Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer.

IntroductionThe purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).MethodsPatients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n=70) or T-DM1 (n=67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction.ResultsHER2 mRNA levels were obtained for 116/137 patients (HT=61; T-DM1=55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR)=0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA≥median (HR=0.39; 95% CI 0.18 to 0.85) versus ConclusionsThis exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median.Trial registrationClinicalTrials.gov NCT00679341

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates. METHODS: Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used. RESULTS: A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V(c)) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure. CONCLUSIONS: T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users

Clinical Application of Fluorescence in Situ Hybridization (FISH) to Detect HER-2 Gene in Breast Cancer

Objective: To investigate the clinical application of the detection of HER-2 gene by fluorescence in situ hybridization (FISH) in breast cancer and the correlation between HER-2 gene amplification and clinicopathology of breast cancer. Methods: Paraffin-embedded breast infiltrating ductal carcinoma from 48 patients were detected by FISH and immunohistochemistry (IHC) respectively for comparing the results of two methods. Results: HER-2 protein expressions were classified into three groups (3+/2+/1+ or 0) and the positive rates of HER-2 gene amplification by FISH were 77.8%, 57.1% and 10.5%, respectively. Of the 29 cases with positive axillary lymph node, 12 were with HER-2 gene amplification (P ＜ 0.05). Of the 10 cases with negative estrogen receptor (ER) and progesterone receptor (PR), 7 were with HER-2 gene amplification (P ＞ 0.05). Conclusion: The false positive and negative rates are higher in HER-2 protein expression by IHC. Compared with IHC, FISH, being more effective and precise, can be applied extensively in clinic. HER-2 gene amplification is concerned with axillary nodes metastases

Investigation of Adverse‐Event‐Related Costs for Patients With Metastatic Breast Cancer in a Real‐World Setting

BackgroundExisting treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2).Materials and methodsPatients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated.ResultsOn average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0$5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs.ConclusionChemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported

Contentious issues of self-defence in Czech case law

Resumé Controversial Issues of Necessary Defense in the Judicial Practice The purpose of my thesis is to analyze some potential problems in the case law of necessary defence. Studying the judicature alw ays helps the law yers to understand better the subject, because in a particular case, the law is used "in action" and explained by the judges. The thesis is composed of five chapters, each of them dealing w ith different aspects of criminal law or more precisely of necessary defence case law . Chapters One to Three introduce and describe the basics of czech criminal law , the intent of criminal law and criminal liability. Which are the ground topics of defence law . Chapter Four is the main chapter of the thesis and deals w ith defences - necessity and necessary defence. Chapter Four is divided into tw o subchapters. The first of them deals, as said before, w ith necessity. The second one w ith necessary defence and is itself divided into nine parts. Part One deals w ith the historically development of necessary defence and shortly introduces four (more precisely only three) different versions of those past and present legal forms. Parts Tw o to Seven examine the basic parts of necessary defence, those are: subsidiarity, attack, adequacy, excess from necessary defence, w eapon use in necessary defence and..