bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B15: Computed tomography for quantitative imaging of live cancer cells with isotropic 3D spatial resolution
Authors: Kelbauskas Laimonas , Shetty Rishabh M. , Cao Bin , Wang Kuo-Chen , Smith Dean , Wang Hong , Chao Shih-Hui , Ashcroft Brian , Kritzer Margaret , Glenn Honor , Niemela Erik , Johnson Roger H. , Eriksson John , Meldrum Deirdre R.
Published: March 2017

Quantitative 3D imaging of live single tumor cells enables direct insights into the intricacies of cellular machinery while offering new ways of assessing intercellular variability. Since its invention, X-ray computed tomography has been indispensable in the clinic for cancer diagnostic and prognostic purposes due to its quantitative manner of imaging owing to the isotropic 3D spatial resolution. Although its principles have recently begun to be implemented in the optical spectral range for single cell imaging, the applications have mainly been directed towards imaging fixed cells in absorption mode for studying an important hallmark of cancer - nuclear architecture. We present an approach that utilizes the concept of computed tomography for quantitative functional 3D imaging of live single cells. The method offers truly isotropic 3D spatial resolution and enables imaging of natural suspension cells, such as non-solid tumor or immune system cells, as opposed to cells attached to substrates, as is common to the majority of other imaging approaches. We report on technical characteristics of the method as well as experimental findings of a nuclear and mitochondrial dynamics study in human myelogenous leukemia and mouse macrophage cells as a validation. The absolute quantification capability of the method makes it a powerful tool in the field of oncology by enabling direct studies of cellular and nuclear architecture dynamics in the context of tumorigenesis and progression.

Citation Format: Laimonas Kelbauskas, Rishabh M. Shetty, Bin Cao, Kuo-Chen Wang, Dean Smith, Hong Wang, Shih-Hui Chao, Brian Ashcroft, Margaret Kritzer, Honor Glenn, Erik Niemela, Roger H. Johnson, John Eriksson, Deirdre R. Meldrum. Computed tomography for quantitative imaging of live cancer cells with isotropic 3D spatial resolution. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B15.
Abstract B52: 2-in-1 “sniper” nanomedicines rescue dendritic cells by two pronged inhibition of JAK2/STAT-3 and p38 MAPK pathways
Authors: Natarajan Siva Kumar , Chandhrasekar Vineethkrishna , Ismail Noha , Swaminathan Sharada , Sengupta Shiladitya , Kulkarni Ashish
Published: March 2017

Immunotherapy has stolen the spotlight as one of the most promising therapeutic strategies for many late stage cancers. Despite exhibiting immense potential, dendritic cell (DC) based immunotherapy has shown limited clinical benefits owing to the antagonistic effects of regulatory T cells. While regulatory T-cells dampen the immune response elicited by T effector cells through known control mechanisms, they also constitute an immune suppressive milieu with several other tumor-derived factors that impair the development and maturation of dendritic cells. This serves as a mechanism for the tumor cells to escape immune surveillance and control. It is well known that inhibition of the JAK2/STAT-3 and p38 MAPK pathways in DCs negates the tumor-induced suppression of their maturation. But it has been shown that inhibition of the STAT-3 pathway alone could counteract the suppressive effects of Interleukin-6 only and inhibition of the p38 MAPK pathway in cancer cells can be counterproductive as it is important for apoptosis. Thus it becomes essential that, to achieve a superior therapeutic response it is imperative to couple the inhibition of STAT-3 along with p38 MAPK pathway and to also ensure that it is targeted towards dendritic cells of the tumor microenvironment. We have catered to these necessities in this study by proposing a novel, supramolecular 2-in-1 nanomedicine designed by the self-assembly of patient compatible lipids that houses a STAT-3 inhibitor and a p38-α inhibitor , thus ensuring the deterministic delivery of both the drugs in a spatially constrained manner. We have shown that the 2-in-1 nanomedicine achieves superior efficacy by releasing both the drugs in a sustained manner during the differentiation of DCs and hence upregulates dendritic cell maturation markers like CD80, CD86 and MHC II. More importantly we aim to program the drug-loaded nanoparticles for selective uptake by dendritic cells of the tumor milieu. In a separate experiment we have shown that dendritic cells favor the uptake of nanoparticles with specific surface charges both in vitro and in vivo in B16F10 mouse melanoma model. Thus we conclude that the proposed 2-in-1 “sniper” nanoparticle can contribute immensely towards a targeted immunotherapy approach for rescuing dendritic cells from immune suppression in aggressive cancers like melanoma.

Note: This abstract was not presented at the conference.

Citation Format: Siva Kumar Natarajan, Vineethkrishna Chandhrasekar, Noha Ismail, Sharada Swaminathan, Shiladitya Sengupta, Ashish Kulkarni. 2-in-1 “sniper” nanomedicines rescue dendritic cells by two pronged inhibition of JAK2/STAT-3 and p38 MAPK pathways. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B52.
Abstract B59: Mathematical Model of Oxygen Transport in Tuberculosis Granulomas
Authors: Datta Meenal , Via Laura , Chen Wei , Baish James , Xu Lei , Barry Clfton , Jain Rakesh
Published: March 2017

Pulmonary granulomas—the hallmark of Mycobacterium tuberculosis (MTB) infection—are dense cellular lesions that, like solid tumors, often feature regions of hypoxia and necrosis partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption, based on models originally derived for avascular tumors, to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution—using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis—was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment.

Citation Format: Meenal Datta, Laura Via, Wei Chen, James Baish, Lei Xu, Clfton Barry, Rakesh Jain. Mathematical Model of Oxygen Transport in Tuberculosis Granulomas. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B59.
Abstract IA07: Single cell functional proteomics and metabolomics: A conduit to physicochemical models of tumor biology
Authors: Heath James R.
Published: March 2017

Advances in single cell methods have opened up fundamentally new ways to think about biology. One new concept involves specific experiments that provide a direct and quantitative bridge between complex biological phenomena and the physico-chemical laws. To this end, we have developed microchip-based methods for measuring large panels of functional proteins and metabolites from statistical numbers of single cells. Functional proteins include secreted signaling proteins that provide measures of immune cell behaviors, and phosphorylated (activated) enzymes that reflect intracellular signaling flux and are often hyperactivated (and thus constitute drug targets) in cancers. For metabolites, we have focused on those associated with cellular energy flux. Importantly, cells sense and respond to their environments by adjusting the levels of such analytes. The following observations are the basis for connecting such measurements to the physico-chemical laws:

1. Cells are finite systems in a thermodynamic sense. This means that otherwise identical cells will have different numbers of the measured analytes.

2. A histogram of levels of the analytes versus frequency of observation across many single cells represents the fluctuations of those cells. In the maximum entropy formulation of thermodynamics, fluctuations can be used to identify the stable steady state of the cells (the state of minimum free energy), as well as constraints that prevent (constrain) the cells from reaching that steady state.

3. When many analytes are measured from the same cells, analyte-analyte correlations are extracted. If the measurements are quantitative (as are ours), then relationships between the chemical potential of a given analyte and its copy numbers is established. These to values represent cognate intensive and extensive parameters, and can allow for precise predictions for how cells respond to a weak perturbation through the Principle of Le Chatelier. They also provide an approach for distinguishing between weak and strong perturbations, since strong perturbations cause a cell-state change, while weak perturbations do not.

In this talk, I will discuss provide detail on the above described experimental platforms, and describe how analyses based on these concepts can yield insight into clinically meaningful problems associated with therapy resistance in glioblastoma and melanoma.

Citation Format: James R. Heath. Single cell functional proteomics and metabolomics: A conduit to physicochemical models of tumor biology. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr IA07.
Abstract IA20: Material-based therapeutic cancer vaccines
Authors: Mooney David J.
Published: March 2017

The recent successes of checkpoint blockade therapy demonstrate the power of immunotherapy. The correlation between patient response to these therapies and the extent of T cell infiltration into tumors suggest that vaccines capable of generating robust T cell responses to cancer antigens may lead to a greater fraction of patients responding to checkpoint blockade. Therapeutic cancer vaccines often depend on extensive manipulation of antigen presenting cells in the laboratory, but subsequent cell infusion typically leads to large-scale cell death and limited efficacy. We are instead developing biomaterials that provide controlled delivery of immunomodulatory factors, in certain ways mimicking aspects of microbial infection, to resident dendritic cells in order to bypass the need to manipulate cells in the laboratory. These material strategies allow control over immune cell trafficking and activation, cause tumor regression in preclinical models, and are currently in a Phase I clinical trial. Recent preclinical studies demonstrate synergy between these material-based vaccines and anti-PD1/CTLA4.

Citation Format: David J. Mooney. Material-based therapeutic cancer vaccines. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr IA20.
Abstract PR08: Mutant KRAS decouples glycolysis from cell mechanics in non-small cell lung cancer
Authors: Park Jin Suk , Sudderth Jessica , Gao Boning , Bachoo Robert , Danuser Gaudenz
Published: March 2017

Reprogramming of the cellular metabolism is an accepted hallmark of cancer. On the other hand, increasing evidence suggests the importance of the microenvironment, including its mechanical properties, in tumor development and metastasis. Whether cellular metabolism and cell mechanics are interdependent has been relatively unexplored, although recent works from several labs seem to suggest a direct link between microenvironment and metabolic state of cells. My project focuses on this mechano-metabolism in cancer. Using metabolic flux analysis, we show that the metabolism of untransformed human bronchial epithelial cells (HBECs) responds to the stiffness of the extracellular matrix. Relative to the cells on soft substrates, the cells on stiff substrates had elevated rates of glycolysis by 2.8-fold and of oxidative respiration by 1.2-fold. However, this mechano-sensitivity is lost in hTert/p53/myc/Kras-transformed lung epithelial cells, as well as non-small cell lung cancer (NSCLC) that harbors the KRAS mutations. Interestingly, these cells assume overall higher rates of glycolysis and oxidative respiration, independent of cell substrate stiffness. Thus far I have been able to identify that the mechano-desensitization is driven by the Kras mutations, which constitutively activate downstream signal cascades including the MAPK pathway. In addition, isotope tracing shows that mutant KRAS is required to generate citrate from glucose on soft substrates, and the absence of KRAS mutations significantly hinder glycolysis upon the treatment with blebbistatin. This study subsequently establishes the novel insight that the metabolic stabilization due to the mechano-insensitivity of cancer cells is driven by mutant KRAS, which may be advantageous when out-competing the surrounding cells over the course of tumorgenesis.

This abstract is also being presented as Poster A55.

Citation Format: Jin Suk Park, Jessica Sudderth, Boning Gao, Robert Bachoo, Gaudenz Danuser. Mutant KRAS decouples glycolysis from cell mechanics in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR08.
Abstract PR10: Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects
Authors: Metcalf Chester , Poll Derek van der , Zhao Liang , Halo Tiffany , Lazarus Doug , Stockmann Adam , Peters Christian , Brown Donna , Case Roy , Rohde Ellen , Jayaraman Lata , Wang Hongwei , Crowell Tiffany , Senderowicz Adrian , Eliasof Scott
Published: March 2017

Cerulean Pharma Inc.'s Dynamic Tumor Targeting™ Platform creates nanoparticle-drug conjugates (NDCs) designed to significantly mitigate a payload's limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. By conjugating drug payloads to our novel β-cyclodextrin-PEG copolymer through linker strategies that allow modulation of release and pharmacokinetics (PK), we provide advantages over entrapped nanoparticle strategies, e.g., polymeric nanoparticles and liposomes. Cerulean has two NDCs in the clinic, CRLX101 and CRLX301, evidencing the translatability of our technology. CRLX101 has been dosed in over 350 patients and CRLX301 is in an ongoing Phase 1/2a trial. Our Dynamic Tumor Targeting Platform is applicable to a diverse range of drug payload possibilities, including small molecules with a host of physiochemical properties, i.e., hydrophobic and hydrophilic payloads, and functional groups with chemical handles for conjugation. To illustrate the capabilities of our platform we will present the biological impact of a series of cabazitaxel-containing NDCs with linkers encompassing a diversity of in vitro release rates. In vivo PK studies showed high and sustained levels of released drug in tumor tissues (>168 hrs), and in vivo mouse tumor model studies demonstrated vastly improved efficacy, i.e., tumor regression and significant tumor growth delay, and survival over separately dosed cabazitaxel including efficacy in a taxane-resistant tumor model. Cerulean continues to expand its platform through the development of new and emerging capabilities to treat patients living with cancer. In this regard, we also will address the future evolution of NDCs, including the conjugation of multiple payloads to a single NDC and the development of antibody-conjugated NDCs.

This abstract is also being presented as Poster B43.

Citation Format: Chester Metcalf, III, Derek van der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Christian Peters, Donna Brown, Roy Case, Ellen Rohde, Lata Jayaraman, Hongwei Wang, Tiffany Crowell, Adrian Senderowicz, Scott Eliasof. Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR10.
Abstract BS1-1: Transcription factor stability and stem cell maintenance
Authors: Dixit VM
Published: March 2017

Proto-oncogenes ETV1, ETV4, and ETV5 belong to the PEA3 family of ETS transcription factors and have been identified recently in prostate cancer chromosomal rearrangements that result in their overexpression. Little is known, however, about their post-translational regulation. We previously showed that ETV1, ETV4, and ETV5 interact with the ubiquitin ligase COP1. COP1 together with its binding partner DET1 ubiquitinates ETV1, resulting in its proteasomal degradation. Importantly, truncation of ETV1 by the TMPRSS2:ETV1 translocation found in prostate cancer removes its COP1 binding motif and thereby enhances its stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors, COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia in vivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein. I will discuss unpublished work that underscores the importance of COP1 as tumor suppressor.

References:

1. Wertz I, O'Rourke K, Zhang Z, Dornan D, Arnott D, Deshaies R, and Dixit VM (2004). Human De-Etiolated-1 Regulates c-Jun by Assembling a CUL4A Ubiquitin Ligase. Science 303: 1371-1374.

2. Vitari AC, Leong KG, Newton K,Yee C, O'Rourke K, Liu J, Phu L, Vij R, Ferrando R, Couto SS, Mohan S, Pandita A, Hongo J-A, Arnott D, Gao W-Q, French DM, and Dixit V (2011) COP1 is a Tumor Suppressor that Causes Deregulation of Proto-oncogenic ETS Transcription Factors. Nature 474: 403-408.

3. Suriben R, Kaihara KA, Reichelt M, Kummerfeld SK, Modrusan Z, Dugger DL, Newton K, Webster JD, Liu J, Hebrok M, Dixit VM (2015). β-cell insulin secretion requires the ubiquitin ligase COP1. Cell 163: 1457-1467.

Citation Format: Dixit VM. Transcription factor stability and stem cell maintenance [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 BS1-1.
Abstract BS2-1: A role of extracellular miRNA in breast cancer metastasis
Authors: Wang SE
Published: March 2017

Extracellular microRNAs (miRNAs) that can be detected in the circulation are novel mediators of intercellular communication and are considered emerging biomarkers for human diseases. Using cell-secreted extracellular vesicles (e.g., exosomes) as vehicles, miRNAs secreted by cancer cells can travel to and enter various types of niche cells in primary and pre-metastatic tumor microenvironments. Upon entering niche cells, miRNAs regulate gene expression to prepare the niche for cancer progression. Our lab focuses on defining the roles of breast cancer secreted miRNAs in adapting local and distal niche cells and tissues in cancer progression and metastasis. Through de novo sequencing and PCR of circulating small RNAs in the pre-treatment sera of stage II-III breast cancer patients we identified circulating miRNAs as biomarkers for cancer progression to metastatic disease. Subsequent mechanistic studies revealed important functions of breast cancer secreted miRNAs in various aspects of cellular behaviours. Our lab is currently exploring additional mechanisms through which breast cancer-derived, extracellular miRNAs contribute to the multifaceted reprogramming of non-cancerous cells in the tumor microenvironment as well as novel therapeutic strategies targeting cancer-derived extracellular miRNAs for their function in cancer-host communication.

Citation Format: Wang SE. A role of extracellular miRNA in breast cancer metastasis [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 BS2-1.
Abstract ES1-1: Non-cell-autonomous drivers of tumor growth and progression
Authors: Polyak K
Published: March 2017

Cancer cells even within the same tumor can display startling differences for many features including migratory/invasive potential and sensitivity to therapeutic agents. This intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. In solid tumors differences in the local microenvironment, in part due to variability in blood supply and topologic differences in the distribution of leukocytes, can lead to high degree of spatial heterogeneity and also select for cancer cells with different properties. While our ability to define intratumor clonal heterogeneity has grown immensely in the past few years due to technologic advances enabling whole genome sequencing studies even at the single cell level, our understanding of the functional relevance of this heterogeneity has been lagging behind. Similarly, our definition of cancer drivers has been based on the relative frequency of the cells within tumors and based on their cell-autonomous function, thus, by definition neglecting the potential relevance of minor clones and non-cell-autonomous (e.g., paracrine and juxtracrine) effects.

In experimental models there is increasing evidence for cooperation among cancer cell clones with different properties, but identifying and characterizing such interactions in clinical samples has been challenging. At the same time, emerging data suggest that intratumor clonal heterogeneity is maintained by non-cell-autonomous drivers and many of these never achieve clonal dominance due to lack of selective advantage. Thus, it is likely that non-cell-autonomous driver clones exist in human tumors and the effects of the microenvironment are mostly non-cell-autonomous as well. Because interactions among clones of cancer cells and between cancer cells and the tumor microenvironment have a major impact on overall therapeutic outcomes, understanding these interactions is necessary for the design of more effective treatment strategies for heterogeneous tumors.

Citation Format: Polyak K. Non-cell-autonomous drivers of tumor growth and progression [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 ES1-1.
Abstract ES1-3: umor-stroma interactions in breast cancer progression
Authors: Isacke CM
Published: March 2017

The interaction of tumor cells with stroma cells and stromal components not only promotes tumor progression and metastasis, but also influences tumor cell responses to chemotherapy, endocrine therapy and targeted agents. As a consequence, there is an urgent need to identify strategies to efficiently target these interaction pathways for the prevention or suppression of metastatic disease and to overcome treatment-resistant tumor progression in advanced breast cancer.

This talk will focus on the tumor-stroma crosstalk pathways underpinning the striking heterogeneity between different breast cancers in their ability to recruit and activate a pro-tumorigenic stroma. In particular (a) the mechanisms involved in the activation of cancer-associated fibroblasts (CAFs), (b) the role of activated pericytes in promoting metastatic dissemination, and (c) the mechanisms by which a productive microenvironmental niche is initiated at metastatic sites.

Citation Format: Isacke CM. umor-stroma interactions in breast cancer progression [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 ES1-3.
Abstract ES3-2: Optimizing Her2- directed treatment in early stage disease
Authors: Tolaney S
Published: March 2017

Amplification of HER2 is present in approximately 18-20% of all breast cancer, and targeted anti-HER2 therapies have transformed our approach for this subtype of disease. Trastuzumab-based chemotherapy remains the standard therapy for these patients, however, there remain several questions in determining the optimal treatment regimen: (1) What is the role of anthracyclines? ; (2) What is the optimal preoperative regimen?; (3) How do we treat small, node-negative HER2+ breast cancers?; (4) Should all patients receive pertuzumab, and in what setting?; (5)Does Trastuzumab-DM1 have a role in the early stage setting? This educational session will review the available data to address each of these questions, and will provide recommendations for optimizing HER2- directed therapy in the early stage setting.

Citation Format: Tolaney S. Optimizing Her2- directed treatment in early stage disease [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 ES3-2.
Abstract ES6-3: ES6-3 Radiation implications post neoadjuvant therapy
Authors: Smith BD
Published: March 2017

Neoadjuvant therapy offers unique challenges and opportunities for the radiation oncologist. Classical indications for radiation have been rooted in the pathologic analysis of tissue resected prior to treating the patient with systemic therapy. However, in patients treated with neoadjuvant therapy, pathologic findings are frequently altered by the administration of systemic therapy, and thus classical indications for radiation may be clouded. Nevertheless, the degree of response to neoadjuvant therapy offers a novel prognostic factor which reflects intrinsic tumor biology and affords the opportunity for a new, precision approach to risk stratification and radiation therapy treatment decision making.

To maximally capitalize on the information gained from treating a patient with neoadjuvant chemotherapy, patients must be meticulously staged, preferably by a multidisciplinary team, prior to initiation of systemic therapy. Ultrasound of the regional nodal basins including the low axillary, infraclavicular, supraclavicular, and internal mammary nodal chains with ultrasound-guided fine needle aspiration of radiographically abnormal nodes enables detailed mapping of the local-regional disease extent. Cross-sectional imaging with CT and/or PET/CT is also helpful to permit customized radiation field design after systemic therapy and surgery. These imaging studies are invaluable to the radiation oncologist and allow for optimal field design to facilitate cure. Additionally, nodal surgery prior to administration of systemic therapy, while helpful in documenting pre-treatment nodal status, results in loss of ability to accurately assess response to chemotherapy in the lymph nodes and is thus avoided in our practice.

The available evidence indicates that patients experiencing a pathologic complete response have exceptional local-regional control. Accordingly, current randomized trials are exploring whether either radiation or surgery can be de-escalated within this context. In contrast, for patients with significant residual tumor burden following neoadjuvant chemotherapy, local-regional control outcomes are suboptimal for those with triple negative or HER2 positive disease. Novel strategies to escalate therapy with radiosensitizers or other biologic agents are needed for this population.

Citation Format: Smith BD. ES6-3 Radiation implications post neoadjuvant therapy [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 ES6-3.
Abstract ES8-1: ES8-1 Managing the aftermath of estrogen deprivation in survivors
Authors: Partridge AH
Published: March 2017

Endocrine therapy is the most important systemic treatment for women with hormone receptor-positive breast cancer, resulting in substantial risk reduction and improvements in survival. Yet, the strategies to reduce or block estrogen including ovarian suppression or ablation, aromatase inhibition or tamoxifen can all lead to symptoms and long-term toxicities associated with estrogen deprivation. The effect of long-term estrogen deprivation on bone, heart and brain health may lead to substantial morbidity and should be considered when making treatment decisions and managed in follow-up. However, even less serious daily symptoms including hot flashes, mood changes, insomnia, weight gain, vaginal dryness and sexual dysfunction can lead to profound negative long term effects on a patient and her relationships. Thus even these more minor concerns should be considered and managed proactively for patient overall health and well-being. For serious co-morbidity risks, attention to optimizing risk factors and monitoring when appropriate (e.g., DEXA scan) is prudent. For symptom management, it is generally recommended that survivors forgo estrogen replacement therapy although sometimes a low dose, short course of replacement therapy is necessary. Otherwise, strategies include a multi-prong approach focusing not only on improving particular symptoms, but also on mitigating the downstream effects and emotional impact. Evidence-based strategies for management of vaginal dryness, hot flashes and other problems will be discussed

Citation Format: Partridge AH. ES8-1 Managing the aftermath of estrogen deprivation in survivors [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 ES8-1.
Abstract ES8-2: ES8-2 Energy balance: The new adjuvant therapy?
Authors: Irwin ML
Published: March 2017

Obesity affects the risk of breast cancer development and the risk of recurrence and death from breast cancer. Furthermore, weight gain after diagnosis of breast cancer (independent of BMI at diagnosis) is associated with higher all-cause mortality rates compared with maintaining body weight. The American Cancer Society (ACS) recommends cancer survivors achieve and maintain a healthy weight, follow a dietary pattern high in vegetables, fruits, and whole grains, engage in 150 minutes per week of aerobic exercise plus two strength training sessions per week, and avoid physical inactivity. Despite these recommendations, over 65% of breast cancer survivors are overweight or obese, and fewer than 30% engage in recommended levels of physical activity. Recently, the American Society of Clinical Oncology (ASCO) published a position statement on obesity and cancer with a multipronged initiative to reduce the impact of obesity on cancer, with one of the initiatives focused on determining best methods to help cancer survivors make effective changes in lifestyle behaviors. The impact of weight loss and exercise trials on breast cancer outcomes, as well as future research opportunities and the role of clinical and community-based weight management programs, will be discussed.

Citation Format: Irwin ML. ES8-2 Energy balance: The new adjuvant therapy? [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 ES8-2.
Abstract MS2-1: MS2-1 Targeting the ATR checkpoint in cancer therapy
Authors: Zou L
Published: March 2017

Rémi Buisson1, Michael S. Lawrence2, Cyril H. Benes1 & Lee Zou1,3

1. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA. 2. Broad Institute of Harvard and MIT, Cambridge, MA. 3. Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA.

Recent cancer genomics studies have revealed that the mutation signatures of APOBEC3A/B are commonly detected in several cancer types, such as bladder, breast, head and neck cancers, lung adenocarcinoma, and lung squamous cell carcinoma. APOBEC3A/B are members of the APOBEC family of cytosine deaminases. While APOBEC3 proteins are important for the innate immunity against viral infection, they are not expressed in normal tissues. When APOBEC3A/B are aberrantly expressed in cancer cells, they become potent “mutators”, which may promote genomic instability and contribute to tumor evolution. Interestingly, recent studies have suggested that APOBEC3A/B may act during DNA replication. However, whether the APOBEC3A/B activity in cancer cells induces DNA replication stress, and whether this activity creates a vulnerability in cancer cells that can be exploited therapeutically, remains unknown.

In this study, we show that APOBEC3A imposes a unique type of mutator-driven DNA replication stress, and that the ATR kinase plays a crucial role in antagonizing this stress. APOBEC3A expression activates ATR during DNA replication through UNG2-generated abasic sites. Surprisingly, ATR inhibition in APOBEC3A-expressing cells results in a drastic surge of abasic sites at replication forks, revealing an ATR-mediated feedback loop countering the action of APOBEC3A during replication. Mechanistically, ATR inhibition unleashes APOBEC3A-driven ssDNA accumulation at replication forks, which propagates the substrate of APOBEC3A and ultimately drives cells into replication catastrophe. In a panel of cancer cell lines, ATR inhibitor selectively induces replication catastrophe in those harboring high APOBEC3A/B activity, showing that the APOBEC3A/B activity in cancer cells confers susceptibility to ATR inhibition. Together, these results suggest that the unique APOBEC-driven replication stress in cancer cells may offer a new opportunity for ATR-targeted therapy.

Citation Format: Zou L. MS2-1 Targeting the ATR checkpoint in cancer therapy [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 MS2-1.
Abstract MS2-3: MS2-3 Clinical implications of DNA repair and genome instability research
Authors: Tutt A
Published: March 2017

Breast cancer has now been subjected to extensive molecular characterisation. Although much attention has focused on transcriptional profiling, with consequent identification of a number of biological sub-types, it is clear that breast cancers show significant variability in their somatic genome. Breast cancers are diseases that are largely dominated by copy number aberrations (CNAs) rather than single nucleotide variants (SNVs). Although HER2 is the poster child CNA driven therapeutic target a number of other mutation and CNA candidates are being pursued. The mutational processes that drive the different forms of genomic instability in breast cancer are increasingly understood and have been described in the last year. These mutational and rearrangement signatures may reveal aberrations in the DNA damage response that themselves represent a vulnerability and a therapeutic target. I will discuss a range of strategies and clinical trials being employed to target DNA repair, genome instability and consequent replicative stress in breast cancer.

I will also discuss the state of development of assays that categorise a range of forms of mutational signature and genome instability which may act in future as predictive biomarkers of therapy response or resistance to DNA damage response targeting therapies with utility in the clinic.

Citation Format: Tutt A. MS2-3 Clinical implications of DNA repair and genome instability research [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 MS2-3.
Abstract OT1-01-02: A phase II trial of neoadjuvant docetaxel/cyclophosphamide followed by epirubicin/cyclophosphamide for triple-negative breast cancer
Authors: Tanaka N , Hirano A , Inoue H , Ogura K , Hattori A , Jibiki N , Yukawa H , Matsuoka A , Kodera A , Kamimura M , Naritaka Y , Shimizu T
Published: March 2017

Background

Currently, an anthracycline followed by a taxane as adjuvant or neoadjuvant chemotherapy is considered the most effective treatment for patients with triple-negative breast cancer. However, docetaxel followed by an anthracycline as neoadjuvant chemotherapy results in a higher rate of pathological complete response (pCR) than the regimen including an anthracycline followed by docetaxel (Iwata et al. Jpn J Clin Oncol 2011). Adjuvant docetaxel/cyclophosphamide (DC) treatment resulted in prolonged survival compared to adjuvant doxorubicin/cyclophosphamide. Therefore, we planned a phase II trial of DC followed by epirubicin/cyclophosphamide (EC) (Trial registration: UMIN000011031).

Trial design

This is a phase II trial to evaluate the efficacy and toxicity of DC followed by EC as neoadjuvant therapy for triple-negative breast cancer. Patients will receive four cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 21 days, followed by four cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 21 days.

Eligibility criteria

Patients with histologically diagnosed triple-negative breast cancer, T1–4, N1–3, or T2–T4, N0 based on a core needle biopsy, will be included in this trial. Eligible patients must be between 20 and 70 years of age with a performance status of 0–2 and adequate organ function. They must not have undergone any prior operation, radiation therapy, chemotherapy, endocrine therapy, or immunotherapy.

Specific aims

The primary endpoint is the pCR rate in the breast and axilla, and the secondary endpoints are the breast-conserving rate, toxicities, feasibility, and 5-year overall survival and relapse-free survival. pCR is defined as disappearance of invasive cancer cells, including those in the axilla, although the presence of residual intraductal cancer is acceptable.

Statistical methods

The sample size was calculated using the Simon method, with a type I error of 10% and a study power of 80%. The expected pCR rate is 25%, with a threshold pCR rate of 10%, and the required number of patients has been estimated to be 33.

Present and target accrual

Patient accrual within two medical centers was started in September 2013. We plan to enroll a total of 34 patients in the trial.

Citation Format: Tanaka N, Hirano A, Inoue H, Ogura K, Hattori A, Jibiki N, Yukawa H, Matsuoka A, Kodera A, Kamimura M, Naritaka Y, Shimizu T. A phase II trial of neoadjuvant docetaxel/cyclophosphamide followed by epirubicin/cyclophosphamide for triple-negative 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 OT1-01-02.
Abstract OT1-02-07: SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer
Authors: Rugo HS , Pegram MD , Gradishar WJ , Cortes J , Curigliano G , Hong S , Wigginton JM , Lechleider RJ , Cardoso F
Published: March 2017

Background: Despite significant advances in targeted therapy, HER2+ metastatic breast cancer (MBC) remains incurable. Ideal treatment includes pertuzumab and trastuzumab in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine on progression. Optimal treatment regimens in the third and greater line of therapy are not defined, but continued anti-HER2 therapy is recommended. Margetuximab is a Fc-modified monoclonal antibody to HER2 that recognizes the same epitope on HER2 as does trastuzumab, with similar affinity. Margetuximab demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to trastuzumab. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to trastuzumab. In a Phase 1 dose escalation and expansion trial, margetuximab showed single agent clinical activity against HER2+ tumors in patients previously treated with trastuzumab and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that margetuximab plus chemotherapy (CTX) is more effective than trastuzumab plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is determined to have 80% power to detect a hazard ratio for OS of 0.75. Secondary endpoints are investigator assessed PFS and centrally assessed overall response rate. Eligibility includes prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine; no more than 3 prior lines of therapy in the metastatic setting; prior demonstration of HER2+ status at a local reference laboratory; and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician's choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either margetuximab or trastuzumab until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13.

Citation Format: Rugo HS, Pegram MD, Gradishar WJ, Cortes J, Curigliano G, Hong S, Wigginton JM, Lechleider RJ, Cardoso F. SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ 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 OT1-02-07.
Abstract OT1-02-09: A phase 2 randomized, double-blinded, controlled study of ONT-380 vs. placebo in combination with capecitabine (C) and trastuzumab (T) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB)
Authors: Hamilton E , Borges V , Murthy R , Anders C , Cameron D , Carey L , Müller V , Curigliano G , Gelmon K , Hortobagy G , Krop I , Loibl S , Pivort X , Pegram M , Slamon D , Hurvitz S , Tsai M , Winer E
Published: March 2017

Background: ONT-380 is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, ONT-380 demonstrated synergistic activity with T, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, ONT-380 was combined with C and T in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and T. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, ONT-380 is now being evaluated in a Phase 2 study in combination with C and T (HER2CLIMB).

Trial Design: The primary study objective is to assess the effect of ONT-380 vs. placebo given with C + T on progression-free survival (PFS) based on independent central review. Additional objectives include ORR, duration of response, clinical benefit rate, and safety. The study population includes adult pts with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, T, pertuzumab and T-DM1 but not C or lapatinib. Pts with brain mets,including untreated or progressive mets, may be enrolled. 180 pts will be enrolled in North America and Europe. Pts are receiving C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and T (8 mg/kg IV loading dose; 6 mg/kg IV once every 21 days), and are being randomized in a 2:1 ratio to ONT-380 300 mg PO BID or placebo. Pts with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee is monitoring pt safety.

Citation Format: Hamilton E, Borges V, Murthy R, Anders C, Cameron D, Carey L, Müller V, Curigliano G, Gelmon K, Hortobagy G, Krop I, Loibl S, Pivort X, Pegram M, Slamon D, Hurvitz S, Tsai M, Winer E. A phase 2 randomized, double-blinded, controlled study of ONT-380 vs. placebo in combination with capecitabine (C) and trastuzumab (T) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB) [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 OT1-02-09.
Abstract OT1-02-10: A phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who have received prior HER2 regimens for MBC
Authors: Lathrop K , Lucas J , Vacirca JL , Bhat G , Choi MR , Naughton M
Published: March 2017

Background: Poziotinib is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the epidermal growth factor receptor (EGFR) family of tyrosine-kinase receptors, including EGFR (HER1/ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4), as well as HER receptor mutations. This, in turn, leads to inhibition of the proliferation of tumor cells that overexpress these receptors. It is well established that breast cancers are associated with a mutation in, or overexpression of, members of the EGFR receptor family. The primary objective of this Phase 2 study is to evaluate the Objective Response Rate (ORR) of poziotinib in patients with human epidermal growth factor receptor 2 (HER2)-positive MBC. The secondary efficacy variables are Progression-Free Survival (PFS), Disease Control Rate (DCR), Overall Survival (OS), and Time to Progression (TTP).

Trial Design: This is a Phase 2, open-label, multicenter study to evaluate the efficacy, safety and tolerability of poziotinib in patients with HER2-positive MBC who have received at least 2 prior HER2- directed treatment regimens. Each treatment cycle is 21 days in duration. During each cycle, eligible patients receive 24 mg of poziotinib orally (as three 8-mg tablets) once daily for 14 days, followed by a 7 day treatment-free period.

Eligibility Criteria: Eligible patients are at least 18 years of age, have confirmed HER2 overexpression, adequate hematologic, renal and hepatic function, and have received at least 2 prior HER2-directed therapy regimens, including trastuzumab and trastuzumab emtansine (TDM-1). Patients are excluded if they have prior exposure to poziotinib, a history of congestive heart failure, left ventricular ejection fraction <50%, unable to take oral medications, or have conditions that cause malabsorption. A 30 day wash out period from previous chemotherapeutic or radiation therapies is required.

Statistical Methods: The purpose of this study is to evaluate the efficacy of poziotinib compared to the efficacy of other standard HER2-positive breast cancer treatments as reported in the literature. The ORR will be analyzed descriptively along with the 95% CI. The secondary efficacy variables will be analyzed descriptively.

Target Accrual: Approximately 70 patients. Enrollment began February 2016.

Contact Information: For more information or to refer a patient,

email: spi-poz-201@sppirx.com or fax: 1-949-398-9711.

Citation Format: Lathrop K, Lucas J, Vacirca JL, Bhat G, Choi MR, Naughton M. A phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who have received prior HER2 regimens for MBC [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 OT1-02-10.