bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A15: Development of an in vitro 3D vessel-spheroid model for investigating cancer metastasis
Authors: Munoz Adam , Miller Joseph , Reinhart-King Cynthia A.
Published: March 2017

During metastasis, cells break free from the primary tumor, migrate through the stroma and enter either the vascular or lymph systems to disseminate into secondary sites. To better understand this process, many groups have developed in vitro models of cancer metastasis using microfluidic based platforms to mimic the tumor microenvironment and the intravasation/extravasation of tumor cells. While these models have provided significant new insights into the mechanisms by which metastatic cells move across the endothelium, they are most often focused on the movement of single cells. Notably, there is significant clinical evidence to suggest that tumor cells can travel collectively though the stroma and can circulate as cell aggregates in the vasculature. Recent advances in the understanding of cancer metastasis have shown that cancer may move more aggressively as a collection of cell when traversing the extracellular matrix (ECM) of the tumor microenvironment as opposed to more studied singular cellular motif. To better mimic these collective movements, we have developed a model that incorporates the following essential elements that exist in the tumor microenvironment: a cylindrical channel lined with a confluent monolayer of endothelial cells, a metastatic tumor analog in close proximity to the channel, the ability to incorporate flow with tunable properties to simulate shear stress due to blood flow, and a tunable collagen microenvironment. Briefly, in a 3D printed cube, Type 1 collagen is added at physiological stiffness. As the collagen is polymerizing in the device, a metastatic tumor analog (spheroid) consisting of labeled MDA-MB-231 cells is placed in proximity of the vessel that is lined with endothelial cells. The platform allows for the visualization of metastatic cell intravasation using confocal microscopy. Notably, this model is easy to build and implement with fairly accessible tools and without the use of a clean room or microfabrication facilities. Importantly, going forward this model has the ability to study the cellular behavior post-intravasation due to the incorporation of physiological flows within the channel.

Citation Format: Adam Munoz, Joseph Miller, Cynthia A. Reinhart-King. Development of an in vitro 3D vessel-spheroid model for investigating cancer metastasis. [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 A15.
Abstract A60: Hyaluronan and cancer cell derived swelling of solid tumors and implications for cancer therapy
Authors: Voutouri Chrysovalantis , Polydorou Christiana , Papageorgis Panagiotis , Stylianopoulos Triantafyllos
Published: March 2017

A solid tumor is an aberrant tissue made of cancer cells and a variety of host cells—all embedded in an extracellular matrix—nourished by blood vessels and drained by lymphatic vessels. Rapid tumor growth in the confined space of the host tissue results in the accumulation of mechanical forces within structural components of the tumor, and between the tumor and the host. These forces can shape the tumor microenvironment and determine in large part tumor progression and response to treatment. Despite the important role that mechanical forces play in tumor growth, the contribution of swelling to tumor mechanics remains unexplored. Tumors rich in hyaluronan exhibit a highly negative fixed charge density. Repulsive forces among these negative charges cause swelling of the tumor and development of swelling solid stress. Additionally, fixed negative charges attract free cations from the tumor interstitial space creating an imbalance of ion distribution and a Donnan osmotic fluid pressure. Furthermore, it has been shown that tumor swelling can be produces not only by hyaluronan but also cancer cells swell due to osmotic regulation, which is required for their survival under compressive forces. In this study, we design an experimental set up to measure hyaluronan derived swelling solid stress in two orthotopic breast tumor models of different extracellular matrix composition. We also calculate the Donnan osmotic pressure and the solid stress owing to interactions with the host tissue, utilizing the experimental data and developing a triphasic biomechanical mathematical model. The mathematical model accounts for the fluid and the solid phase of a tumor and the transport of anions and cations. Furthermore, we measure the swelling of cancer cell spheroids under compressive mechanical forces in order to quantify cell derived tumor swelling. We will present data showing that swelling stress contributes significantly to tumor mechanics, whereas Donnan osmotic pressure is negligible. Interestingly, histological analysis revealed a linear correlation between swelling stress and the ratio of hyaluronan to collagen content. Our analysis further suggested an inverse relation of swelling stress to vessel diameter and tumor perfusion. These results provide guidelines for emerging therapeutic strategies that target the tumor microenvironment to alleviate swelling stress and improve perfusion and drug delivery.

Citation Format: Chrysovalantis Voutouri, Christiana Polydorou, Panagiotis Papageorgis, Triantafyllos Stylianopoulos. Hyaluronan and cancer cell derived swelling of solid tumors and implications for cancer therapy. [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 A60.
Abstract B06: Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells
Authors: Rong Fan , Emery Travis , Zhang Yongguo , Xia Yuxuan , Sun Jun , Wan Jiandi
Published: March 2017

During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a physiologically relevant circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant shear stresses were applied. High shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing shear stress. These data provided molecular based explanation for the observed cell viability at high shear. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.

Citation Format: Fan Rong, Travis Emery, Yongguo Zhang, Yuxuan Xia, Jun Sun, Jiandi Wan. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells. [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 B06.
Abstract B07: Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel
Authors: Wong Andrew D. , Silvestri Vanesa , Ewald Andrew J. , Searson Peter C.
Published: March 2017

Metastasis is responsible for the majority of cancer related deaths; however, many of the biological and physical details surrounding the critical steps (e.g. invasion and intravasation) are largely unknown, in part due to the difficulty in recapitulating and visualizing these dynamic processes. To elucidate these mechanisms, we have developed an in vitro model of invasion and intravasation that comprises tumor cells embedded within an extracellular matrix (ECM) surrounding an engineered microvessel. The microvessel is cylindrical, 150 μm in diameter, and lined with endothelial cells forming a functional barrier that is maintained under constant perfusion at a shear stress of 2-8 dyne cm-2. Using this biomimetic tumor-microvessel platform, we have previously visualized invasion and intravasation of single MDA-MB-231 breast cancer cells into the microvessel and escape into flow. Here, we present mechanistic details of intravasation from both single tumor cells (MDA-MB-231) and mouse mammary tumor organoids (MMTV-PyMT). For single cells, we observe a mitosis-mediated mechanism of intravasation where tumor cell entry into flow is prefaced by cell division at the ECM-vessel interface. For tumor organoids, we see vascular deformation and destabilization from growing tumors that impinge upon proximal vessels, and that bulk intravasation is mediated by shear stress and tumor cell adhesion. As we characterize the various ways in which tumor cells interact with the vessel endothelium and intravasate, we can explore strategies involving the tumor vasculature and clinically relevant drugs to inhibit critical steps in the metastatic cascade.

Citation Format: Andrew D. Wong, Vanesa Silvestri, Andrew J. Ewald, Peter C. Searson. Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel. [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 B07.
Abstract B16: The detection of ductal carcinoma using noninvasive hyperspectral imaging
Authors: Khouj Yasser , Dawson Jeremy , Coad James , Vona-Davis Linda
Published: March 2017

Introduction: Hyperspectral imaging (HSI) technology is an optical medical imaging modality that has great potential for noninvasive tissue analysis in breast cancer. This imaging method may be able to enhance the detection of cancer tissue and lead to advances in the optical diagnosis of patients. Objective: The goal of this study was to use high resolution hyperspectral imaging microscopy to differentiate marked biopsies of normal and breast cancer tissues. Methods: For our hyperspectral imaging platform, we obtained stained (n=10) and unstained (n=10) pathology slides from ductal carcinomas of the breast and compared them. To capture the HSI, we used a hyperspectral camera that generates a spectral cube containing the spectra of each pixel between 460 to 640 nm and normalized the data to a gray scale to maximize data stability. The spectral signatures were graphed using MATLAB software. Results: The system was able to detect a clear spectral difference between cancer and normal tissues in hematoxylin and eosin stained slides. The spectrum of cancer tissue had a relatively lower intensity than that of normal tissue in the wavelength range between 480 and 610 nm. Conclusions: Our preliminary study showed a clear hyperspectral snapshot differentiating normal breast tissue from ductal carcinoma. Further HSI and quantitative analysis will demonstrate the feasibility of using this new imaging technique in breast cancer.

Citation Format: Yasser Khouj, Jeremy Dawson, James Coad, Linda Vona-Davis. The detection of ductal carcinoma using noninvasive hyperspectral imaging. [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 B16.
Abstract B26: A novel applicator for endoscopic gene electrotransfer
Authors: Bahrami Arya J. , Connolly Richard J. , Campbell Jean S. , Pierce Robert H.
Published: March 2017

Intratumoral gene delivery is a novel immunotherapy showing promise in cutaneous cancers such as melanoma. However, the broad application of this technology is limited by delivery efficiency and tumor accessibility. Efficient gene delivery requires intimate association of DNA and cells and a coincident electric field. Due to the low diffusion of plasmid DNA combined with the single bolus injection provided by a standard syringe, conventional electrogene transfer yields a small volume of transfected tissue. Our novel use of a corkscrew delivery needle provides the dual benefit of increased DNA-tissue interface and anchoring of the device necessary for endoscopic use. This device has yielded efficient and repeatable delivery of cytokine-encoding plasmid DNA and reporter genes in several tumor models including spontaneous mammary carcinomas (MMTV-PyVT) as well as syngeneic tumor models. Anchoring associated with the action of corkscrew deployment ensures co-localization of the electric field with the injected tissue volume. The small form factor of this device makes it compatible with standard medical devices, including trocars, endoscopes and other catheter based devices, enabling intratumoral gene immunotherapy of previously inaccessible cancers, including breast cancer, lung cancer, and hepatocellular carcinoma.

Citation Format: Arya J. Bahrami, Richard J. Connolly, Jean S. Campbell, Robert H. Pierce. A novel applicator for endoscopic gene electrotransfer. [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 B26.
Abstract B31: Development of an implanted pump for metronomic delivery of chemotherapy and biological compounds: the virtue of local delivery
Authors: Chen Thomas C. , Adell Frank , Schachar Joshua
Published: March 2017

The development of an implanted pump that can locally and metronomically deliver drugs and biological agents is crucial in the treatment of cancer. For the last eight years, we have worked on an implanted pump that can deliver precisely at microliter doses. The Ipsum pump (Cognos Therapeutics) has three components: a double lumen catheter, a sampling reservoir, and a pump. The drug is pumped out of the bellows (5 ml) via a hermetically sealed MRI compatible piezoelectric pump. The drug is delivered via the delivery catheter lumen into the target. The sampling lumen can draw from the target to determine levels of drug delivered, allowing for in-vivo pharmacokinetic measurements. The reservoir is connected to the catheter and can be used to sample fluid. An optical sensor (embedded spectrophotometer) is set a specific frequency to determine absorbance for pharmacokinetic measurements of drug delivered. The pump is powered by a long term battery (good for up to five years) and is wirelessly controlled externally by the physician operator. Our first disease model will be delivery of methotrexate to the cerebrospinal fluid in the treatment of leptomeningeal carcinomatosis.

Citation Format: Thomas C. Chen, Frank Adell, Joshua Schachar. Development of an implanted pump for metronomic delivery of chemotherapy and biological compounds: the virtue of local delivery. [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 B31.
Abstract B32: Feedback optimized gene electrotransfer for immunotherapy
Authors: Brown Douglas W. , Bahrami Arya J. , Canton David A. , Xu Yi , Tse Gavin Y. , Campbell Jean S. , Pierce Robert H. , Connolly Richard J.
Published: March 2017

Intratumoral electroporation of proinflammatory cytokine-encoding plasmid DNA promotes innate and adaptive immune responses that correlate with abscopal effects. The conditions selected to electroporate tumors are typically fixed parameters optimized in preclinical tumor models. These conditions have little translatability to clinically relevant tumors, as idealized models fail to capture the variability encountered in clinical tumors. Variables that affect treatment outcome include tumor size, degree of vascularization, fibrosis, and necrosis. These variables can result in sub-optimal gene transfer and variable therapeutic outcomes. To address the need to advance the practice of electroporation, a feedback controlled electroporation generator has been developed, which is capable of assessing the electrophysiological properties of tissue in real-time. Determination of these properties is accomplished by electrochemical impedance spectroscopy and model parameter estimation. Model parameters that estimate membrane integrity are used to adjust electroporation parameters for each applied pulse and stop the process when optimum gene transfer conditions are identified. Studies performed in syngeneic colon carcinoma tumors (MC38) and spontaneous mammary tumors (MMTV-PyVT) have demonstrated feedback-based electroporation is capable of achieving maximum expression of reporter genes with minimal collateral cell death. These findings represent an unprecedented advancement to the practice of gene electro-transfer, as retaining the viability of transfected cells is paramount to treatment success.

Citation Format: Douglas W. Brown, Arya J. Bahrami, David A. Canton, Yi Xu, Gavin Y. Tse, Jean S. Campbell, Robert H. Pierce, Richard J. Connolly. Feedback optimized gene electrotransfer for immunotherapy. [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 B32.
Abstract B45: Silencing ß3 integrin by targeted ECO/siRNA nanoparticles inhibits EMT and metastasis of triple-negative breast cancer
Authors: Parvani Jenny G. , Gujrati Maneesh D. , Mack Margaret A. , Schiemann William P. , Lu Zheng-Rong
Published: March 2017

Metastatic breast cancer is the second leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Because previous studies coupled β3 integrin (ITGB3) to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/siβ3). Treatment of TNBC cells with ECO/siβ3 was sufficient to effectively silence β3 integrin expression, attenuate TGFβ;-mediated EMT and invasion, restore TGFβ-mediated cytostasis, and inhibit three-dimensional organoid growth. Modification of ECO/siβ3 nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/siβ3 nanoparticles in vivo alleviated primary tumor burden and, more importantly, significantly inhibited metastasis. In the span of 16 weeks of the experiments and observations, including primary tumor resection at week 9 and release from the treatment for 4 weeks, the mice bearing orthotopic, TGFβ-prestimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/siβ3 nanoparticles were free of metastases and relapse, in comparison with untreated mice. Collectively, these results highlight ECO/siβ3 nanoparticles as a promising therapeutic regimen to combat TNBC.

Citation Format: Jenny G. Parvani, Maneesh D. Gujrati, Margaret A. Mack, William P. Schiemann, Zheng-Rong Lu. Silencing ß3 integrin by targeted ECO/siRNA nanoparticles inhibits EMT and metastasis of triple-negative breast 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 B45.
Abstract IA16: Spherical nucleic acids as a powerful new platform for cancer immunotherapy
Authors: Mirkin Chad A.
Published: March 2017

Spherical nucleic acids (SNAs) are nanoparticle-oligonucleotide conjugates characterized by a dense, spherical shell of radially oriented oligonucleotides. SNAs enter cells without the need for auxiliary transfection reagents, are more resistant to nuclease degradation than their linear counterparts, and show minimal toxicity and off-target immunogenicity. These emergent properties of the SNA platform enable the design of powerful immunotherapy agents against cancer cells.

The SNA platform allows simultaneous delivery of Toll-like receptor (TLR) agonist oligonucleotides and cancer-associated antigen peptides to antigen-presenting cells (APCs). The oligonucleotides on the surface of the SNAs activate of the innate immune system through TLRs to mature the APCs, which in turn activates effector immune cells to target cell displaying the cancer-associated peptide. Compared to mixtures of free peptides and oligonucleotides, SNAs exhibit up to 80-fold increase in potency, 400-fold higher cellular response to antigens and improve median survival in mice with lymphomas through antigen-specific targeting of cancer cells. The enhancement of the immune properties arises from a combination of increase in cellular uptake, polyvalent binding of SNAs to TLRs and the co-delivery of the TLR agonist oligonucleotides and peptide to the same cell. Additionally, the SNA architecture enables the control of oligonucleotide to peptide ratio, subcellular release location of the peptide and release kinetics. Combined with their high serum stability, at-scale synthesis and minimal toxicity profile, SNAs hold great promise for the development of cancer vaccines.

Citation Format: Chad A. Mirkin. Spherical nucleic acids as a powerful new platform for cancer immunotherapy. [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 IA16.
Abstract BS3-1: Unfolding the unfolded protein response in breast cancer
Authors: Chen X
Published: March 2017

During tumor development and progression, cancer cells encounter cytotoxic conditions such as hypoxia, nutrient deprivation, and low pH due to inadequate vascularization. To maintain survival and growth in the face of these physiologic stressors, a set of adaptive stress response pathways are induced. One adaptive pathway well studied in other contexts is the unfolded protein response (UPR), which is induced by factors affecting the endoplasmic reticulum (ER). Triple negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options and TNBC-targeted therapies do not yet exist. We found that XBP1, a key component of the UPR, is activated in TNBC and plays a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. Depletion of XBP1 blocked primary tumor growth, inhibited tumor relapse and reduced the population of chemotherapy-resistant tumor initiating cells (TICs). Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 regulates the hypoxia response through controlling HIF1α transcriptional activity and the expression of HIF1α targets. Notably, we identified a gene expression signature indicative of XBP1 pathway activation that is associated with poor prognosis in two independent cohorts of patients with TNBC. Our findings reveal a key function for this branch of the UPR in TNBC, opening new therapeutic avenues for patients with TNBC.

Citation Format: Chen X. Unfolding the unfolded protein response in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS3-1.
Abstract CS1-2: CS1-2 Clinical utility of multi-gene testing in metastatic breast cancer
Authors: Bedard P
Published: March 2017

The goal of many ongoing precision medicine initiatives is to match patients to targeted treatment(s) based upon the identification of specific driver mutations in their tumors. Although large-scale research projects have elucidated the genomic landscape of breast cancer, they have not provided insight into the clinical utility of genomic testing. Institutional studies of small, targeted sequencing panel-based testing approaches involving patients with advanced, metastatic disease demonstrate that only a small proportion of patients ultimately receive genotype-matched treatment. The reasons for this low treatment matching rate include: institutional and/or geographic barriers to access to genotype-matched clinical trials; patient deterioration after testing results are reported; and the limited range of somatic mutations that are “druggable” with approved or investigational drug therapies. While there are promising signals of activity from early phase clinical trials with novel drug treatments targeting specific genomically defined subpopulations - including AKT1, ERBB2, ESR1 and PIK3CA mutations as well as FGFR1 amplification - and advances in circulating tumor DNA technology may allow for greater integration at the point of care, further evidence is needed before multi-gene testing can be recommended in routine clinical practice.

Citation Format: Bedard P. CS1-2 Clinical utility of multi-gene testing in 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 CS1-2.
Abstract ES6-1: ES6-1 Assessment of residual disease and treatment implications post neoadjuvant therapy
Authors: Chang JC
Published: March 2017

Breast cancer is a highly heterogeneous disease with various molecular subtypes that differ in regard to treatment approach as well as unresolved treatment issues.

In women with HER2-amplified breast tumors, standard neoadjuvant therapy consisting of dual HER2 blockade with trastuzumab/pertuzumab plus chemotherapy can induce a high pathologic complete response (pCR) rate (60%), which translates into better overall survival (>90% at 3 years). A critical unresolved issue in the neoadjuvant treatment of HER2-amplified tumors is minimizing toxicity in select patients. Selection of non-cardiogenic regimens and chemotherapy-free or lighter chemotherapy regimens should be the focus for women whose disease is highly addicted to the HER2 pathway. New research directions are also exploring ways to minimize the extent of local surgery in the breast and axilla.

Approximately 30% of patients with triple-negative breast cancer (TNBC) achieve pCR after neoadjuvant chemotherapy. While these patients tend to have a favorable prognosis, those with residual disease (RD) at the time of surgical resection may expect significantly worse outcomes and, at present, do not have targeted therapeutic options. Molecular analysis of tumor tissue from such patients may be used to identify the genetic alterations responsible for disease recurrence and to help individualize treatment with available agents. Transcriptome and sequencing analyses have identified important pathways and aberrations in the majority of residual tumors. Targeting these molecular abnormalities in conjunction with the tumor immune microenvironment may represent an effective therapeutic avenue to improve the outcomes of TNBC patients who have RD after standard neoadjuvant therapy. Adaptive clinical trials investigating neoadjuvant treatments directed against key pathways active in residual tumors are underway.

Citation Format: Chang JC. ES6-1 Assessment of residual disease and treatment 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 ES6-1.
Abstract ES6-2: ES6-2 Surgical considerations in patients receiving neoadjuvant therapy
Authors: King TA
Published: March 2017

Early randomized trials of neoadjuvant chemotherapy failed to show an improvement in overall survival compared to adjuvant therapy, yet it reduces the need for mastectomy and axillary lymph node dissection, thus decreasing the morbidity of surgery, without increasing the risk of locoregional recurrence. It is also now increasingly clear that the impact of neoadjuvant chemotherapy varies by molecular subtype; whereby patients with high-grade estrogen receptor negative and/or HER2 positive breast cancers are more likely to experience pathologic complete response to NAC that those with low-grade, estrogen receptor positive cancers. The increasing rates of pCR following neoadjuvant chemotherapy have had a significant impact on local-regional treatment considerations. However, patient selection for this approach remains critical.

Sentinel node biopsy after neoadjuvant chemotherapy accurately stages the axilla and is associated with a low rate of nodal recurrence in patients presenting with a clinically negative axilla. Sentinel node biopsy after neoadjuvant chemotherapy in patients with proven axillary metastases prior to neoadjuvant chemotherapy who become clinically node negative has a false negative rate of less than 10% only when 3 or more sentinel nodes are identified and there are no data on nodal recurrence rates after sentinel node biopsy alone in this population. Hence, strategies to ensure a low false negative rate are critical if sentinel node biopsy is offered to patients with proven axillary metastases prior to neoadjuvant chemotherapy. The relative contribution of pre-treatment stage and post-treatment stage (degree of pathologic response) to local control is also uncertain and tailoring of local therapy based on the degree of response is the subject of ongoing trials.

Citation Format: King TA. ES6-2 Surgical considerations in patients receiving 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 ES6-2.
Abstract OT2-01-16: Evaluating targets in localized and advanced breast cancer by sequencing tumor DNA at diagnosis and after progression (ELSA)
Authors: Gaba AG , Powell SF , Jennifer WL , Megan LL , Chun-Hung C , Lora BJ , Ford JM
Published: March 2017

Background: Breast cancer therapy exerts strong selection pressure that shapes the evolution of the cancer. Despite the importance of these treatment-induced changes for the success of subsequent therapy, tumors have been rarely resampled and reanalyzed, with the exception of hematopoietic malignancies. The availability of next generation sequencing (NGS) has made it possible to get highly accurate sequencing that allows detection of mutations and other genetic alterations not only from tumor biopsies but also from circulating DNA fragments.

Objectives: To demonstrate the evolution of the molecular genotype of breast cancer as patients are diagnosed, treated, and upon relapse. This will be accomplished by NGS of the tumor at key time points during the natural history of the disease. The molecular profile at diagnosis will be compared to the profile at recurrence/metastasis and after treatment for metastasis. Correlation with treatment response and adverse clinical outcomes will be determined.

Study Design and Eligibility: We have initiated a prospective observational study in patients with a new diagnosis of Stage I, II and III breast cancer and an ECOG performance status of 0, 1 or 2. Patients should be medically suitable to give informed consent for a biopsy or surgical procedure. Enrollment will occur at community-based cancer centers with inclusion of under-served populations.

Methodology: Tumor samples and blood samples are collected at - initial diagnosis/definitive surgery, first local relapse, diagnosis of metastasis and at first progression after treatment for metastatic disease. Molecular genotype will be analyzed from the tumor samples and from the circulating tumor DNA (ctDNA) in blood samples at each of the time points. ctDNA will also be assessed on blood samples collected annually till the diagnosis of metastasis and then more frequently at 3-6 month intervals in patients with high risk breast cancer.

Statistical Design/Size of study sample: Formal sample size calculations are not required for this study as by design, it is based on participation. There is no discrete endpoint that can be powered by sample size calculation for this study. We are screening all patients who are diagnosed with breast cancer at our facility. The proposed enrollment is 300 patients per year. The study launched in December 2015 at 4 of our community-based cancer centers. Current enrollments is 46 patients.

Citation Format: Gaba AG, Powell SF, Jennifer WL, Megan LL, Chun-Hung C, Lora BJ, Ford JM. Evaluating targets in localized and advanced breast cancer by sequencing tumor DNA at diagnosis and after progression (ELSA) [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 OT2-01-16.
Abstract OT2-03-03: A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation
Authors: Mutter RW , Park SS , Hieken TJ , Vargas CE , Mei-Yin PC , Kathryn RJ , Hector VR , Kimberly CS , Elizabeth YS , Daniel VW
Published: March 2017

Background: Post-mastectomy radiotherapy improves survival in women with node-positive breast cancer. Pencil beam scanning proton therapy is attractive due to potential to reduce the dose to the heart and lungs compared with traditional photon techniques while improving conformality and limiting skin dose compared with passively scanned proton therapy. The optimal dose and fractionation for pencil-beam scanning proton therapy remains unknown.

Trial Design: This is a multi-center open label phase II randomized controlled trial to determine the safety of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation.

Eligibility Criteria: Patients ≥ 18 years with primary, non-inflammatory invasive breast cancer who have undergone mastectomy with or without immediate reconstruction and chest wall and regional nodal irradiation planned.

Aims: To determine whether the 24 month complication rate (defined as grade 3 or greater late adverse events, and unplanned surgical intervention in patients who undergo mastectomy with reconstruction) of 15 fraction chest wall and regional node pencil beam scanning proton radiotherapy is acceptable relative to 25 fraction chest wall and regional nodal pencil beam scanning proton radiotherapy and worthy of further investigation.

Statistical methods: The study is designed as a non-inferiority/superiority “hybrid” design using the approach of Freidlin et al. It is Using a one-sided type I error rate of 0.05 (corresponding equivalently to constructing a 1-sided 95% confidence limit), 72 evaluable patients will have 80% power to reject the null hypothesis that the 24-month complication rate in the experimental arm is higher than that of the control arm by more than 10% (i.e. rule out inferiority) under the alternative hypothesis that the complication rate in the experimental arm is 5% less than that of the control arm (i.e. superiority). However, the design will have only 41% power when the two treatment arms are equivalent (i.e. the complication rate is 10% for both arms).

Accrual: The study opened in June 2016. Five of a planned eighty-two patients have been accrued to date.

Citation Format: Mutter RW, Park SS, Hieken TJ, Vargas CE, Mei-Yin PC, Kathryn RJ, Hector VR, Kimberly CS, Elizabeth YS, Daniel VW. A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation [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 OT2-03-03.
Abstract OT2-04-01: Study on the usefulness of the skin wound therapeutic agent 'Neo dermal activator' in breast cancer surgery
Authors: Kim JH , Lim SM , Kim SI , Park SH , Park HS , Kim JY
Published: March 2017

Background : Wound infection after breast cancer surgery is considered to be factors that increase the discomfort of the patient and increase of the extension and the use of antibiotics in the treatment time period, in particular breast cancer postoperative wound infection resulting slow the implementation of adjunctive therapy such as radiation therapy or chemotherapy after surgery can cause, it is important to effectively prevent, there has been a development of a variety of skin wound therapeutic agent to reduce them. The purpose of this study was to evaluate the effects of the wound dressing with existing wound dressing Neo dermal activator compared to the patients receiving preoperative chemotherapy.

Methods : A total of 54 breast cancer patients who recieved BCS & mastectomy devided two group(each 27 patients) through the random assignment between Jan, 2016 and June, 2016. Day one weeks after surgery to examine the wound infection rate (surgical site infection, SSI rate). After six months of outpatient surgery visits to check the wounds of patients, using the VAS records the scar of the wound satisfaction. For patients who underwent radiation therapy, check out the time it took to begin radiation therapy after surgery.

All tests were two-sided. All statistical analyses were performed using SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA).

Eligbility criteria is :

- one side breast cancer

- not inflammatory breast cancer

- recieved BCS and mastectomy only (without immediate reconstruction surgery)

- stage IV breast cancer.

Citation Format: Kim JH, Lim SM, Kim SI, Park SH, Park HS, Kim JY. Study on the usefulness of the skin wound therapeutic agent 'Neo dermal activator' in breast cancer surgery [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 OT2-04-01.
Abstract OT3-01-01: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
Authors: Santa-Maria CA , Jain S , Flaum L , Park J-H , Kato T , Gross L , Uthe R , Tellez C , Stein R , Rademaker A , Gradishar WJ , Nakamura Y , Giles FJ , Cristofanilli M
Published: March 2017

Background

A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PD-L1. This strategy has complementary and non-redundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit.

Methods

A single arm Phase II study was designed to determine the efficacy of PD-L1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PD-L1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ER-positive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer.

Citation Format: Santa-Maria CA, Jain S, Flaum L, Park J-H, Kato T, Gross L, Uthe R, Tellez C, Stein R, Rademaker A, Gradishar WJ, Nakamura Y, Giles FJ, Cristofanilli M. A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in 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 OT3-01-01.
Abstract P1-01-20: Inertial focusing circulating breast cancer cells based on the novel 3D-printed serpentine microfluidic chips
Authors: Yin P , Hu B , Zhu S , Tian J
Published: March 2017

This abstract was not presented at the symposium.
Abstract P1-02-01: Circulating tumor DNA analysis to predict relapse and overall survival in early breast cancer – Longer follow-up of a proof-of-principle study
Authors: Turner NC , Garcia-Murillas I , Chopra N , Beaney M , Kilburn L , Cutts R , Osin P , Nerurkar A , Schiavon G , Hrebien S , Bliss J , Dowsett M , Smith I
Published: March 2017

Background

In a previous proof-of-principle study we demonstrated that detection of circulating tumour DNA (ctDNA) in the adjuvant setting, after completion of surgery and chemotherapy for early stage breast cancer, was associated with a high risk of early relapse. Here we present longer follow-up of the same series, to define the predictive power of ctDNA analysis for disease free survival, and assess the potential to predict overall survival.

Methods

We recruited a cohort of 55 women presenting with early stage, primary breast cancer, who were all scheduled to receive neo-adjuvant chemotherapy. The primary tumour was sequenced to identify somatic mutations, identifying at least one mutation in 43 patients. Mutations were tracked with digital PCR to identify ctDNA, in plasma samples taken either at a single post-surgical time point (2-6 weeks post-surgery) or with serial plasma samples taken every 6 months in the adjuvant setting.

Results

At a median 31.7 months follow-up, 42% (18/43) patients had relapsed. Detection of ctDNA at the single post-surgical time point was associated with poor disease free survival, HR=13.6 95%CI (4.5, 41.2) p<0.001, and overall survival HR=84.7 95%CI (9.8, 730.4) p<0.001. All patients with ctDNA detected in a single post-surgical time point relapsed and died in the follow-up period (7/7, 100% specificity), although the single post-surgery time point had modest 39% (7/18) sensitivity for relapse. Detection of ctDNA at any point in serial sampling was associated with poor disease free survival HR=25.7 95%CI (8.3, 79.8) p<0.001 and overall survival HR=47.1 95%CI (6.1, 366.1) p<0.001. All patients with ctDNA detected in a serial mutation tracking relapsed in the follow-up period (14/14, 100% specificity), with 78% (14/18) sensitivity for relapse. Sensitivity was limited by 3 cases of brain only relapse and one case of solitary ovarian relapse. Detection of ctDNA in serial sampling had a median lead-time of 8.1 months over clinical relapse.

Conclusion

Detection of ctDNA in the adjuvant setting has a high predictive power for future relapse and death from breast cancer. Therapeutic trials are required to determine whether mutation tracking identifies relapse sufficiently early to allow for further adjuvant therapy.

Citation Format: Turner NC, Garcia-Murillas I, Chopra N, Beaney M, Kilburn L, Cutts R, Osin P, Nerurkar A, Schiavon G, Hrebien S, Bliss J, Dowsett M, Smith I. Circulating tumor DNA analysis to predict relapse and overall survival in early breast cancer – Longer follow-up of a proof-of-principle study [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 P1-02-01.
Abstract P1-02-13: Differential expression of exosomal miRNAs between breast cancer patients with recurrence and no-recurrence
Authors: Sueta A , Yamamoto Y , Tomiguchi M , Takeshita T , Ibusuki M , Iwase H
Published: March 2017

Background

In recent years, there has been a concerted effort to identify biomarkers derived from body fluid in various cancers. Exosomal microRNA (miRNA) has been used as one of useful diagnostic or prognostic biomarkers. We aimed to investigate the prognostic role of the exosomal miRNAs in serum samples derived from patients with primary breast cancer. Additionally, we evaluated whether the exosomal miRNA in serum reflect the origin of primary tumor by means of comparing their expression levels between in serum and tumors.

Patients and Methods

Exosomes in serum sample (500uL) were extracted using ExoQuick (System Biosciences) and miRNAs were isolated using SeraMirTM Exosome RNA Amplification Kit (SBI). We compared the miRNA profile derived from exosome between the patients with breast cancer with recurrence (n=16) and without recurrence (n=16) by miRNA PCR array. Further, we examined the expression of miRNA derived from tumor tissues in the patients with breast cancer recurrence (n=35) and without recurrence (n=39) by qRT-PCR. All samples were collected before treatment and surgery.

Results

Of the 384 miRNAs, 11 miRNAs were significantly expressed; three miRNAs (miR-338-3p, miR-340-5p, and miR-124-3p) were significantly up-regulated and eight (miR-29b-3p, miR-20b-5p, miR-17-5p, miR-130a-3p, miR-18a-5p, miR-195-5p, miR-486-5p, and miR-93a-5p) were significantly down-regulated in the patients with recurrence compared to those without recurrence. Next, we evaluated expression of the above miRNAs in tumor tissues. The patients with recurrence have higher levels of miR-340 at their primary site as well as in the serum. On the contrary, miR-195-5p, miR-17-5p, miR-93-5p, and miR-130a-3p derived from tumor tissues that were down-regulated in the patients with recurrence in serum, were highly expressed in the patients with recurrence than those with no-recurrence. In logistic regression analysis, tumor size, miR-340-5p, miR-17-5p, miR-130a-3p, and miR-93-5p were significantly associated with breast cancer recurrence (each P < 0.05).

Conclusions

Several exosomal miRNAs at diagnosis may be useful biomarker to predict the breast cancer recurrence. Moreover, we showed the different expression pattern of miRNAs between tumor tissues and serum. These findings may suggest selective mechanism of release of exosomal miRNA by cancer cells to regulate their progression. Further studies to confirm our results are needed.

Citation Format: Sueta A, Yamamoto Y, Tomiguchi M, Takeshita T, Ibusuki M, Iwase H. Differential expression of exosomal miRNAs between breast cancer patients with recurrence and no-recurrence [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 P1-02-13.
Abstract P1-03-15: Clinicopathologic and immunophenotypic characterization of angiomatosis of the breast: A rare vascular entity mistaken for low-grade angiosarcoma
Authors: McIntire PJ , Ginter PS , Shin SJ
Published: March 2017

This abstract was withdrawn by the authors.