Polymorphisms to Predict Outcome to the Tyrosine Kinase Inhibitors Gefitinib, Erlotinib, Sorafenib and Sunitinib (original) (raw)
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Pharmacogenomics, 2011
medical practice . When planning this conference 2 years ago, we thought it would be interesting to synthesize some knowledge gained in the field of pharmacogenetics and pharmacogenomics in the last 50 years, in order to identify the current pharmacogenetic/ pharmaco genomic tests that could be used in routine medical practice. Our aim was to determine, through daily discussions involving all participants, which pharmaco genetic information might be useful for patient therapy. In addition, we wanted to attempt to make some recommendations on which pharmacogenetic tests should be performed in routine medicine and decide what advice we might give to physicians regarding some of these pharmacogenetic/pharmaco genomic tests. The conference could not cover the whole field of pharmaco genetics/pharmaco genomics. Therefore, we limited the program to examples that we considered the most clinically relevant in the field of oncology, cardio vascular diseases, adverse drug reactions (ADRs) and organ transplantation. This choice is naturally subjective, excluding large parts of pharmaco genetics/ pharmaco genomics such as neuropsychopharmacology, pain, addiction and rheumatology. We present herein our conclusions on pharmacogenetic information that might be useful in ten clinical situations: guidance recommendations on which tests to be performed, and advice to physicians concerning these tests.
On the use of pharmacogenetics in cancer treatment and clinical trials
European journal of cancer (Oxford, England : 1990), 2014
There are an increasing number of studies devoted to the identification of associations between anticancer drug efficacy and toxicity and common polymorphisms present in the patients' genome. However, many articles presenting the results of such studies do not bring the simple and necessary background information allowing the evaluation of the relevance of the study, its significance and its potential importance for patients' treatment. This position paper first addresses clinical oncologists with the aim of giving them the basic knowledge on pharmacogenetics and on the potential use of gene polymorphisms as predictive biomarkers in routine and clinical research. A secondary objective is to give molecular biologists some recommendations on how to conceive protocols and how to publish their results when they develop pharmacogenetic studies appended to clinical trials or with autonomous goals.
Polymorphisms in Pharmacogenetics of Personalized Cancer Therapy
Genetic Polymorphisms
Therapy process of personalized cancer management covers surgery, chemotherapy, radiation therapy and targeted therapies. The choice of cancer chemotherapeutic agents and doses depends upon the location and stage of tumor, as well as the general state of the patient. On the chemotherapy, radiotherapy, and targeted therapy processes, pharmacogenetics offers customized solutions according to the personal genetic information. Especially for clinicians, genetic information obtained from polymorphism-based pharmacogenetic tests is highly crucial for the better prediction ability of drug response and life-threatening toxic reactions due to the narrow therapeutic index of cancer chemotherapeutic agents. Pharmacogenotyping utilizes different examination strategies, such as single nucleotide polymorphism analysis, somatic/germline mutation analysis and partial/full genome sequencing. The promising effect of pharmacogenetics on the solving of the individual variability in drug response and toxic reactions is being observed with the accumulation of the information that unravel the human genomic variations from large-scale population and multi-parameter-based pharmacogenetic studies of the postgenomic era. Polymorphisms contribute wide variations in human genome and may define how individuals respond to medications, either by changing the pharmacokinetics and pharmacodynamics of drugs or by altering the cellular response to therapeutic agents. To define the effect of polymorphisms on the targets of chemotherapeutics is necessary for the prediction of altered pharmacokinetics of therapeutic agents.
The basic principals of pharmacogenetics testing in cancer treatment
Hospital Pharmacology - International Multidisciplinary Journal
Introduction: Precision medicine is an approach that considers genetics, environment and lifestyle factors when prevent and treat diff erent diseases. The important part of precision medicine is pharmacogeneticss, a branch of clinical pharmacology that analyzes how genetic makeup aff ects the response to the drugs. Methods: Since oncology is a fi eld of particular interest in precision medicine, this article summarizes the basic principles of pharmacogenetics testing in cancer treatment. Topic: The following topics have been discussed: Samples for pharmacogenetics testing (peripheral blood, tumor biopsy, liquid biopsy), methods in pharmacogenetics testing (conventional hotspot methods and comprehensive genome profi ling), comprehensive genome profi ling (CGP) in clinical settings and oncology therapy in Serbia that depends on genetic testing. Conclusion: Pharmacogenetics testing provides the delivery of safe and effi cient therapy. The usage of CGP methods opens up the possibility for the usage of therapies directed to genetic markers across tumor types. However, this approach needs evaluation through well-designed research projects and clinical trials.
Molecular Cancer Therapeutics, 2010
EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR −191C/A (P < 0.001), −216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR −191C/A, −216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.