Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine.

PurposeThis article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.BackgroundThe development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody-drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab.ResultsPreclinical and phase 1-3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line-based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies.ConclusionT-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer

Field and thermal factors in field–assisted consolidation of powder materials

Possible thermal and field factors, which may influence densification during spark-plasma sintering (SPS), are considered. Two experimental setups revealing the role of both groups of factors for SPS processing of conductive and semi-conductive materials are described. To de-convolute the influence of the electrical current, spark plasma sinter-forging experiments are conducted to compare the constitutive behavior of a copper powder under current-insulated and current-assisted SPS process conditions. The processing mode with specimen’s free lateral surface enables the direct in-situ measurement of the powder material temperature. The experimental results are interpreted in the framework of the developed constitutive model of the spark-plasma sintering of conductive powders, taking into consideration thermal and non-thermal factors. The micro inhomogeneity of the temperature distribution and its effect on the densification rate of conductive powders during current assisted sintering is analyzed. The role of thermal factors is displayed by a developed method for conducting flash spark plasma sintering (SPS) type experiments with an industrial SPS device. The effectiveness of this technique is studied for consolidation of SiC powder. Specially constructed dies are designed to heat the pre-compacted SiC powder specimens to a critical temperature before applying any voltage to the specimens. The dies incorporating a sacrificial metal bushing heat the specimen allowing the electrode-punch of the SPS device setup to contact the specimen and pass current through it under elevated temperatures. The experimental results demonstrate that flash sintering phenomena can be studied using conventional SPS devices. The role of the thermal runaway phenomena for material processing by flash sintering is theoretically analyzed. It is shown that the thermal runaway may affect the scalability of the powder consolidation

Spark-Plasma Sintering and Related Field-Assisted Powder Consolidation Technologies

Electromagnetic field-assisted sintering techniques have increasingly attracted attention of scientists and technologists. Spark-plasma sintering (SPS) and other field-assisted powder consolidation approaches provide remarkable capabilities to the processing of materials into configurations previously unattainable. Of particular significance is the possibility of using very fast heating rates, which, coupled with the field-assisted mass transport, stand behind the purported ability to achieve high densities during consolidation and to maintain the nanostructure of consolidated materials via these techniques. Potentially, SPS and related technologies have many significant advantages over the conventional powder processing methods, including the lower process temperature, the shorter holding time, dramatically improved properties of sintered products, low manufacturing costs, and environmental friendliness

Mergers and acquisitions (M&A) as modern ways of investments

The decrease in business activity and the fall in the production volume in the sectors of economy relying on long-term crediting is characteristic feature of the modern recessions. The pessimistic expectations of entrepreneurs concerning product demand leads to falling direct investment into business despite unlimited investment opportunities due to the developed capital markets nowadays. As a result it has created the opportunity for the development of the acquisition of enterprises. Potential investors are different and their investment motivation is different, but the goal is the same – to increase the value of the business and its efficiency as a result of mergers and acquisitions. However, purchasable enterprises are exposed to several financial risk factors.peer-reviewe

Fabrication of Net-Shape Functionally Graded Composites by Electrophoretic Deposition and Sintering: Modeling and Experimentation

It is shown that electrophoretic deposition (EPD) sintering is a technological sequence that is capable of producing net-shape bulk functionally graded materials (FGM). By controlling the shape of the deposition electrode, components of complex shapes can be obtained. To enable sintering net-shape capabilities, a novel optimization algorithm and procedure for the fabrication of net-shape functionally graded composites by EPD and sintering has been developed. The initial shape of the green specimen produced by EPD is designed in such a way that the required final shape is achieved after sintering-imposed distortions. The optimization is based on a special innovative iteration procedure that is derived from the solution of the inverse sintering problem: the sintering process is modeled in the “backward movie” regime using the continuum theory of sintering incorporated into a finite-element code. The experiments verifying the modeling approach include the synthesis by EPD of Al2O3/ZrO2 3-D (FGM) structures. In order to consolidate green parts shaped by EPD, post-EPD sintering is used. The fabricated deposits are characterized by optical and scanning electron microscopy. The experimentally observed shape change of the FGM specimen obtained by EPD and sintering is compared with theoretical predictions

Stability analysis for forging of porous bodies

The continuum theory of sintering is used for the analysis of the stability of forging of a cylindrical powder specimen. The constitutive properties of the powder material are assumed to follow a power-law creep relationship. Temperature-coupled linear non-uniform stability analyses are carried out. Stability maps are obtained for forging of copper powder components

Multi-Scale Modeling of Liquid Phase Sintering Affected by Gravity: Preliminary Analysis

A multi-scale simulation concept taking into account impact of gravity on liquid phase sintering is described. The gravity influence can be included at both the micro- and macro-scales. At the micro-scale, the diffusion mass-transport is directionally modified in the framework of kinetic Monte-Carlo simulations to include the impact of gravity. The micro-scale simulations can provide the values of the constitutive parameters for macroscopic sintering simulations. At the macro-scale, we are attempting to embed a continuum model of sintering into a finite-element framework that includes the gravity forces and substrate friction. If successful, the finite elements analysis will enable predictions relevant to space-based processing, including size and shape and property predictions. Model experiments are underway to support the models via extraction of viscosity moduli versus composition, particle size, heating rate, temperature and time