New CPIC Guideline: CYP2D6 and tamoxifen

The CPIC Guideline for tamoxifen and CYP2D6 is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB page for tamoxifen, and the CPIC website. 

Tamoxifen is a selective estrogen receptor modulator (SERM) and is utilized in breast cancer treatment. Tamoxifen is extensively metabolized, in part by CYP2D6. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer.

The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

For further details see the guidelines and supplement on CPIC, or on the pages for tamoxifen on PharmGKB. 

Researchers interested in a highly curated genotype-phenotype data set for women treated with tamoxifen, please see the International Tamoxifen Pharmacogenetics Consortia (ITPC) paper published in Clin Pharmacol Ther (2014; PMID 24060820) with the associated data set at PharmGKB.

2018 Precision Medicine Conference

UF Precision Medicine Conference is focused on implementing PGx and genomic medicine, happening March 2018 in Orlando, Florida. See the website for registration and more information. 

Curators' Favorite Papers

The first paper from Genetics in Medicine by Khoury et al. (From Public Health Genomics to Precision Public Health: a 20-Year Journey) reviews developments in the field of public health genomics over the last twenty years. Public health genomics deals with the “effective and responsible translation of genomic research into population health benefit” through assessment, policy, and assurance. It summarizes current research projects in the field and describes the role of organizations, including the Centers for Disease Control and Prevention (CDC) in the development and implementation of evidence-based guidelines for genetic testing. The authors recognize that genomics cannot be isolated from other determinants of health including behaviors or socioeconomic factors such as housing, education, and access to care and the need for subsequent developments in “precision public health” to integrate genomics data with other health determinants to improve public health outcomes.


Despite the fact that over 100 GPCRs are targeted by approximately 34% of FDA-approved drugs, the frequency of genetic variation of GPCRs is not known according to a study by Hauser et al. from the December issue of Cell (Pharmacogenomics of GPCR Drug Targets). The study evaluates pharmacogenetic (PGx) variation in 108 G-protein coupled receptors (GPCRs) using datasets from the exome aggregation consortium (ExAC) and the 1000 Genomes Project that include over 60,000 individuals and estimates that there is an average of 128 rare and 3.7 common variants per receptor and that 25% of all positions in each GPCR contains a missense variant. In addition approximately 120 of the 60,706 individuals from the dataset harbored loss of function mutations in a GPCR drug target and each GPCR had approximately two duplications and three deletions. The authors support their findings with an analysis of the molecular literature, including data from PharmGKB Clinical Annotations, functional PGx studies of GPCRs on drug response and efficacy and an economic analysis of how incorporation of GPCR PGx could decrease the UKs National Health Service (NHS) financial burden.

PharmCAT commentary in Clinical Pharmacology & Therapeutics

A commentary about the Pharmacogenomics Clinical Annotation Tool (PharmCAT) was recently published in Clinical Pharmacology & Therapeutics.  PharmCAT is developed in a collaboration between the former PGRN Statistical Analysis Resource (P-STAR) and the Pharmacogenomics Knowledgebase (PharmGKB) with input from other groups (click here for a list of participants). PharmCAT will extract PGx variants, beginning with variants in genes with CPIC guideline recommendations, from VCF files, infer diplotypes/genotypes, and generate an interpretation report containing the relevant CPIC recommendations.

In the article, Teri Klein and Marylyn Ritchie highlight challenges in the field and describe the rationale for PharmCAT. The tool's workflow is depicted graphically and the different components are briefly introduced.

For more information about PharmCAT read the complete commentary at Clinical Pharmacology & Therapeutics.

Curators' Favorite Papers

The first of two papers selected for the November edition of ”Curators' Favorite Papers" is from Nature Reviews Genetics (“Prioritizing diversity in human genomics research”). It highlights the necessity of including individuals from diverse backgrounds in genomic research, both as subjects and as researchers. The authors discuss several proposals to achieve these goals beginning with awareness of genetic and environmental factors that contribute to disparities in health outcomes, establishing sources of dedicated funding, recruiting subjects, researchers and clinicians from diverse backgrounds, and the integration of genomics into existing healthcare systems in underserved communities. The authors mention two pharmacogenomic (PGx) examples to remark on the importance of genetic and geographic diversity for clinical genomics: the risk of Stevens-Johnsons Syndrome/ toxic epidermal necrolysis in individuals of Asian ancestry who carry the HLA-B*15:02 allele that are administered carbamazepine as well as the risk of hemolysis in African-American males harboring G6PD alleles that are administered quinine. 

According to a new paper from the journal Oncotarget (“Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials.”), metastatic endometrial cancer (EC) is the fourth most common cancer affecting women, with increased incidence and relatively poor prognosis but no new treatments have been approved in approximately two decades. The paper summarizes the findings from a recent meeting of Gynecologic Cancer Steering Committee (GCSC) and the National Cancer Institute (NCI). Experts gathered to review the literature and generate reports to design early phase clinical trials based on molecular pathway research in EC to improve treatment outcomes in women with EC. The authors generated reports for therapies targeting mutations in those pathways that are commonly implicated in a variety of cancers including DNA-damage repair and cell-cycle checkpoint pathways including ERBB2/HER2, PI3K/ATK/mTOR, WNT pathways as well as the dysregulation of those pathways involving ubiquitin-ligase complex, the immune system and metabolic disorders. 

You can read more about HLA-B and carbamazepine, G6PD and quinine, ERBB2/HER2 and other targeted cancer therapies at the Cancer Pharmacogenomics portal on PharmGKB and CPIC. 

CPIC Guideline Update: DPYD and Fluoropyrimidines

The 2017 update of the CPIC Guideline for Fluoropyrimidines and DPYD is now available as an advance online publication in Clinical Pharmacology and Therapeutics. CPIC extensively reviewed the literature up to March 2017. Both the dosing recommendations and supplemental information were updated. The accepted article can currently be viewed on the PharmGKB pages for capecitabine and fluorouracil, and the CPIC website. 

Fluoropyrimidines are mainly used to treat solid tumors, such as colorectal, breast and aerodigestive cancers. Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) is the rate-limiting enzyme for fluoropyrimidine metabolism and is therefore responsible for the detoxification of these types of drugs. The 2017 update includes the following updates and additions:

• Dosing recommendations were modified to only apply to fluorouracil and capecitabine; they no longer apply to tegafur.
• Dosing recommendations are now given in the context of DPYD activity score.

For further details see the guidelines and supplement on CPIC, or on the pages for capecitabine and fluorouracil on PharmGKB. 

PharmVar Published in CPT

The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database has been published in the journal Clinical Pharmacology and Therapeutics.  The paper describes the goals of the consortium and the database that will house pharmacogene variants and nomenclature.

Visit the PharmVar website to learn more.