breast cancer (TNBC) cell lines tested. We have confirmed the selectivity of our compound by kinase profiling and by comparing the gene expression profile by RNA-seq of cells treated with compound or infected with CRISPR sgRNA targeting Cdk12 and/or Cdk13. Importantly, our compound acts in synergy with the chemotherapeutic agents Cisplatin, Irinotecan and Olaparib. Finally, in preclinical efficacy studies, our lead compound blocked tumor progression in two different PDX models of TNBC and demonstrated tumor regression and enhanced efficacy over single treatment when dosed in combination with selected chemotherapeutic agents.
Citation Format: Quereda V, Bayle S, Francesca V, Andrii M, William R, Derek D. A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-03.
Abstract P1-06-08: A p53-independent DNA damage response that regulates breast cancer phenotypes
Authors: Fagan-Solis KD , Simpson DA , Kapustina M , Martelotto L , Reis-Filho JS , Petrini JH , Gupta GP 
Published: May 2019

Abstract
Defects in the DNA damage repair system result in increased genomic instability and have recently been implicated as being drivers of tumorigenesis in both familial and sporadic breast cancers. To maintain genomic integrity, cells have a DNA damage response (DDR) mechanism that functions to repair damaged DNA efficiently and commits cells to death if damage is irreparable. Failure of this mechanism results in genomic instability and cancer predisposition. Widespread chromosomal instability is a characteristic feature of Triple-Negative Breast Cancer (TNBC), making it difficult to decipher between genes that drive cancer development from those that play a bystander role. Little is known about what gives rise to the extensive genomic instability of TNBC, and presents a major deficit in our scientific and clinical knowledge.
Oncogene induced hyper-proliferation results in replication-associated double strand breaks (DSBs) that engage an Mre11-Rad50-Nbs1 complex-dependent DDR. Classically, the oncogene induced DDR is believed to suppress tumorigenesis due to downstream activation of p53. Using genetically engineered primary mammary epithelial cell models, we demonstrate p53-independent effects of the Mre11-dependent DDR in suppressing proliferation and DNA damage induced by diverse oncogenic drivers. Single cell whole genome sequencing in Her2/Neu expressing primary mammary epithelial cells reveals a landscape of stochastic copy number aberrations induced by oncogenic stress that becomes enriched for a genomic scar pattern of larger-size deletions in cells with Mre11 hypomorphism. We identify Mre11 pathway hypomorphism in a subset of basal-like breast cancers (BLBC), which confers vulnerability to specific DNA damaging agents and DDR inhibitors in murine models of p53-deficient BLBC. Thus, assessing the functional status of the Mre11-dependent DDR pathway in p53-mutant breast cancers may provide an opportunity for therapeutic exploitation.
Citation Format: Fagan-Solis KD, Simpson DA, Kapustina M, Martelotto L, Reis-Filho JS, Petrini JH, Gupta GP. A p53-independent DNA damage response that regulates breast cancer phenotypes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-08.
Abstract P1-08-04: Withdrawn
Authors: Trabert B , Bauer DC , Brinton LA , Buist DS , Cauley JA , Dallal CM , Gierach GL , Falk RT , Hue TF , Lacey JV , LaCroix AZ , Tice JA , Xu X 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Trabert B, Bauer DC, Brinton LA, Buist DS, Cauley JA, Dallal CM, Gierach GL, Falk RT, Hue TF, Lacey, Jr. JV, LaCroix AZ, Tice JA, Xu X. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-04.
Abstract P1-08-06: Changes in breast cancer diagnosis and treatment after Medicaid expansion in Pennsylvania
Authors: Spada N , Geramita E , van Londen G , Sabik L 
Published: May 2019

Abstract
Background: In January 2015, Pennsylvania expanded Medicaid eligibility to all legally present adults in the Commonwealth of Pennsylvania with household incomes up to 138 percent of the federal poverty level under the Affordable Care Act. Pennsylvania is the most populous state to expand Medicaid that did not previously have a large expansion of the program to adults, making it an ideal setting to study the impacts of the program. By March 2017, an estimated 716,000 people had enrolled in Pennsylvania's expanded Medicaid program. We aim to determine how Pennsylvania's Medicaid expansion has impacted breast cancer diagnosis and treatment in the state.
Methods: The Pennsylvania Cancer Registry was queried for all women aged 18 to 64 years newly diagnosed with breast cancer between 2007 and 2015. Demographic, tumor, and treatment characteristics were evaluated for each year during this time span. In order to assess the impact that Medicaid expansion had on these variables, they were compared for the years 2007 to 2014 (before Medicaid expansion) and the year 2015 (after).
Results: Between 2007 and 2015, 49,606 cases of invasive breast cancer were diagnosed among women aged 18-64 and residing in the state of Pennsylvania, 43,920 of which were diagnosed and treated between 2007 and 2014, and 5,686 of which were diagnosed and treated in 2015. Initial analysis indicates that more women were diagnosed with localized breast cancer (SEER summary stage 1) following Medicaid expansion in 2015 compared to the period of 2007 to 2014 (63.07% v. 60.62%, p = 0.0004). Meanwhile, the proportion of women diagnosed with metastatic breast cancer did not change before and after Medicaid expansion (6.52% v. 6.86%, p = 0.3298). Subsequent analysis will assess changes in treatment outcomes including time to treatment and receipt of guideline-concordant care.
Conclusion: The expansion of Medicaid in Pennsylvania in 2015 under the Affordable Care Act resulted in an increase in the proportion of localized (SEER summary stage 1) breast cancer diagnoses, though there was no change in the proportion of metastatic cases in the first year following expansion. The results suggest a possible increase in earlier stage diagnosis associated with increased access to health insurance. Additional analysis will examine the impact on treatment-related outcomes.
Citation Format: Spada N, Geramita E, van Londen G, Sabik L. Changes in breast cancer diagnosis and treatment after Medicaid expansion in Pennsylvania [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-06.
Abstract P1-08-09: Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012
Authors: van Maaren MC , Lagendijk M , Tilanus-Linthorst MM , de Munck L , Pijnappel RM , Schmidt MK , Wesseling J , Koppert LB , Siesling S 
Published: May 2019

Abstract
Background
The incidence of ductal carcinoma in situ (DCIS) has drastically increased over the past decades. Since DCIS is resected after diagnosis similarly to invasive breast cancer, the natural cause and behaviour of DCIS is not well known. We aimed to determine breast cancer-specific (BCSS) and overall survival (OS) according to grade in DCIS patients after surgical treatment in the Netherlands.
Patients and methods
All DCIS patients diagnosed between 1999-2012 were selected from the Netherlands Cancer Registry. Cause of death was obtained from 'Statistics Netherlands'. BCSS and OS were estimated using multivariable Cox regression in the entire cohort and stratified for grade.
Results
In total, 12,256 patients were included, of whom 1,509 (12.3%) presented with grade I, 3,675 (30.0%) with grade II, 6,064 (49.5%) with grade III and 1,008 (8.2%) with an unknown grade. During a median follow-up of 7.8 years, 1,138 (9.3%) deaths were observed, and 179 (1.5%) were breast cancer-related. Of these, 10 patients had grade I, 46 grade II, 95 grade III and 28 an unknown grade. After adjustment for confounding, grade II and III were related to worse BCSS compared to grade I with HRs of 1.92 (95% CI:0.97-3.81) and 2.14 (95% CI:1.11-4.12), respectively. No association between grade and OS was observed.
Conclusion
BCSS and OS rates in DCIS patients are excellent. Since superior rates were observed for low-grade DCIS, and earlier studies have shown that low-grade DCIS have a very low chance on recurrence or upstage to invasive cancer, it seems justified to investigate whether active surveillance may be a balanced alternative for conventional surgical treatment.
Citation Format: van Maaren MC, Lagendijk M, Tilanus-Linthorst MM, de Munck L, Pijnappel RM, Schmidt MK, Wesseling J, Koppert LB, Siesling S. Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-09.