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.

Study of Reimbursement of Preemptive Pharmacogenetic Testing by Health Insurance Payers

Researchers from the University of Mississippi School of Pharmacy and St. Jude Children’s Research Hospital have taken on one of the crucial barriers remaining in the movement of pharmacogenetic testing to the clinic--coverage and reimbursement of the preemptive pharmacogenetic testing by health insurance payers. The results appeared recently online in Genetics in Medicine.

Reimbursement of pharmacogenetic testing varies widely across settings and payers.  Little is known about reimbursement for preemptive pharmacogenetic testing where testing is completed proactively and integrated into the electronic health record to be available to clinicians at the point of prescribing. The current study provides an in-depth look into the decision making processes of insurance payers regarding the coverage policies for preemptive pharmacogenetic testing.

In-depth interviews with pharmacy and medical directors from a variety of regional and national health plans as well as pharmacy benefit management companies were conducted. The authors were interested in these decision-makers’ knowledge and opinions on the preemptive testing model for pharmacogenetic testing. Numerous issues from the clinical, economic, and policy domains were identified that impact coverage decisions for preemptive pharmacogenetics.

Although insurance payers understood the potential clinical and economic benefits for both patients and the health system by using preemptive pharmacogenetics, payers seemed reluctant to cover germ-line pharmacogenetic testing because of the difficulty in seeing an immediate return on the investment in the testing cost.  Payers often think in a one-year time frame, but the value of preemptive testing accrues over years. Payers found great value in the work of the Clinical Pharmacogenetics Implementation Consortium (CPIC) to guide clinical decision making for pharmacogenetics.  (CPIC is an international consortium interested in facilitating use of pharmacogenetic tests for patient care.)  CPIC is focused on providing clinicians guidance when pharmacogenetic information is available, but many of the payers wanted an organization such as CPIC to define who should be tested. 

Payers were asked about the clinical evidence they needed to cover preemptive pharmacogenetics.  Some payers remained focused on randomized controlled trials (RCT). Others expressed a willingness to consider alternative study designs, and some found value in learning from the experiences of sites currently implementing pharmacogenetics.

The costs of the medications that would be modified based on pharmacogenetic information entered into the decision making process for these payers.  They expressed a willingness for a trial-and-error approach when the medication is inexpensive. However, there was great interest in pharmacogenetics for expensive medications where the testing may indicate if the patient should receive the medication.   For most other medications, potential downstream economic benefits and improved patient safety are important predictors of utility to some payers.

Government entities like the Centers for Medicare & Medicaid Services (CMS) and the US Food & Drug Administration (FDA) were key reference points for the payers interviewed. The workings of the CMS “coverage with evidence development” program was used a benchmark to discuss similar programs among payers. While some thought themselves willing to take on pilot-type studies, others believed that CMS would have to lead the setting of coverage policies in this space and others would follow suit. FDA labeling remains an important reference for coverage to these payers even though the FDA label may not always contain all the information needed to guide pharmacogenetic testing. One payer noted the United States Preventive Services Task Force (USPSTF) could identify pharmacogenetic testing as a priority for routine screening.  An endorsement from a group like the USPSTF would prompt reimbursement and could be a mechanism for widespread coverage.

This study brings to light the mental model of payers and their remaining barriers and facilitators to coverage in preemptive pharmacogenetics. The pharmacogenetics community will likely find the results of this study valuable as they continue to design and implement the research and implementation projects that demonstrate the clinical and economic utility of pharmacogenetics.

Blog by James M. Hoffman, PharmD, MS

See more about CPIC guidelines on PharmGKB and the CPIC website. See more about FDA labels with PGx information on PharmGKB.

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Curators' Favorite Papers

October’s edition of "Curators' Favorite Papers" features “Introducing personalized health for the family: the experience of a single hospital system”, a discussion about a preemptive pharmacogenomic (PGx) testing program in newborns at a Virginia hospital. The program, called MediMap Baby was initiated in 2014 with with the recruitment of participants from a longitudinal family-based whole genome sequence study at the Inova Translational Medicine Institute (ITMI). Initial efforts included the formation of small focus groups to gauge patient interest in the project. The MediMap project began implementation in 2016 where preemptive PGx testing was offered to all families of the newborns born at the hospital. 4,257 PGx tests were conducted at no additional cost and results were entered into the patient’s electronic health record. The program necessitated the training of a multidisciplinary staff and the development of patient educational materials. Genes assayed included TPMT, CYP2C9, VKORC1, CYP2C19, SLCO1B1, CYP2D6 and CYP3A5, which the authors describe as having potential utility for 24 prescription medications.

Dosing and prescribing guidelines involving these and other genes are available on PharmGKB and CPIC.