bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-305: Soluble CD23 levels increase following lumiliximab dosing in relapsed chronic lymphocytic leukemia patients
Authors: Harris Sarah , Woodworth James , Ranuio-Kelley Julie , Estrellado Annalee , Cesano Alessandra , Mu Hua , Tangri Shabnam
Published: May 2019

Lumiliximab is an anti-CD23 monoclonal antibody under investigation for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL). Lumiliximab binds specifically to human CD23, a glycoprotein expressed on the majority of CLL B cells. CD23 is a trimeric molecule with both membrane-bound (mCD23) and soluble (sCD23) forms. mCD23 is a 45 kD glycoprotein expressed on B cells, monocytes/macrophages, eosinophils, platelets, and dendritic cells, with increased levels observed on chronic lymphocytic leukemia (CLL) cells. Soluble CD23 is produced by the cleavage of mCD23 by endogenous proteases into various fragments, with the 25 kD fragment found in normal human serum at concentrations around 2 ng/ml. Increased levels of sCD23 are found in the serum of patients with several disease states including CLL. Data from a Phase 1 lumiliximab monotherapy trial in relapsed CLL showed that levels of sCD23 rapidly increased in the serum of some patients after dosing with lumiliximab. To confirm this phenomenon, serum sCD23 levels and their relationship with treatment response were evaluated in a Phase 1/2 study of lumiliximab in combination with fludarabine, cyclophosphamide, rituximab (FCR) in patients with relapsed CLL. The pharmacokinetic (PK) profiles of both lumiliximab and rituximab were also compared to sCD23 profiles.

Methods: Thirty-one patients with relapsed CLL were enrolled to receive up to 6 cycles treatment with lumiliximab plus FCR. Lumiliximab PK, Rituxan PK and sCD23 levels were each measured in 31 patients using validated enzyme-linked immunosorbant assays. PK data was analyzed with WinNonlin.

Results and Conclusions: Our analysis shows that sCD23 increases from the ng/ml range to the ug/ml range immediately after each dosing with lumiliximab/FCR, then declines throughout the remainder of the treatment cycle. The levels of sCD23 increase again with subsequent lumiliximab/FCR doses, until the there are little to no B-CLL cells remaining in the circulation. The pattern of increase parallels the PK profile of lumiliximab. The intensity of sCD23 increase varied from patient to patient, and did not appear to correlate with treatment outcome. These data demonstrate that although lumiliximab/FCR dosing increases serum levels of sCD23, there is no apparent impact on patient response. This will be evaluated further in upcoming clinical trials. The mechanism of sCD23 release is also currently being investigated.
Abstract P3-01-07: BI-RADS classification in daily practice: Keep it simple
Authors: Menezes GLG , Winter-Warnars GAO , Koekenbier EL , Groen EJ , Verkooijen HM , Pijnappel RM
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P3-04-14: Zoledronic acid sensitized breast cancer cells to fulvestrant via ERK/FOXO3a/HIF-1 α inhibition through nuclear FOXO3a translocation
Authors: Jia X , Liu G , Shen Z , Shao Z
Published: May 2019

This abstract was not presented at the symposium.
Abstract P4-21-36: Splenic enlargement and bone marrow hyperplasia in patients receiving trastuzumab-emtansine for metastatic breast cancer
Authors: Kosmin M , Makris A , Jawad N , Miles D , Padhani AR
Published: May 2019

Introduction

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate used for treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. An association between T-DM1 and splenic enlargement was noted anecdotally on sequential whole-body MRI (WB-MRI) examinations. A retrospective analysis of WB-MRI examinations of patients on T-DM1 was undertaken to investigate the hypothesis that an increase in splenic volume is due to either a generalised hyperplasia of the bone marrow and reticulo-endothelial system and/or an increase in portal venous pressure.

Methods

12 patients underwent 29 serial WB-MRIs before and during T-DM1 therapy. Splenic volume, portal vein diameter, bone marrow muscle-normalised signal intensity (nSI), water diffusivity (apparent diffusion coefficient, ADC) and fat fraction were measured. Changes in splenic volume were analysed, and correlations between the measured variables were obtained.

Results

An increase in splenic volume was observed in 92% of patients. Mean splenic volume increased from 144cm3 (95%CI 110-177cm3) to 209cm3 (95%CI 161-257cm3) on T-DM1 therapy (p=0.006). Increase in splenic volume correlated with treatment duration (r2=0.71). Increase in normal bone marrow signal was seen (nSI 3.5 to 4.8, p=0.12), along with a decrease in fat fraction (64.3% to 57.3%, p=0.12), and reduced ADC (655µm2/s to 543µm2/s, p=0.11). No consistent changes to portal vein diameter were seen.

Discussion

An increase in splenic volume was consistently observed in patients on T-DM1 therapy. This was unrelated to portal vein changes but correlated with bone marrow hyperplasia. Caution should be applied when assessing metastatic disease in bone to avoid incorrectly attributing T-DM1-related changes in normal bone marrow to disease progression.

Citation Format: Kosmin M, Makris A, Jawad N, Miles D, Padhani AR. Splenic enlargement and bone marrow hyperplasia in patients receiving trastuzumab-emtansine for metastatic 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 P4-21-36.
Abstract P5-14-01: Chemotherapy randomization of the EORTC 10041/ BIG 3-04 MINDACT (microarray in node-negative and 1 to 3 positive lymph node disease may avoid chemotherapy) trial
Authors: Cardoso F , Piccart M , Rutgers E , Slaets L , van 't Veer L , Viale G , Pierga J-Y , Brain E , Causeret S , Golfinopoulos V , Goulioti T , Knox S , Matos E , Neijenhuis P , Nitz U , Passalacqua R , Rubio IT , Saghatchian M , Smilde TJ , Sotiriou C , Stork L , Straehle C , Thomas G , Thompson A , Vrijaldenhoven S , Vuylsteke P , Tryfonidis K , Bogaerts J , Delaloge S
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-01-09: MiRNA-200b suppresses triple negative breast cancer metastasis by targeting ARHGAP18 and causing sustained Rho A activation
Authors: Wang Z , Humphries B , Li Y , Yang C
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-01-16: The phosphorylation-specific association of STMN1 with GRP78 promotes breast cancer metastasis
Authors: Kuang X , Jiang H , Hu X , Shao Z , Lin Y
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-08-11: Histone acetyltransferase 1 interacts with estrogen receptor alpha (ERα) and affects the transcriptional activity of ERα in breast cancer cells
Authors: Dhamad A , Zhou Z , Zhou J , Du Y
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-10-05: A pilot study of radiation (RT) and CTLA4-mediated checkpoint blockade with tremelimumab for the treatment of breast cancer brain metastases (BCBM)
Authors: McArthur HL , Beal K , Halpenny D , Henrich M , Patil S , Young R , Kaley T , Hamilton N , Hudis C , Wolchok J , Norton L
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-10-08: Preliminary results of a first in human Phase 1 clinical trial to demonstrate safety and feasibility of chimeric antigen receptor T (CART) cells directed against c-Met in the treatment of breast cancer
Authors: Tchou J , Zhang PJ , Levine BL , Zhao Y , Matro J , DeMichele A , Amy C , Schuchter L , Plesa G , Vonderheide RH , June C
Published: May 2019

This abstract was withdrawn by the authors.
Abstract CS1-1: Polygenic risk scores for breast cancer: Ready or not?
Authors: Evans D
Published: May 2019

There are increasing attempts to try to stratify cancer risks to enable more targeted early detection and prevention strategies and in particular to balance the risks and benefits of population screening for breast cancer. An increasing number of common genetic variants called Single Nucleotide Polymorphisms (SNPs) have been identified which alter breast cancer risk. Although individually their effect sizes are small they can be used multiplicatively to provide a polygenic risk score (PRS) that accurately predicts risk in both the familial and population setting. Although the first 18 SNPs produce a highly calibrated PRS that is ready for use there are now PRSs of 143 or even 313 SNPs that increase risk stratification although with some loss of calibration. Using data from 9362 women in the Predicting the Risk Of Cancer At Screening (PROCAS) study (500 prospective cancers) and 2000 women in the FH-Risk familial cohort (500 prospective cancers) we have validated the PRS alongside mammographic density (density residual-DR) and standard risk factors to assess future risk of different types of breast cancer. The combined score accurately predicts breast cancers rates with 18-21% of women being predicted in the moderate or high risk categories (≥5% 10 year risk) that developed 41.5-45% of the stage 2+ cancers. In contrast SNP143 is able to identify alongside density and standard risk factors 21% of the general population at <1.4% 10-year risk aged 46-73 years who develop only 9% of the breast cancers. These are also more likely to be potentially 'overdiagnosed' grade 1 and DCIS. The SNP143 is also predictive for oestrogen receptor negative cancers using a 20 SNP PRS.

Conclusions: A combined approach using Tyrer-Cuzick, mammographic density and a PRS provides accurate risk stratification not only overall but also for worse prognosis cancers. This provides support for reducing screening intervals in the high and increasing them in the low risk groups. It is high time these highly informative tests were used in risk stratification

Citation Format: Evans D. Polygenic risk scores for breast cancer: Ready or not? [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 CS1-1.
Abstract CS1-2: Breast cancer genetic testing and results in diverse populations
Authors: Kurian A
Published: May 2019

Sequencing multiple (20-100) cancer-associated genes has rapidly become the clinical standard for hereditary cancer risk assessment. In patients with breast cancer and/or ovarian cancer the BRCA1 and BRCA2 genes have been most widely tested, but a significant number of patients are now found to carry pathogenic (or likely pathogenic) variants in many other genes whose cancer risks are less well-characterized. Moreover, multiple-gene sequencing is associated with a higher rate of uncertain results (variants of uncertain significance), which are more prevalent among racial/ethnic minorities.

While pathogenic variants in less well-characterized genes are prevalent, the appropriate management of carriers remains unclear. Questions remain about the magnitude of risk associated with a pathogenic variant in a specific gene; the spectrum of associated cancers; and the extent to which these factors are modified by family cancer history. Data are emerging from epidemiologic studies in various settings. However, clinical practice requires real-time decisions about whom to test, and for which cancers to screen, despite an incomplete evidence base.

This lecture will review the current state of the science on genetic testing for hereditary breast and ovarian cancer risk. We have recently collaborated with genetic testing laboratories to link the results of clinical genetic testing to Surveillance, Epidemiology and End Results (SEER) registry records of >150,000 breast cancer and/or ovarian cancer patients. I will present results from the SEER-GeneLINK research initiative, focusing on the use, correlates and outcomes of genetic testing on the population level.

Citation Format: Kurian A. Breast cancer genetic testing and results in diverse populations [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 CS1-2.
Abstract CS1-3: Moderate penetrance mutations: What to do?
Authors: Domchek S
Published: May 2019

Genetic testing for breast and ovarian cancer susceptibility has expanded beyond sequencing of BRCA1 and BRCA2. Panel testing has allowed for rapid, affordable, and routine testing of multiple genes simultaneously. There is no one standard “panel” – panels range in types and number of genes tested and panel composition is at the discretion of the ordering provider. Some of the genes commonly included have been long associated with specific genetic syndromes with high lifetime risks of the associated cancers, e.g. mutations in PTEN and Cowden's Syndrome, TP53 and Li Fraumeni Syndrome, STK11 and Peutz-Jeghers Syndrome, and CHD1 and Hereditary Diffuse Gastric Cancer. The inclusion of these “high penetrance genes” on broad cancer panels can lead to challenges regarding discussion and management when detected in families which are not syndromic (for example, the discussion of prophylactic gastrectomy in individuals with CDH1 mutations and no family history of gastric cancer). Mutations in other genes are clearly associated with breast cancer but with lower lifetime risks than for BRCA1 and BRCA2; for example, the lifetime risk of breast cancer for a PALB2 mutation is approximately 40-50%, whereas for ATM and truncating CHEK2 mutations this risk is 25-30%. Mutations in BRIP, RAD51C, and RAD51D are clearly associated with ovarian cancer with lifetime risks of approximately 10% (significantly lower than for BRCA1 mutations). This lecture will address the current understanding of associated cancer risks for mutations in genes included in hereditary cancer panels with a focus on implications for risk reduction and treatment.

Citation Format: Domchek S. Moderate penetrance mutations: What to do? [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 CS1-3.
Abstract ES11-2: Current status of diagnosis, monitoring, and non-surgical management of lymphedema
Authors: McLaughlin S
Published: May 2019

Lymphedema (LE) is a common but underreported complication of breast cancer treatment since most studies lack baseline and follow-up measurements or follow-up that is long enough to adequately record true incidence. Contemporary prospective randomized trials continue to document the occurrence of lymphedema after any axillary treatment and note that combination therapy with axillary surgery and radiation nearly doubles LE risk. Over the last 5 years clinicians have witnessed a paradigm shift in the diagnostic practices of LE with concerted efforts focusing on early detection as opposed to reactionary interventions. Controversy however has existed over how to define and diagnose LE and as such the literature surrounding diagnosis is heterogeneous with respect to incidence and recommendations. Existing guidelines emphasize the need for routine monitoring for LE and the critical importance of baseline, bilateral, and longitudinal limb assessments but do not embrace one measurement technique. A growing body of prospective observational data is systematically challenging the value of precautionary behaviors. Further, prospective randomized data demonstrates exercise does not promote the development of LE. Complex decongestive therapy remains the cornerstone of non-surgical LE treatment. With the NCI predicting over 4 million breast cancer survivors in the US by 2024, lymphedema is potentially a significant public health burden.

Citation Format: McLaughlin S. Current status of diagnosis, monitoring, and non-surgical management of lymphedema [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 ES11-2.
Abstract ES12-2: Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis
Authors: Li R
Published: May 2019

Breast cancer risk is significantly elevated for women who carry germ-line mutations in the tumor suppressor gene BRCA1. BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. These precancerous cells of origin are defective in luminal differentiation in BRCA1 mutation carriers before any clinical evidence of cancer. While BRCA1 is best known for its functions in double strand break DNA repair and response to DNA replication stress, it is unclear whether loss of these ubiquitously important functions of BRCA1 is sufficient to account for lineage-specific breast tumor development in BRCA1 mutation-carrying women. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention.

Recent discoveries from others and us challenge the prevailing DNA repair/replication-centric paradigm. First, in vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Using breast tissue of cancer-free BRCA1 mutation-carrying women, we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1 knockout mouse mammary epithelium. Of note, this BRCA1/COBRA1 interaction occurs in a DSB repair-independent manner. Based on these findings, we suggest that as part of its tumor suppressor activity, BRCA1 promotes luminal epithelial differentiation by mitigating Pol II pausing-dependent transcriptional stress at luminal fate genes. We further propose that accumulation of transcriptional stress in BRCA1-deficient luminal cells redirects luminal transcription and alters luminal homeostasis, which ultimately contributes to lineage-specific BRCA1-associated tumorigenesis.

Citation Format: Li R. Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis [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 ES12-2.
Abstract ES12-3: BRCA 1/2/3 and p53 in replication fork stability
Authors: Schlacher K
Published: May 2019

Genome instability is a hallmark of cancer, whereby the vast majority of cancer mutations are caused by defective DNA replication processes. BRCA and p53 genes are critical breast cancer suppressors and “guardians of the genome”. Genetically, BRCA and p53 are frequently found co-inactivated in breast cancer patients. The predominant molecular gene functions ascribed to BRCA genes lies in DNA repair, while p53 is best understood for its transcription activities. Yet these respective functions are insufficient to explain cancer patient genotypes and phenotypes. Recently, novel roles for BRCA and p53 genes in stabilizing DNA replication forks that are separable from their canonical functions have been described.

During this session, we will review BRCA-p53 genetic collaborations during embryogenesis and cancer, with focus on their functional convergence at the level of DNA replication fork stability. We will further discuss BRCA/p53 DNA replication functions as critical new and distinct aspects for cancer therapy approaches and patient variant prediction.

Citation Format: Schlacher K. BRCA 1/2/3 and p53 in replication fork stability [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 ES12-3.
Abstract ES3-2: Multidisciplinary management of breast cancer brain metastases
Authors: Tsien C
Published: May 2019

The management of breast cancer brain metastases requires a multi-disciplinary approach. Local treatment approaches including stereotactic radiosurgery (SRS) and surgery remain an integral component in the management of breast cancer patients. Systemic therapies with better penetration across the blood–brain barrier are currently being investigated. In this session, we will review the role of local therapies in the treatment of brain metastases and considerations on combining these different treatment modalities. We wish to exploit the novel interactions of SRS and systemic agents. We will discuss the evolving role of surgery, stereotactic radiosurgery and whole brain radiotherapy in the treatment of breast cancer brain metastases. We will review recent clinical trial data emphasizing the importance of preserving neurocognitive function in these patients and the general impact on current clinical practice. We will discuss issues regarding the optimal timing of systemic therapies in combination with local therapies and their impact on local control. Overall, there is a changing landscape in the treatment of breast cancer brain metastases with greater emphasis on preserving patients' neurologic function. Clinical trial research continues to be a priority. Ultimately, our goal is a significant paradigm shift in the management of breast cancer brain metastases with the prevention of central nervous system (CNS) metastases.

Citation Format: Tsien C. Multidisciplinary management of breast cancer brain metastases [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 ES3-2.
Abstract ES5-3: Late recurrence in ER-positive breast cancer
Authors: Gralow J
Published: May 2019

The risk of recurrence in early stage, ER-positive breast cancer patients persists for 15-20+ years after diagnosis, and never declines to zero. Rates of late recurrence can be reduced by extending tamoxifen therapy beyond 5 years, with additional tamoxifen or a switch to an aromatase inhibitor. The benefits of extending aromatase inhibitors beyond 5 years remains unclear. The benefit of extended adjuvant endocrine therapy for the average early stage breast cancer patient is small. Extended therapy can be associated with serious increased risks, including thromboembolic events and endometrial cancer with tamoxifen, and fractures and possibly cardiovascular events with aromatase inhibitors. Quality of life can also be impacted, including vasomotor symptoms, sexual dysfunction, and arthralgias. Determining which patients have high residual risk of recurrence beyond 5 years, and importantly whether additional therapy is likely to mitigate that risk, has been the subject of considerable recent research.

Tumor size, nodal status and grade of the primary tumor at the time of diagnosis have been shown to be associated with risk of late recurrence in ER-positive breast cancer. Several multi-parameter molecular biomarker assays performed on the primary tumor are able to separate patients into groups at low and high risk for recurrence beyond 5 years when using retrospective data sets. To date, no specific assay has been felt to have high enough level evidence to recommend inclusion in treatment guidelines or use in decision-making regarding continuing, stopping or switching endocrine therapy.

Recent studies have evaluated whether there are better determinants of late risk of recurrence, beyond the biology of the primary tumor, that can be performed years after the original diagnosis. Assays that may predict the presence of dormant tumor cells and late relapse include Circulating Tumor Calls (CTCs), Disseminated Tumor Cells (DTCs) in the bone marrow, and circulating tumor DNA, proteins or metabolites. While early data is promising, further research is needed before incorporating into clinical decision-making. Identifying a biomarker to determine patients most likely to benefit from longer duration endocrine therapy, or additional therapeutic approaches, could help in reducing late relapse as well as minimizing the risk of side effects and overtreatment.

Citation Format: Gralow J. Late recurrence in 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 ES5-3.
Abstract ES6-1: Oxidative stress responses in cancer
Authors: Brugge J
Published: May 2019

Generation of reactive oxygen species (ROS), a natural byproduct of oxygen metabolism, occurs in all aerobic organisms at a controlled rate. Cancer cells are subjected to numerous cellular insults, including dysregulated oncogenes and loss of their natural extracellular matrix (ECM) interactions, that lead to the generation of high levels of ROS and selection for upregulation of anti-oxidant programs that allow adaptation to elevated ROS. Although cancer cells possess enhanced canonical antioxidant programs that neutralize ROS, they nevertheless exhibit prominent ROS levels in response to these insults, suggesting the existence of additional programs that allow cancer cells to tolerate elevated ROS.

My presentation will include a discussion of the evolving concepts about the role of oxidative stress and anti-oxidants in distinct processes associated with tumor initiation and progression and the potential for targeting anti-oxidants for therapeutic intervention. In addition, I will describe studies from our laboratory using 3-dimensional culture systems to model early events in breast cancer which have highlighted the critical role of oxidative stress in eliminating aberrantly proliferating breast epithelial cells, as well as the role of endogenous anti-oxidants in promoting proliferation and survival of pre-malignant cells. I will also discuss studies providing evidence for an unconventional mechanism whereby cancer cells co-opt the ROS-activated neuronal Ca2+-permeable TRPA1 channel in order to adapt to oxidative environments.

Citation Format: Brugge J. Oxidative stress responses in 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 ES6-1.
Abstract ES6-3: Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states
Authors: Graeber T
Published: May 2019

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

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

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

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

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

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 <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

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

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

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.