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

An Analysis of Exports and Growth in Pakistan

The paper examines the export-led growth (ELG) paradigm for Pakistan, using data of the period from 1970-71 to 2003-04. The paper uses a number of analytical tools, including Unit Root Test, Phillips- Perron Tests, Co-integration Johansen Test, and the Granger Tests. The paper sets three hypotheses for testing the ELG paradigm for Pakistan; (a) whether GDP and exports are cointegrated, (b) whether exports Granger cause growth, and (c) whether exports Granger cause investment. The time series data on GDP growth, export growth and investment GDP ratio (proxy for capital formation), and the labour employed were used. The data were tested for stationarity using the Augmented Dickey-Fuller (ADF) test and Phillips-Perron test (1988), and then the relationship between GDP growth rate and the growth rate of other variables was determined using OLS with AR (1). The major finding of the present study is that growth rate of export, total investment, and labour employed have positively affected the GDP growth rate

Independent sets of some graphs associated to commutative rings

Let $G=(V,E)$ be a simple graph. A set $S\subseteq V$ is independent set of $G$, if no two vertices of $S$ are adjacent. The independence number $\alpha(G)$ is the size of a maximum independent set in the graph. %An independent set with cardinality Let $R$ be a commutative ring with nonzero identity and $I$ an ideal of $R$. The zero-divisor graph of $R$, denoted by $\Gamma(R)$, is an undirected graph whose vertices are the nonzero zero-divisors of $R$ and two distinct vertices $x$ and $y$ are adjacent if and only if $xy = 0$. Also the ideal-based zero-divisor graph of $R$, denoted by $\Gamma_I(R)$, is the graph which vertices are the set {x\in R\backslash I | xy\in I \quad for some \quad y\in R\backslash I\} and two distinct vertices $x$ and $y$ are adjacent if and only if $xy \in I$. In this paper we study the independent sets and the independence number of $\Gamma(R)$ and $\Gamma_I(R)$.Comment: 27 pages. 22 figure