Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses.

Purpose: The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). As third-generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management.

Experimental Design: As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy.

Co-development of a companion diagnostic for targeted cancer therapy.

Oncology drug development is a long and costly process associated with a success rate of 5-10%. The parallel development of companion diagnostic tests that will identify patients most likely to receive benefit has the potential to increase the success rate for oncology drugs and decrease development time and associated costs. Metastatic melanoma is a challenging disease that has been associated with poor survival.

Clinical applications of microarray-based diagnostic tests.

Nearly 15 years have passed since the possibility of analyzing nucleic acid analytes in a massively parallel fashion was proposed using the then new concept of microarrays. A decade ago, proof of principle demonstration projects established the use of high density microarrays to genotype multiple polymorphisms within a large gene [cystic fibrosis transmembrance regulator (CFTR)], to rapidly analyze DNA sequences by hybridization and to ascertain differential gene expression of the entire genome of an organism. The use of microarrays has had an explosive influence on the rate at which new biological information can be learned, including in a nonhypothesis driven manner.

The External RNA Controls Consortium: a progress report.

Standard controls and best practice guidelines advance acceptance of data from research, preclinical and clinical laboratories by providing a means for evaluating data quality. The External RNA Controls Consortium (ERCC) is developing commonly agreed-upon and tested controls for use in expression assays, a true industry-wide standard control.

Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness.

This study tested the association between tardive dyskinesia (TD) and polymorphic variations in (a) 2 cytochrome P450 (CYP) genes (CYP2D6 or CYP3A5), (b) 2 DRD2 variants (Ser311Cys and -141C Ins/del) and the Ser9Gly DRD3 variants, (c) 2 glutathione S-transferases (GSTT1 and GSTM1), and (d) variations in the PgP gene, MDR1. The study sample included 516 severely mentally ill patients from Central Kentucky facilities. Logistic regression models that included clinical variables associated with TD were developed.

The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?

Background: Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (>/= 3) of the CYP2D6 allele.

The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation.

Objective: The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone. CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of other races). This study tested whether the CYP2D6 poor metabolizer phenotype was associated with adverse drug reactions (ADRs) and discontinuation due to ADRs.

Technology platforms for pharmacogenomic diagnostic assays.

Rapid advances in the understanding of genomic variation affecting drug responses, and the development of multiplex assay technologies, are converging to form the basis for new in vitro diagnostic assays. These molecular diagnostic assays are expected to guide the therapeutic treatment of many diseases, by informing physicians about molecular subtypes of disease that require differential treatment, which drug has the greatest probability of effectively managing the disease, and which individual patients are at the highest risk of experiencing adverse reactions to a given drug therapy. This article reviews some of the relative strengths and limitations of the most widely used technologies and platforms for such assays.

Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships.

Background: There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing.

Methods: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay.