bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract ES6-3: Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states
Authors: Graeber T 
Published: May 2019

Abstract
Targeted therapies have demonstrated clinically impactful efficacies. Upfront and adaptive tumor heterogeneity and plasticity present a next challenge to advancing cancer therapeutics further. We are using systems biology and integrative omic approaches towards identifying i) vulnerabilities of aggressive tumor types and ii) combination therapies for preventing resistance. We are incorporating functional datasets defining drug sensitivities (drug screens) and genetic vulnerabilities (shRNA knockdown and CRISPR knockout screens) to identify phenotype-associated cellular susceptibilities. In cancer cells highly dependent upon glucose for survival, we found that glucose withdrawal activates a positive feedback loop involving reactive oxygen species (ROS), ROS-mediated inhibition of tyrosine phosphatases, and tyrosine kinase signaling. This loop amplifies ROS to toxic levels, resulting in cell death. In a process that has parallels to the epithelial to mesenchyme transition (EMT), melanoma cells can undergo dedifferentiation. New standard of care therapies, such as kinase inhibition and immunotherapy, can promote dedifferentiation as a therapy escape route. We found that de-differentiated melanomas have increased sensitivity to ferroptosis - a cell death mechanism tied to metabolism and oxidized lipid membranes. Targeting ferroptosis in combination with standard therapies can block this dedifferentiation resistance escape route.
Citation Format: Graeber T. Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states [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 ES6-3.
Abstract ES8-1: Windows of susceptibility across the lifecourse and breast cancer
Authors: Kushi L 
Published: May 2019

Abstract
With increasing knowledge regarding the role of various factors in the development of breast cancer, a concept that has attracted substantial attention is that of windows of susceptibility. This concept suggests that there are periods over the lifecourse during which a woman may be particularly vulnerable to the influence of modifiable factors in determining long-term risk of breast cancer. This concept is not new; for example, among atomic bomb survivors in Japan, it has been observed that the effect of radiation exposure on subsequent breast cancer risk is substantially higher if women were exposed earlier in life than in their later years. However, the impact of hormonally-active agents that are ubiquitous in environment has raised concern that the risk of breast cancer may be altered during windows of susceptibility, such as during the in utero period, the pubertal transition, or between puberty and first full-term pregnancy.
In order to better understand the interplay of environmental and lifestyle factors with timing of exposures during the lifecourse, the National Cancer Institute and the National Institute for Environmental Health Sciences established the Breast Cancer and the Environment Research Program, including both laboratory and epidemiologic studies to investigate the potential role of hormonally-active agents in altering early life factors that may influence breast cancer risk. These include, for example, epidemiologic studies that have focused on impacts on age-at-onset of puberty, and others that focus on impacts on breast density. In conjunction with other studies that have examined body size or other metabolic parameters measured at different periods over the lifecourse, a growing body of literature indicates that breast cancer risk factors may operate differently depending on when exposures to these risk factors occur. These observations indicate that establishment of breast cancer risk is complex, and that approaches to prevention likely need to recognize the importance of windows of susceptibility in influencing long-term likelihood of developing breast cancer. This presentation will review some of the key concepts and findings underlying this growing area of interest in the epidemiology of breast cancer.
Citation Format: Kushi L. Windows of susceptibility across the lifecourse and 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 ES8-1.
Abstract ES8-2: New data on hormones and risk of breast cancer
Authors: Hankinson S 
Published: May 2019

Abstract
This session has two primary objectives: (1) to provide a review of recent research findings relating both endogenous and exogenous hormone exposures to later risk of breast cancer in women, and (2) to put these findings into context with what we already knew. For example, circulating levels of anti-Mullerian hormone (AMH), a hormone measureable only in premenopausal women, has recently been associated with increased risk of both premenopausal and postmenopausal breast cancer in a large prospective pooled analysis. Thus, circulating levels of AMH can now be considered along with the plasma estrogens and androgens (where weaker but consistent associations are observed) to be a probable or confirmed breast cancer risk factor. In postmenopausal women, plasma concentrations of sex steroid hormones, factors consistently linked with increased risk of breast cancer, were shown in recent studies to significantly improve breast cancer risk prediction models (such as the Gail Model). From older epidemiologic studies, we knew that recent or current use of oral contraceptives modestly increases risk of breast cancer, and this increase in risk subsides with duration since quitting use. Recent studies of newer contraceptives now add additional insight into this important issue.
Citation Format: Hankinson S. New data on hormones and risk of 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 ES8-2.
Abstract GS1-01: Landscape of the breast tumour microenvironment at single-cell resolution
Authors: Swarbrick A , Wu SZ , Roden D , Al-Eryani G , O'Toole S , Lim E 
Published: May 2019

Abstract
Breast cancers are a complex 'ecosystem' of diverse cell types, whose heterotypic interactions play central roles in defining the aetiology of disease and its response to therapy. The next generation of therapies will likely be based upon an integrated understanding of the malignant, microenvironmental and immune states that define the tumour and inform treatment response. However, our poor understanding of the tumour microenvironment (TME) of breast cancers has limited the development and implementation of new drugs that target stromal and immune cells.
Single cell genomics (SCG) is a remarkable new platform to examine the compositional, gene expression and other parameters of thousands of cells, rapidly and at scale. We have used a multi-dimensional SCG approach to characterise the TME in a unique cohort of early and metastatic breast cancers with rich clinico-pathological annotation. We have conducted single cell RNA-Sequencing on more than 125,000 cells collected from 22 patients.
Malignant cells showed remarkable intra-tumoural heterogeneity for canonical breast cancer features, such as intrinsic subtype, hormone receptor expression and activity, drug targets, drug resistance signatures and transcriptional drivers.
Cancer Associated Fibroblasts (CAFs), which are classically studied as a single cell type, were heterogeneous across primary and metastatic sites. Interestingly we identified a myofibroblast-like subset and an inflammatory-mediator subset and propose multi-faceted roles in regulating malignancy and tumour immunity. Distinct transcription factor networks regulated these polarised states.
We applied a new method known as CITE-Seq to measure cell surface immune markers and checkpoint proteins simultaneous to RNA-Sequencing. We resolve the tumour-immune milieu with high precision and generate new transcriptional signatures of breast tumour-infiltrating leukocytes.
To track lymphocyte clonal dynamics through space and time, we developed a novel method known as RAGE-Seq to permit simultaneous full length lymphocyte receptor- and RNA-sequencing at single cell resolution. We observe clonal expansion and trafficking of CD4+ and CD8+ T lymphocytes between the lymph nodes, blood and tumor of patients. In comparison, B cells were polyclonal, suggesting an absence of antigen-dependent clonal expansion.
This data provides by far the most extensive insights into the cellular landscape of breast cancer and will reveal new biomarkers and opportunities for stromal- and immune-based therapy.
Citation Format: Swarbrick A, Wu SZ, Roden D, Al-Eryani G, O'Toole S, Lim E. Landscape of the breast tumour microenvironment at single-cell resolution [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 GS1-01.
Abstract OI: Breast Cancer in Young Women: Understanding Differences to Improve Outcomes
Authors: Partridge A 
Published: May 2019

Abstract
Breast cancer is the leading cause of cancer related deaths in women age 40 years and younger in the United States, and a major cause of morbidity and mortality worldwide. Young women are more likely to develop more aggressive subtypes of breast cancer. Emerging data suggest the effect of age on breast cancer recurrence and death varies by tumor subtype, with young age particularly prognostic in women with ER-positive disease. Greater understanding of the biologic and genetic underpinnings of cancers that arise in younger women, potential differences in tumor and host responses including disease presenting in very premenopausal women or recently pregnant women, is critical to develop novel treatments to improve outcomes. There is also mounting evidence that access to care and behavioral differences leading to suboptimal treatment contribute to disparities in young women, including relatively poor adherence to adjuvant hormonal therapy. Prevention, detection and management of non-adherence, with attention to unique issues facing young women including desire for future fertility and pregnancy, has been the subject of recent research for this vulnerable population who, unsurprisingly, are at increased risk of psychosocial distress compared with older breast cancer survivors. Decision-support tools, and innovative, acceptable, scalable interventions to address anxiety and distress are under investigation. Finally, given that most young women will live for many decades after a diagnosis of breast cancer, it is imperative that we follow this population, in particular, over time and study their long-term, late effects in survivorship.
Citation Format: Partridge A. Breast Cancer in Young Women: Understanding Differences to Improve Outcomes [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 OI.
Abstract OT1-01-02: An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation
Authors: Plourde PV , Schwartzberg LS , Greene GL , Portman DJ , Komm BS , Jenkins SN , Liu P-Y , Portman MD , Goetz MP 
Published: May 2019

Abstract
Endocrine based therapy is the standard treatment for estrogen receptor positive (ER+) MBC. Agents targeting the ER pathway including aromatase inhibitors (AIs), fulvestrant and tamoxifen along with CDK 4/6 inhibitors are considered standard for first and 2nd line treatment. However, endocrine resistance develops in nearly all patients and the optimal systemic therapy after progression on a CDK 4/6 inhibitor is unknown.
Lasofoxifene is a third generation SERM previously investigated for the treatment of osteoporosis and vulvo-vaginal atrophy (VVA). In a large phase 3 trial evaluating the efficacy of lasofoxifene for the postmenopausal treatment of osteoporosis, lasofoxifene significantly reduced the incidence of ER+ breast cancer. Further unpublished preclinical data have demonstrated significant in vitro and in vivo efficacy in non-clinical breast cancer models including models with and without ESR1 mutants. Moreover, lasofoxifene significantly reduced metastases in ESR1 mutated models. These non-clinical and clinical data provide a strong rationale to pursue a phase 2 clinical trial in women with ER+, ESR1 mutated MBC.
This open-label, multi-center study will compare the efficacy and tolerability of lasofoxifene (5 mg orally daily) to fulvestrant (IM 500 mg D1,15,29 and then q30 D) in a 1:1 randomization. Inclusion criteria include postmenopausal women with ER+ advanced breast cancer; progression on a non-steroidal AI in combination with a CDK 4/6 inhibitor; and a known ESR1 mutation. Approximately 90 patients with measurable or evaluable disease (i.e. bone only) will be recruited to have at least 40 patients per treatment arm. The primary endpoint will be progression free survival (PFS) with secondary endpoints of objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and time to response (TTR). It is assumed that lasofoxifene will double the median PFS compared to fulvestrant in this ESR1 mutation patient population for a hazard ratio 0.5 and a power of 89% to reach a 1-sided p of &lt;0.05.
The study will commence in 4Q2018 and will complete recruitment in 1 year. It is anticipated that 25-30 centers in the US will be participating.
Citation Format: Plourde PV, Schwartzberg LS, Greene GL, Portman DJ, Komm BS, Jenkins SN, Liu P-Y, Portman MD, Goetz MP. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation [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 OT1-01-02.
Abstract OT1-01-04: Phase 1 study of D-0502, an orally bioavailable SERD with optimized pharmacological and PK/PD property for ER-positive breast cancer
Authors: Zhang L , Dai D , Shi Z , Jiang J , Wang Y 
Published: May 2019

Abstract
Background: Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of HR+ (ER+ and PR+) and HER2- breast cancer patient, either alone or in combination with CDK4/6 inhibitors such as palbociclib or abemaciclib. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft model and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development.
Trial Design: D-0502 is currently being evaluated in a phase 1 trial of women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). This is a multicenter, open-label phase I study of D-0502 single agent and D-0502 in combination with standard dose of palbociclib. The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objective is to evaluate the PK properties and the preliminary anti-tumor activities. Patients will receive D-0502 orally every day and treatment will be administered as 28-day cycles. The study has two parts: Dose Escalation (phase 1a) and Dose Expansion and Combination (phase 1b). In phase Ia, patients will be enrolled using a conventional dose-escalation algorithm (3+3 subjects per dose level) with 4 sequential dose cohorts to identify the MTD and RDE (recommended dose for expansion) in phase 1b) which will be at or below MTD. In phase 1b, there will be 2 cohorts, one is D-0502 single agent administered at RDE and the other is D-0502 in combination with standard dose of palbociclib, each with approximately 12 patients.
Key Eligibility Criteria: Eligible patients included women with confirmed HR+, HER2- MBC who have previously received no more than 2 prior chemotherapies for MBC; ECOG 0-1; evaluable (phase 1a) or measurable (phase 1b) disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions.
Current Status and Contact Information: At the time of abstract submission, the first cohort of 50 mg patients have started the study treatment. For inquiry of the study, please contact ling.zhang@inventisbio.com.
Citation Format: Zhang L, Dai D, Shi Z, Jiang J, Wang Y. Phase 1 study of D-0502, an orally bioavailable SERD with optimized pharmacological and PK/PD property for ER-positive 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 OT1-01-04.
Abstract OT2-01-01: Not presented
Authors: Yang B , Wu J 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: Yang B, Wu J. Not presented [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 OT2-01-01.
Abstract OT2-05-02: International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1)
Authors: Imoto S , Futamura M , Toi M , Fujiwara Y , Ueno T , Im Y-H , Im S-A , Ahn SG , Lee JE , Park YH , Wang K , Kitagawa Y , Nishiyama M 
Published: May 2019

Abstract
Breast cancer (BC) is so-called “systemic disease”, because disseminated cancer cells in bone marrow and blood are detected even in early BC patients. Despite adjuvant therapy and postoperative radiation therapy, patients with triple negative BC and Luminal B-like BC often relapse early and systemic therapy is the only way to control disease progression. On the other hand, some BC patients relapse several years later. In such patients, oligometastases are occasionally diagnosed, because metastatic cancer cells are slowly growing and indolent. Oligometastatic BC is defined as low volume metastatic disease with limited number and size of metastatic lesions (up to five and not necessarily in the same organ). This definition is proposed in the Advanced Breast Cancer guidelines that are developed as a joint effort from European School of Oncology and European Society of Medical Oncology. Several retrospective studies demonstrated survival benefit of locoregional therapy in addition to systemic therapy. Locoregional therapy consisted of surgical resection, radiation therapy, ablation therapy, etc. However, it remains unclear about survival benefit of combined therapy in oligometastatic BC. To improve the standard of cancer treatment through the cooperate studies on more effective therapeutic strategies based on drugs, surgery and/or radiotherapy, Federation of Asian Clinical Oncology (FACO) was established in 2012 by Chinese Society of Clinical Oncology (CSCO), Korean Society of Medical Oncology (KSMO) and Japan Society of Clinical Oncology (JSCO). Thus, FACO conducted a retrospective cohort study on oligometastatic BC. The primary endpoint is to compare the estimated 5-year overall survival (OS) of oligometastatic BC patients treated with combined therapy and systemic therapy alone. To hypothesize that combined therapy has more advantage of OS in oligometastatic BC, the 5-year OS rates are expected to be 50% and 40%, respectively. The estimated sample size is calculated to be the number of 698 cases (349 cases in each group) needed to prove the superiority of survival with a two-sided type I error rate of 5% and a statistical power of 80%. Case registry opened in February 2018 and will close in January 2019. We planned to register 700 cases, i.e., 234 cases each from investigators of CSCO, KSMO and JSCO. Update information will be discussed.
Citation Format: Imoto S, Futamura M, Toi M, Fujiwara Y, Ueno T, Im Y-H, Im S-A, Ahn SG, Lee JE, Park YH, Wang K, Kitagawa Y, Nishiyama M. International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1) [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 OT2-05-02.
Abstract OT3-02-01: RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC)
Authors: Wöckel A , Fasching PA , Guderian G , Heim J , Jackisch C , Lück H-J , Lüftner D , Marmé F , Reimer T , Decker T 
Published: May 2019

Abstract
Background: In the pivotal phase 3 MONALEESA-2 trial, ribociclib, a highly selective oral CDK4/6 inhibitor in combination with letrozole significantly prolonged progression-free survival (PFS) compared to letrozole alone. In the year 2017, based on the results of MONALEESA-2, ribociclib in combination with an aromatase inhibitor (AI) was approved for the treatment of HR+, HER2– aBC in postmenopausal women with no prior therapy for their advanced disease (first-line treatment). Beyond phase 3 trials, further data for ribociclib are now becoming available from the phase 3b trials, RIBECCA and COMPLEEMENT-1, involving approximately 500 and 3000 patients with aBC, respectively. However, real-world evidence for the effectiveness, safety, and tolerability of ribociclib + AI in the routine clinical practice is needed to further support the use of this combination in the first-line therapy.
Methods: RIBANNA is a non-interventional study, which started in October 2017 and plans to enroll 3020 patients across ˜400 sites in Germany. Postmenopausal women diagnosed with aBC will be enrolled into 3 cohorts (cohort 1: ribociclib + AI; cohort 2: endocrine monotherapy; and cohort 3: chemotherapy). Across all cohorts, patients will be treated in accordance with the respective German-prescribing guidelines. Data related to efficacy (with PFS as the primary efficacy criterion), safety, tolerability, duration of therapy, and impact on quality of life (QoL) will be collected. QoL will be assessed using the validated patient questionnaires. This study was especially designed to analyze the patient data from sequential lines of therapy in all three cohorts over a period of up to 7 years. For this purpose, RIBANNA will collect the data on each line of treatment and the reason for changing treatment in all 3 cohorts. The same accounts for QoL, which will also be assessed periodically, regardless of disease progression and initiation of subsequent therapies.
RIBANNA is the first study to provide the real-world evidence regarding treatment of HR+, HER2− aBC with the CDK4/6 inhibitor, ribociclib. This study includes 3 treatment cohorts (ribociclib + AI, endocrine monotherapy, and chemotherapy) with subsequent treatment algorithms and assessment of QoL over the entire study period.
Citation Format: Wöckel A, Fasching PA, Guderian G, Heim J, Jackisch C, Lück H-J, Lüftner D, Marmé F, Reimer T, Decker T. RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC) [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 OT3-02-01.