Treatment of HER2-positive breast cancer
ABSTRACT OPINION STATEMENT: About 15-20% of patients with early stage breast cancer present with tumors that have overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene. Before 2005, these individuals had an increased risk of recurrence and death, but since then their outcomes have substantially improved with the adoption in most countries of adjuvant trastuzumab as a standard component of therapy for HER2-positive early-stage breast cancer. Consequently, access to high-quality and accurate HER2 testing methods is critical to accurately determine HER2 status, guide treatment decisions, and ultimately improve clinical outcomes. In 2012, the humanized monoclonal anti-HER antibody trastuzumab was the only approved HER2-targeted therapy in the adjuvant setting. Data from the first generation of trials combining it with various chemotherapy regimens showed significant improvements in disease-free and overall survival (DFS/OS). Based on results from five randomized clinical trials, a trastuzumab-containing regimen for up to 1 year is now considered standard for all patients with HER2-positive tumors larger than 1 cm in size who would have fulfilled eligibility to those studies, and this recommendation is sometimes extended to patients with stage I tumors greater than 0.5 cm (T1b). Second generation adjuvant studies with other HER2-targeted agents like lapatinib and pertuzumab are ongoing, and newer drugs like T-DM1 and neratinib are being actively tested in the metastatic setting.
- SourceAvailable from: Klarissa D Hardy
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- "Lapatinib is the very first orally available epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) dual kinase inhibitor approved by the FDA. It is now used as a first-line treatment for HER2-positive breast cancers or metastatic breast cancer patients in combination with capecitabine or letrozole (Gomez et al., 2008; Jelovac & Wolff, 2012). Although lapatinib has demonstrated success in the pharmacotherapy of breast cancer, several issues remain in its clinical use. "
ABSTRACT: Abstract Mechanism-based inactivation (MBI) of CYP450 enzymes is a unique form of inhibition in which the enzymatic machinery of the victim is responsible for generation of the reactive metabolite. This precondition sets up a time-dependency for the inactivation process, a hallmark feature that characterizes all MBI. Yet, MBI itself is a complex biochemical phenomenon that operates in different modes, namely, covalent binding to apoprotein, covalent binding of the porphyrin group and also complexation of the catalytic iron. Using lapatinib as a recent example of toxicological interest, we present an example of a mixed-function MBI that can confound clinical drug-drug interactions manifestation. Lapatinib exhibits both covalent binding to the apoprotein and formation of a metabolite-intermediate complex in an enzyme-selective manner (CYP3A4 versus CYP3A5), each with different reactive metabolites. The clinical implication of this effect is also contingent upon genetic polymorphisms of the enzyme involved as well as the co-administration of other substrates, inhibitors or inducers, culminating in drug-drug interactions. This understanding recapitulates the importance of applying isoform-specific mechanistic investigations to develop customized strategies to manage such outcomes.Drug Metabolism Reviews 02/2015; 47(1):1-8. DOI:10.3109/03602532.2014.1003648 · 6.29 Impact Factor
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ABSTRACT: Personalized medicine is based on the established principle that each individual is born with unique biological characteristics. Genomics, the science of studying the genes in a genome and their interactions with each other, forms the foundation of personalized medicine. Several genomic methods are currently used to identify susceptibility loci for diseases or phenotypic traits, namely, linkage analysis, candidate gene association studies, and genome-wide association studies. The success of personalized medicine depends on having accurate diagnostic tests capable of identifying patients who can benefit from targeted therapy. Larger cohort studies plus the application of genome-wide association studies offer great potential for identifying the genetic factors that influence the pharmacology of specific drugs. By combining these approaches, physicians can predict health risks, determine and quantify the dynamics of disease development, and tailor therapeutic protocols to the needs of the individual. In this review, we focus on the effect of genetic profiling on disease outcomes as well as the potential of genomic methods to predict disease and drug response.06/2013; 3(2):66–72. DOI:10.1016/j.biomed.2012.12.005
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ABSTRACT: Achieving approval of new oncologic drugs in breast cancer (BC) is lengthy and costly. After approval in a randomized Phase III trial in metastatic BC, an agent is then evaluated in stage I-III BC. It can take a decade for drug approval in early-stage BC, given the large sample size and long follow-up to detect improvements in disease-free or overall survival. One way to reduce this time period is conducting preoperative trials. In neoadjuvant BC trials, improvements in pathologic complete response in randomized trials of chemotherapy with and without a new agent can lead to accelerated approval. In exploratory investigational new drug trials, such as Phase 0 trials, new drugs can be evaluated for a limited time prior to traditional dose escalation trials. The US FDA has released guidelines for utilization of preoperative trials. The goal is to administer a new agent to the right subset of BC patients quicker and more effectively.07/2013; 2(4):393-403. DOI:10.2217/cer.13.35