bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract ES4-1: Her2 testing - 2017 guidelines for HER2 testing
Authors: Jenkins RB 
Published: February 2018

Abstract
Currently the use of anti-HER2 directed therapy (HDT) is predicated on the identification of HER2-postive breast cancers. Immunohistochemistry (IHC) and in situ hybridization (ISH) are the most common (and FDA-approved methods) for detecting HER2-positive breast cancers. While IHC and ISH are generally robust testing modalities, both can be subject to various pre-analytic, analytic and post-analytic issues/problems. In response to these issues/problems, ASCO and CAP formed a joint HER2 Guideline Committee. The initial guidelines of this committee were released in 2007 and a first revision of the guidelines was released in 2013. Since 2013, additional issues with HER2 testing have arisen and the ASCO/CAP Committee will be releasing a second revision to the guidelines in late 2017 or early 2018. This educational presentation will discuss HER2 testing – with a focus on fluorescent in situ hybridization (FISH). It will outline the 2013 ASCO/CAP guidelines and describe some of the issues that have arisen with these guidelines. The presentation will conclude with a discussion of the pending 2017/2018 ASCO/CAP guidelines for HER2 testing.
Citation Format: Jenkins RB. Her2 testing - 2017 guidelines for HER2 testing [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES4-1.
Abstract ES4-2: Adjuvant therapy for HER2-positive breast cancers: is less more?
Authors: O'Regan RM 
Published: February 2018

Abstract
The use of trastuzumab-based chemotherapy has dramatically improved outcome for patients with early stage HER2-positive breast cancer. Given the excellent outcomes seen to date and the toxicities associated with therapy, it is critical to establish whether additional therapies can further improve outcome, and conversely if there are patients who would have a favorable outcome with less therapy.
The addition of pertuzumab to trastuzumab-based chemotherapy results in improved survival for patients with metastatic HER2-positive breast cancer and higher response rates in the pre-operative setting. Although results of the AFFINITY trial demonstrated improved outcome for adding pertuzumab to trastuzumab-based chemotherapy, the benefit was largely restricted to patients with node-positive breast cancer. Additionally, it is unclear if patients treated pre-operatively require the continued addition of pertuzumab to trastuzumab. Neratinib, a pan-HER tyrosine kinase inhibitor, reduces recurrence rate when used following adjuvant trastuzumab, but the benefit appears restricted to hormone receptor-positive breast cancers and diarrhea is a significant issue with this agent. In contrast, de-escalating treatment for patients with stage 1 HER2-positive breast cancer with the use of paclitaxel and trastuzumab is associated with extremely favorable outcomes.
To date, the treatment of HER2-positive early stage breast cancer has not taken hormone receptor status into account when selecting HER2-directed therapies. Breast cancers that express both hormone receptors and HER2 are heterogeneous and a significant proportion have a luminal A phenotype, suggesting the possibility that combined estrogen receptor and HER2 inhibition may be especially important, given the crosstalk between these pathways. Further evaluation of non-chemotherapeutic approaches in triple positive breast cancers is justified.
Citation Format: O'Regan RM. Adjuvant therapy for HER2-positive breast cancers: is less more? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES4-2.
Abstract ES4-3: Can we improve treatment tailoring in advanced HER2+ breast cancer?
Authors: Piccart MJ 
Published: February 2018

Abstract
In the 1980s the importance of HER2 signalling to the aberrant behaviour of certain breast cancer cells was recognized for the first time. The intervening 3 decades have seen an immense international translational and clinical research effort that at first identified a hitherto unknown subtype of breast cancer – HER2-positive breast cancer - and then went on to entirely transform the natural history of this aggressive disease. For women with metastatic HER2-positive breast cancer, this has meant in practical terms a doubling of median overall survival and 5-year survival rate. First with the advent of trastuzumab, followed closely by lapatinib, pertuzumab and T-DM1, the lives of thousands of women have been made both longer and better. Nevertheless, metastatic HER2-positive breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including about the “real-life” benefit of pertuzumab and T-DM1 since both the CLEOPATRA and EMILIA trials were conducted on populations that no longer exist in practice. Furthermore, despite significant research efforts with translational research and new imaging techniques, in both the advanced and early settings, no predictive biomarkers has been clinically validated to help decision making for this patient population and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens, including the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as new host of pan-HER inhibitors, drug antibody conjugates and bi-specific antibodies which may in coming years further push the boundaries of what we can do for our patients.
Citation Format: Piccart MJ. Can we improve treatment tailoring in advanced HER2+ breast cancer? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES4-3.
Abstract ES6-1: How tumor metabolism contributes to the immunosuppressive microenvironment
Authors: Rathmell JC 
Published: February 2018

Abstract
Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that T cell subsets require distinct metabolic programs. The effector CD4 T cell fates (Th1, Th2, Th17) activate a highly glycolytic program. Regulatory CD4 T cells (Treg), in contrast, utilize a more oxidative metabolism and utilize lipids as a major fuel. These metabolic distinctions may allow new understanding of T cell function in tumors and approaches to manipulate immunity. We have now examined the metabolism of Treg in detail and found that FoxP3 itself can promote oxidative metabolism characteristic of Treg and that this is critical to maximize Treg suppressive capacity. Treg can be glycolytic and proliferative in vivo. We found, however, that glucose uptake and glycolysis impaired Treg stability. Thus, Treg regulate glycolytic and oxidative metabolism to balance proliferation and suppressive function. Conversely, the requirement of effector T cells for glucose uptake and glycolysis poses a barrier to inflammatory function in tumors. We have analyzed the metabolism of CD8 T cells in clear cell Renal Cell Carcinoma (ccRCC) and identified multiple metabolic defects. Importantly, bypassing these defects can enhance T cell function, demonstrating that metabolic alterations pose barriers to anti-tumor immunity. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector and regulatory populations.
Citation Format: Rathmell JC. How tumor metabolism contributes to the immunosuppressive microenvironment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-1.
Abstract ES6-2: Do tumors overcome immune surveillance by blocking dendritic cell development
Authors: DeNardo DG 
Published: February 2018

Abstract
Tumors must evade immune-surveillance in order to progress. To this end, tumor-induced inflammation expands immune-suppressive immature granulocytes and monocytes, while limiting the functions of immune-stimulatory conventional dendritic cells (cDCs). cDC1s, a cDC subset, activate CD8+ T cells through antigen cross presentation and are marked by CD141 in humans and CD103 or CD8α in mice. cDC1s support anti-tumor CD8+ T cell responses, but cDC1 numbers are limited within the tumor environment. To understand how cDC1s are restricted in the tumor, we interrogated their development in the bone marrow (BM). We found the program responsible for the expansion of immature granulocytes and monocytes from progenitors in the BM is simultaneously suppressing the generation of cDC1s, decreasing the systemic numbers of cDC1s in breast and pancreatic cancer patients. We found that tumor-induced granulocyte stimulating factor (GCSF) mediates the down-regulation of the transcription factor IFN regulatory factor 8 (IRF8) in BM progenitors. IRF8 loss reprograms the BM progenitors, reducing their potential to develop into cDC1s. We demonstration, independent of monocyte and granulocyte expansion, that tumor-induced loss of cDC1s reduces the systemic ability to mount anti-tumor CD8+ T cell responses. Further, systemic decreases in cDC1s in breast cancer patients correlate with reduced response to chemotherapy. These data suggest a new mechanism of immune-escape whereby tumors down-regulate cDC1 differentiation from BM progenitors to impair anti-tumor CD8+ T cell immunity.
These data beg the question; are some patients unresponsive to immunotherapy because of tumor-induced impairments in dendritic cell development?
Citation Format: DeNardo DG. Do tumors overcome immune surveillance by blocking dendritic cell development [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-2.
Abstract ES8-1: Liquid biopsies in breast cancer - challenges and opportunities
Authors: Dawson S-J 
Published: February 2018

Abstract
Cell-free circulating DNA containing tumor-specific sequences can be identified in the plasma of cancer patients, providing a liquid biopsy alternative to tissue biopsies for monitoring cancer genetic changes over time. Circulating tumor DNA (ctDNA) analysis can allow real-time monitoring of tumor dynamics and treatment response from a simple blood test that is safe, reliable and easy to perform at regular intervals during therapy. Serial analysis of ctDNA provides a unique opportunity to study the evolving genomic landscape of a cancer during therapy, identify the early emergence of treatment resistance and guide targeted therapeutic decisions. The use of ctDNA for molecular disease monitoring has the potential to facilitate precision medicine and optimize cancer management across a range of malignancies. A summary of current approaches for ctDNA analysis will be presented, together with an overview of clinical applications for the use of liquid biopsies in breast cancer management.
Citation Format: Dawson S-J. Liquid biopsies in breast cancer - challenges and opportunities [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES8-1.
Abstract GS4-06: Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance
Authors: Couch FJ , Shimelis H , Hart SN , Moore RM , Thomas A , Lipton GB , Iversen E 
Published: February 2018

Abstract
Background: Germline genetic testing of individuals with a diagnosis of triple negative breast cancer, young age at diagnosis, or a family history of breast and/or ovarian cancer has led to the identification of many unique BRCA2 missense variants of uncertain significance (VUS). VUS in BRCA2 are predominantly missense mutations that have unclear relevance to breast, ovarian, and other cancers. Thus, patients found to have a germline BRCA2 VUS do not know if the variant is associated with high risks of these cancers similar to truncating mutations, intermediate risks more similar to CHEK2 mutations, or low risks of no clinical significance. Furthermore, it is unclear if germline BRCA2 VUS, or somatic VUS identified by tumor sequencing, are associated with hypersensitivity to selected DNA damaging and cross-linking agents.
Methods: We have used a homology directed repair (HDR) cell-based assay to characterize missense variants in the DNA binding domain (DBD) of BRCA2. The method has been validated using known pathogenic and known non-pathogenic BRCA2 missense variants and has 100% sensitivity (95% confidence interval (CI): 75.3%–100%) and 100% specificity (95% CI: 81.5%–100%) for pathogenic BRCA2 variants. A classifier of variant pathogenicity based on the mean and variances of the distributions of the HDR results of the known pathogenic and neutral variants has been established. We have also developed PARP inhibitor and cisplatin drug response assays for BRCA2 missense variants.
Results: Assessment of 207 BRCA2 missense variants, identified in public databases such as BRCA exchange and ClinVar, by the HDR assay identified 71 deleterious variants with &gt;99% probability of pathogenicity, 116 neutral variants with &gt;99% probability of neutrality, and 20 with hypomorphic activity and potentially intermediate risk. A combination of the functional data and sequence-based predictors of protein activity in a Bayesian prediction model resulted in classification of the deleterious variants as pathogenic cancer predisposing variants and the neutral variants as non-pathogenic with low clinical significance. The influence of the deleterious/pathogenic variants on PARPi and cisplatin response was also assessed.
Conclusion: The HDR assay is effective for characterization of BRCA2 VUS. The combination of functional data and in silico prediction models provides a robust tool for clinical annotation of BRCA2 VUS. HDR function of BRCA2 missense variants is strongly correlated with response to targeted therapy.
Citation Format: Couch FJ, Shimelis H, Hart SN, Moore RM, Thomas A, Lipton GB, Iversen E. Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-06.
Abstract GS5-04: Prediction of occult invasive disease in ductal carcinoma in situ using deep learning features
Authors: Lo JY , Grimm LJ , Mazurowski MA , Baker JA , Marks JR , King LM , Maley CC , Hwang E-SS , Shi B 
Published: February 2018

Abstract
Background: Deep learning, especially deep convolutional neural network (CNN), has emerged as a promising approach for many image recognition or classification tasks, demonstrating human or even superhuman performance. Used as feature extractor, some pre-trained CNN models can match or surpass the performance of domain-specific, “handcrafted” features. In this study, we aim to determine whether deep features extracted from digital mammograms using a pre-trained deep CNN are prognostic of occult invasive disease for patients with ductal carcinoma in situ (DCIS) on core needle biopsy.
Materials and Methods: In this retrospective study, we collected digital mammography magnification views for 99 subjects with DCIS at biopsy, 25 of which were subsequently upstaged to invasive cancer. We utilized a deep CNN model that was pre-trained on non-medical images (e.g., animals, plants, instruments) as the feature extractor. Through a statistical pooling strategy, we extracted deep features at different levels of convolutional layers from the lesion areas, without sacrificing the original resolution or distorting the underlying topology. A multivariate classifier was then trained to predict which tumors contain occult invasive disease. This was compared to the performance of traditional “handcrafted” computer vision (CV) features previously developed specifically to assess mammographic calcifications. The generalization performance was assessed using Monte Carlo cross validation and receiver operating characteristic (ROC) curve analysis.
Results: Deep features were able to distinguish DCIS with occult invasion from pure DCIS, with an area under the ROC curve (AUC-ROC) equal to 0.70 (95% CI: 0.68-0.73). This performance was comparable to the "handcrafted" CV features (AUC-ROC = 0.68, 95% CI: 0.66-0.71) that were designed with prior domain knowledge.
Conclusion: In spite of being pre-trained on only non-medical images, the deep features extracted from digital mammograms demonstrated comparable performance to "handcrafted" CV features for the challenging task of predicting DCIS upstaging.
Acknowledgments: This work was supported in part by NIH/NCI R01-CQA185138 and DOD Breast Cancer Research Program W81XWH-14-1-0473.
Citation Format: Lo JY, Grimm LJ, Mazurowski MA, Baker JA, Marks JR, King LM, Maley CC, Hwang E-SS, Shi B. Prediction of occult invasive disease in ductal carcinoma in situ using deep learning features [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-04.
Abstract GS6-06: Identifying metastatic drivers in patient-derived xenograft models of triple negative breast cancer
Authors: Powell E , Shao J , Picon HM , Ge Z , Echeverria GV , Peoples M , Bristow C , Cai S , Tu Y , McCoy AM , Piwnica-Worms D , Draetta G , Edwards JR , Moulder SL , Symmans WF , Heffernan TP , Liang H , Piwnica-Worms H 
Published: February 2018

Abstract
Metastases are responsible for the vast majority of deaths due to breast cancer. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of metastasis and poor prognosis. We are employing patient derived xenograft (PDX) models of TNBC to identify drivers of metastasis. Tumor samples are obtained from the breast tumors of patients with TNBC and engrafted immediately into the humanized mammary fat pads of immune compromised mice. Lentiviral transduction was employed to express bioluminescent and fluorescent markers in two independent PDX models of TNBC. Using these models, we demonstrated that human breast tumors are capable of completing all stages of the metastatic cascade in mice, and metastatic lesions are observed in organs normally found in patients with metastatic breast cancer including lung, liver, bone, brain, and lymph nodes. Dynamic and reversible epithelial to mesenchymal transition (EMT) was observed as tumors metastasized to lung and were re-passaged to recipient mouse mammary glands. Lung metastases were isolated using bioluminescence imaging and lung metastasis gene expression signatures were generated. Metastasis signatures from two independent PDX models were compared to identify genes that were commonly de-regulated in lung metastases relative to corresponding mammary tumors. Comprehensive gain-of-function screens were then conducted in vivo to identify functional drivers of TNBC metastasis. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a metastatic driver in this screen. CEACAM5 mRNA and protein levels were elevated in lung metastases relative to corresponding mammary gland tumors in mice. In addition, we demonstrated that CEACAM5 expression was upregulated in the lung metastases of breast cancer patients, and its expression inversely correlated with patient survival. Our data indicate that the metastatic function of CEACAM5 is to promote growth of breast tumors in the lung by inducing MET (mesenchymal to epithelial transition).
Citation Format: Powell E, Shao J, Picon HM, Ge Z, Echeverria GV, Peoples M, Bristow C, Cai S, Tu Y, McCoy AM, Piwnica-Worms D, Draetta G, Edwards JR, Moulder SL, Symmans WF, Heffernan TP, Liang H, Piwnica-Worms H. Identifying metastatic drivers in patient-derived xenograft models of triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-06.
Abstract IS-2: The challenge of definition and adoption; perspective from the Middle East
Authors: Al Sukhun S 
Published: February 2018

Abstract
Cancer has become one of the leading causes of morbidity and mortality worldwide. The World Health Organization has warned the number of cancer diagnoses in the Middle East (ME) in the next two decades will nearly double unless authorities take action. This means the ME will have the highest relative increase of all regions in the world. Breast cancer is the most common cancer in ME (15%) and the second most common in terms of cancer related mortality (9%).
Across the world, the cost of healthcare is rising faster than economies are growing, creating the case for value based healthcare (VBHC), with value based medicine taking center stage. VBHC helps healthcare providers manage cost increases, make the best use of finite resources and deliver improved care to patients. The challenge for effective control of cancer is multifaceted. It mandates integration of effective cancer prevention, encouraging early detection, and utilization of resource adapted therapeutic and supportive interventions. Overly expensive drugs may consume resources; not just drugs for other conditions but paying for these may reduce the ability to invest in other cancer services like surgery, radiotherapy or early detection services. Access to cancer drugs is imperative but their price tag is creating a significant barrier to access.
Countries in the ME are heterogeneous in terms of income. However, they all have different aspects of challenge when it comes to implementing value based models. Many have other priorities such as improving quality and increasing access to basic health services. Others struggle with the challenges of fragmented systems, and the limits of existing healthcare infrastructure and operations. A particular challenge among others is the deficiency in the core components focusing on objective measures of outcomes and costs; including policies and institutions for value in healthcare. These obstacles are, indeed, shared by many other countries. As technology advances and new value-based approaches take hold in wealthy economies, those countries that are still investing in developing their health systems have an opportunity to learn from their experience, saving precious resources and delivering better long-term care for their societies.
Citation Format: Al Sukhun S. The challenge of definition and adoption; perspective from the Middle East [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr IS-2.