bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-11-17: Mutations in PIK3R1 activate multiple pathways in breast cancer
Authors: Abukhdeir AM , Turturro SB , Najor MS , Brar SS , Cobleigh MA 
Published: May 2019

Abstract
It has been estimated that by the end of this year, 270,000 American women will be newly diagnosed with breast cancer, while 40,000 women that already have breast cancer will succumb to the disease. Considerable attention has been given to the PI3K signaling cascade following the discovery that PIK3CA is the most frequently mutated oncogene in breast cancer.However, few studies have explored the function of PIK3R1, which is the regulatory domain of the PI3K complex, despite being mutated in ~3% of all breast cancers.
Several studies have demonstrated that expression of PIK3R1 is downregulated in human cancers. Decreased expression of the PIK3R1 protein leads to tumor formation, suggesting its role as a tumor suppressor gene and a potential prognostic marker in breast cancer. However, PIK3R1 is a gene with little pre-clinical evidence to recommend experimental therapies. Despite this lack of evidence, commercial services that perform molecular analyses of tumors suggest the use of an mTOR inhibitor for patients whose breast cancers carry mutant PIK3R1.
In order to determine if mTOR inhibitors were indeed effective in mutant PIK3R1 tumors, we created and characterized a model for mutant PIK3R1 in the non-tumorigenic, human breast epithelial cell line, MCF-10A. Surprisingly, we observed that mTOR inhibitors were ineffective in these cells. However, in searching for other classes of small molecule inhibitors that were effective, we observed that mutations in PIK3R1 sensitized cells to MAPK inhibitors.
Herein, we present the first evidence for the use of targeted therapies in breast cancers carrying mutant PIK3R1. We provide evidence against the use of mTOR inhibitors and provide a rationale for the use of MAPK inhibitors.
Citation Format: Abukhdeir AM, Turturro SB, Najor MS, Brar SS, Cobleigh MA. Mutations in PIK3R1 activate multiple pathways in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-17.
Abstract BL2: The Challenge of Doing Less
Authors: Winer E 
Published: May 2019

Abstract
There are three groups of individuals with breast cancer who present distinct challenges from the standpoint of clinical care and research. First, there are individuals with breast cancer who develop disease that is refractory to all available therapies and ultimately lose their life to breast cancer. Second, there is a large group of women who do not have adequate access to high quality care or choose not to receive it. It is critical, if we are to eliminate mortality from breast cancer, that we bring effective treatment to these individuals. Finally, and importantly, there is a large group of individuals with breast cancer who are unlikely to die from breast cancer and in whom we need to consider minimizing toxic anti-cancer therapy.
In recent years, a number of clinical trials have been conducted to reduce treatment intensity in breast surgery, radiation oncology, and medical oncology. These trials are often difficult to conduct. Both physicians and patients worry about leaving benefit on "the table", and hence many may be reluctant to participate. Many individuals are particularly risk averse when there is the potential for loss. In addition, statistical considerations can be challenging and often result in extremely large trials to demonstrate that there is significant loss of benefit when treatment is de-escalated. While the advantage of de-escalation is a reduction in toxicity, many physicians and patients underestimate the impact of side effects, both long- and short-term, on a patient. Examples of de-escalation trials will be reviewed and possible study designs will be discussed.
Citation Format: Winer E. The Challenge of Doing Less [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 BL2.
Abstract ES11-1: Lymphedema management in 2018: Are we making any progress?
Authors: Mehrara B 
Published: May 2019

Abstract
Lymphedema is a common and morbid complication of cancer treatment. To date, lymphedema treatment has been palliative aiming to prevent disease progression and improve symptoms of swelling. Development of novel therapies for lymphedema has been limited by the fact that the pathophysiology of the disease remains unknown. While it is true that lymphatic injury during surgery is an important initiating event, the mechanisms that regulate the development of the disease in a subset of patients remain unknown. Recent studies in our lab have suggested that the pathophysiology of lymphedema is related to inflammatory changes that occur following surgery. We have shown that CD4+ T cells play a key role in the pathology of lymphedema by orchestrating a variety of changes including tissue fibrosis, lymphatic leakiness, impaired collecting vessel pumping, and changes in the lymphatic smooth muscle cells. More importantly, in preclinical models we have shown that inhibition of this response can prevent development of lymphedema following surgery or reverse it once it has been initiated. These findings have led to novel treatments for lymphedema that may be effective either as standalone therapies or used in conjunction with surgical treatments for lymphedema.
Citation Format: Mehrara B. Lymphedema management in 2018: Are we making any progress? [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 ES11-1.
Abstract ES2-1: The EMT and metastasis controversy: Where things stand in 2018
Authors: Ford H 
Published: May 2019

Abstract
A pubmed search for epithelial-mesenchymal transition (EMT) and metastasis brings up almost 9000 papers, the vast majority which provide a positive link between this developmental process, which is hijacked by many tumor cells, and tumor progression. As the field has evolved, it has become apparent that there is not a “one size fits all” definition for EMT, and that the process is instead plastic, with epithelial and mesenchymal states being on the far left and right ends of a continuum where cells can exist in various intermediate states. How do these different intermediate states contribute to metastasis, if they do at all? And do these EMT cancer cells work in isolation, or do they form part of a cooperative network of heterogeneous tumor cells, together facilitating the metastatic process? In this talk, I will discuss the controversy around whether and how EMT is involved in the metastatic process, and the significant progress that we and other labs across the country have made in understanding its role in, and contribution to, the metastatic cascade.
Citation Format: Ford H. The EMT and metastasis controversy: Where things stand in 2018 [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 ES2-1.
Abstract ES2-3: Exosome-mediated stimulation of metastasis
Authors: Minn A 
Published: May 2019

Abstract
Although cancer cell intrinsic mechanisms are important in driving aggressive features of cancer, stromal cells in the tumor microenvironment also serve critical roles. In particular, heterotypic interaction between cancer cells and stromal fibroblasts can generate signals for cancer progression, therapy resistance, and inflammatory responses. Among the signals resulting from cellular cross-talk include anti-viral pathways that induce interferon-stimulated genes (ISGs). These observations suggest 1) the existence of signals in the tumor microenvironment that mimic a viral infection, 2) resulting activation of anti-viral signaling may contribute to how stromal cells promote aggressive features of cancer, and 3) mechanisms must exist to prevent this anti-viral signaling under non-pathological conditions. We have demonstrated that exosomes and their RNA produced by stromal fibroblasts represents one such “virus mimic” by engaging RNA pattern recognition receptors (PRRs) such as RIG-I. Triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous non-coding RNA normally shielded from PRR recognition by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 that is deployed in stromal exosomes. After these stromal exosomes are transferred to immune cells, the unshielded RN7SL1 can drive an inflammatory response. Upon exosome transfer to breast cancer cells, unshielded RN7SL1 activates the RIG-I to enhance tumor growth, metastasis, and therapy resistance. The significance of this “virus mimicry” and failure to shield endogenous RN7SL1 from PRR activation is corroborated by evidence from patient tumors and blood. In total, these results demonstrate how exosomes, unshielding of endogenous RNAs, and engagement of pattern recognition receptors couple stromal activation with aggressive features of breast cancer.
Citation Format: Minn A. Exosome-mediated stimulation of metastasis [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 ES2-3.
Abstract ES3-1: Brain metastases of breast cancer
Authors: Steeg P 
Published: May 2019

Abstract
Brain metastases are devastating consequences of breast cancer. Both the lesions and their treatments cause physical and neurocognitive complications. Translational investigations have provided several new insights into the brain metastatic process which are hoped to lead to new preventive and therapeutic approaches. First, DNA sequencing of matched primary tumors and brain metastases revealed that nearly half of the brain lesions harbor potentially actionable mutations not present in the primary tumor. Second, model systems reveal that brain metastatic colonization arises through a complex interplay between the tumor cells and their microenvironment. Astrocytes are found in the normal blood-brain barrier and activate and surround a developing metastasis. They have been reported to modulate metastatic growth via several pathways. Additional investigations have uncovered other mechanistic contributions from activated microglia and other cells. The blood-brain barrier is also a contributor to heterogeneous and insufficient uptake of drugs to brain metastases. When a metastasis forms, the blood-brain barrier is termed a blood-tumor barrier (BTB). Multiple facets of the BBB are altered in the BTB. Alterations to the sphingosine-1 phosphate receptor 3 (S1P3) pathway in neuroinflammatory astrocytes of the BTB functionally altered BTB permeability. These data indicate that the BTB is a tractable structure to improve drug uptake and efficacy. Finally, investigators have identified brain permeable drugs and hormonal therapies that prevent the development of brain metastases in models, and which stand as support for new trials.
Citation Format: Steeg P. Brain metastases 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 ES3-1.
Abstract ES4-1: Partial breast irradiation: Efficacy and patient selection
Authors: Coles C 
Published: May 2019

Abstract
Partial breast irradiation is an attractive option for patients and clinicians as a smaller region of the breast is irradiated in (usually) a shorter time period compared with whole breast radiation therapy (RT). The hypothesis for this approach is that a smaller irradiated volume is likely to translate into decreased toxicity, whilst maintaining good local control and survival (efficacy).
This educational lecture will examine in detail the efficacy of the four “modern” large, randomised partial breast RT trials that have been published in the last 5 years. These include the ELIOT, Targit-A, GEC-ESTRO and IMPORT LOW studies1-4.
In addition, the eligibility criteria and baseline characteristics of recruited patients will be considered for each trial in the context of ipsilateral breast tumour relapse rates. Current national and international guidelines regarding patient selection for partial breast RT will also be discussed.
References:
1.Veronesi U et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Dec;14(13):1269-77.
2.Vaidya JS et al; TARGIT trialists' group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014 Feb 15;383(9917):603-13.
3.Strnad V et al; Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016 Jan 16;387(10015):229-38.
4.Coles CE et al; IMPORT Trialists. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017 Sep 9;390(10099):1048-1060.
Citation Format: Coles C. Partial breast irradiation: Efficacy and patient selection [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 ES4-1.
Abstract ES5-1: Tumor dormancy and recurrence
Authors: Chodosh L 
Published: May 2019

Abstract
Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality in women, largely due to distant, incurable recurrences that arise years, or even decades, after treatment of the primary tumor. Recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells (DTCs) that survive primary treatment in tissues at sites throughout the body where they persist in a presumed dormant state. Early studies demonstrated that an immunohistochemical assay can detect cytokeratin-positive DTCs in bone marrow aspirates of a substantial fraction of breast cancer patients lacking any clinical signs of metastasis. Importantly, women who harbor detectable DTCs in their bone marrow have a substantially increased risk of distant recurrence, as well as poorer breast cancer-specific and overall survival, and this measure has repeatedly been shown to be an independent predictor of recurrence-free survival and overall survival in multivariate analysis.
Since DTCs constitute the reservoir from which recurrent cancers arise, understanding their biology is a critical priority in cancer research. We hypothesize that effectively disabling the survival mechanisms by which DTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. At present, however, the mechanisms enabling these cells to survive in a dormant state and ultimately recur are poorly understood and clinical methods to detect DTCs, as well as DTC-directed therapeutic approaches, are still in their infancy.
To address this critical gap and elucidate critical pathways in dormant tumor cell survival, we and others have developed a variety of mouse models for human breast cancer that recapitulate key features of human breast cancer progression, including metastasis, residual disease, dormancy and recurrence. Investigation of these models using both genetic and pharmacological approaches has identified several mediators of dormant DTC survival and recurrence, demonstrated their relevance to pathways that contribute to therapeutic resistance in human breast cancers following targeted therapy or chemotherapy, and revealed that pharmacological targets for dormancy and recurrence may be unique to these stages of tumor progression. These findings have, in turn, led to the initiation of clinical trials to test the ability of targeted therapies to deplete the burden of DTCs in the bone marrow of breast cancer patients and thereby decrease risk of relapse. If successful, the ability to therapeutically target survival mechanisms utilized by DTCs would constitute a powerful, paradigm-shifting approach to preventing cancer recurrence and the mortality associated with it.
Citation Format: Chodosh L. Tumor dormancy and recurrence [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 ES5-1.
Abstract ES6-2: PI3K in breast cancer, glutamine changes and methionine addiction
Authors: Toker A 
Published: May 2019

Abstract
Mutations in the PI 3-kinase and AKT signaling pathway are highly prevalent in breast cancer. In luminal, estrogen receptor-positive breast cancer patients, oncogenic mutations in PIK3CA, the gene that encodes the catalytic subunit of class 1a PI3K occur with a frequency of approximately 40%. By contrast, inactivating mutations and loss of heterozygosity in the tumor suppressors PTEN and INPP4B that normally terminate PI3K signaling, are found more frequently in basal-like, triple negative breast tumors. Regardless, in all cases the net result is hyperactivation of PI3K/AKT signaling leading to induction of phenotypes associated with malignancy. In spite of the frequency of genetic lesions in the PI3K pathway and the development of potent and specific small molecule inhibitors targeting the PI3K pathway, results from clinical trials with these inhibitors have been disappointing most often due to dose-limiting on-target toxicities. Consequently, numerous combination trials with PI3K inhibitors and other targeted therapies are underway. Separate pre-clinical and clinical efforts have also been initiated targeting PI3K oncogene addition with therapies that impact cellular states and programs, including metabolic pathways and enzymes. The concept that metabolic reprogramming is a feature of all cancer cells, and not merely a byproduct of accelerated growth, goes back to the days of Otto Warburg who in the 1920s proposed that increased levels of aerobic glycolysis followed by lactate fermentation occurs in tumor cells undergoing rapid growth. This so-called 'Warburg effect' spurred the recent development of numerous drugs that target glycolysis in human tumors, many of which are in clinical trials. Equally promising are strategies that target non-essential amino acid metabolism. The concept of metabolic starvation, whereby one or more metabolite is limiting or removed has gained traction in the field, with the finding that certain non-essential amino acids, particularly glutamine, can be synthesized by normal cells, whereas tumor cells rely on an extracellular supply to the extent that glutamine deprivation sensitizes tumor cells to death. Glutamine is the most widely studied nutrient, other than glucose, in the field of tumor metabolism. The presentation will focus on the intersection of PI3K, AKT and glutamine metabolism in breast cancer, as well as how these pathways modulate methionine dependency in breast cancers that display PI3K pathway hyperactivation. A greater understanding of the mechanisms by which glutamine and methionine sustain cancer cells may lead to the development or repurposing of other successful targeted metabolic therapies and use of the pathway enzymes and metabolites as biomarkers.
Citation Format: Toker A. PI3K in breast cancer, glutamine changes and methionine addiction [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 ES6-2.
Abstract GS1-02: Towards a human breast cell atlas
Authors: Seth TK , Bai S , Hu M , Sei E , Wood A , Wiley J , Chen H , Contreras A , Teshome M , Lim B , Navin NE 
Published: May 2019

Abstract
The human breast tissue consists of lobules connected to a complex network of ducts that are evolutionarily designed to produce and transport milk to nourish offspring. Histopathology has identified 10 major cell types based on morphological features but have provided limited information on cell states - the transcriptional programs of cell types that reflect different biological functions. In this study, we have generated an unbiased 'cell atlas' of the normal human breast to define the cell types and cell states using single cell RNA sequencing methods. We performed 3' microdroplet based single cell RNA sequencing of 31,442 stromal cells from 11 women with pathologically normal breast tissues that were collected from mastectomies. Unbiased expression analysis identified three major cell types: epithelial cells (luminal and basal), fibroblasts and endothelial cells, in addition to several minor cell types: macrophages, T-cells, natural killer cells, pericytes and smooth muscle cells. Analysis of cell states of these cell types revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types. These data provide a valuable reference for the research community and will provide new insights into how normal cell types are transformed in the tumor microenvironment to promote or inhibit the progression of breast cancer.
Citation Format: Seth TK, Bai S, Hu M, Sei E, Wood A, Wiley J, Chen H, Contreras A, Teshome M, Lim B, Navin NE. Towards a human breast cell atlas [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 GS1-02.
Abstract MS2-1: Overtreatment: First, do no harm
Authors: Jagsi R 
Published: May 2019

Abstract
Perhaps more than for any other type of cancer, the management of breast cancer has been supported by a steady trajectory of research that has discovered ways to safely de-escalate therapy and identify patients who may safely forego potentially toxic treatments. This talk will begin with a brief overview of landmark clinical trials that have established the safety of de-escalating breast surgery, axillary surgery, radiotherapy, and systemic therapy for select patients. It will then turn to the research that shows that many women diagnosed with breast cancer today pursue considerably more aggressive treatments than needed to achieve excellent outcomes in terms of survival and recurrence, followed by a focus on the toxicity and costs that can result. Seeking to gain actionable insights on how to prevent shared decision-making from resulting in overtreatment, it will then discuss insights from decision psychology. It will include reflections on the heuristics that can lead patients and physicians alike towards overtreatment, the critical role of patients' underlying proclivities for medical maximizing versus medical minimizing, and the importance of naming and framing to ensure accurate risk communication.
Citation Format: Jagsi R. Overtreatment: First, do no harm [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 MS2-1.