Klein, Teri E.

Abstract To move beyond a select few genes/drugs, the successful adoption of pharmacogenomics into routine clinical care requires a curated and machine-readable database of pharmacogenomic knowledge suitable for use in an electronic health record (EHR) with clinical decision support (CDS). Recognizing that EHR vendors do not yet provide a standard set of CDS functions for pharmacogenetics, the Clinical Pharmacogenetics Implementation Consortium (CPIC) Informatics Working Group is developing and systematically incorporating a set of EHR-agnostic implementation resources into all CPIC guidelines. These resources illustrate how to integrate pharmacogenomic test results in clinical information systems with CDS to facilitate the use of patient genomic data at the point of care. Based on our collective experience creating existing CPIC resources and implementing pharmacogenomics at our practice sites, we outline principles to define the key features of future knowledge bases and discuss the importance of these knowledge resources for pharmacogenomics and ultimately precision medicine.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org ).

Abstract Background: An estimated 1.3 million women worldwide will be diagnosed this year with early stage breast cancer. The majority of women have estrogen receptor (ER) positive breast cancer and are candidates for endocrine therapy. Tamoxifen remains the most commonly employed agent worldwide and substantially reduces recurrence and mortality. Tamoxifen is a pro-drug. CYP2D6 converts tamoxifen to endoxifen, which is primarily responsible for inhibition of estrogen-stimulated breast cancer growth in vitro. There have been conflicting reports regarding the relationship between CYP2D6 genotype/phenotype and tamoxifen clinical outcome. The ITPC was established to collect the worldwide experience relating to genetic variation in CYP2D6 and the outcomes of women with ER positive breast cancer treated with adjuvant tamoxifen. Establishment of the predictive value of CYP2D6 would enable the a priori identification of patients that could be spared ineffective therapy.Methods: Individual patient data including tumor characteristics, genotype, medication data, and recurrence information were requested from all published and non-published reports of clinical outcomes related to CYP2D6 and deposited at PharmGKB. CYP2D6 genotype was available for the following null (*3, 4, 5 and 6) and IM (*10, 17 and 41) alleles. CYP2D6 inhibiting medication data was requested for weak and potent CYP2D6 inhibitors. The primary analysis was to determine the association of CYP2D6 phenotype (combined genotype and medication) with breast cancer recurrence in tamoxifen treated early stage, ER positive invasive breast cancer.Results: At this time, the ITPC has received patient data on 3432 patients from the U.S., Sweden, UK, Germany, Belgium, and Japan. Median age at diagnosis was 62 years. CYP2D6 genotype was available in 3,392 (99%). The allele frequency for CYP2D6*4, the most common allele associated with the CYP2D6 poor metabolizer phenotype, was q=0.23. A total of 1152 recurrences representing first events (either local, regional, distant, or contralateral breast cancer) were recorded. At the time of abstract submission, patient and genotype data from an additional 1300 tamoxifen treated patients were pending submission.Conclusions: The ITPC represents the largest collection of individual patient data in regard to the potential importance of CYP2D6 phenotype in adjuvant tamoxifen therapy. The findings from this consortium are expected to substantially improve the global understanding of CYP2D6 and tamoxifen clinical outcome. Final results will be presented at the meeting Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 33.