Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Synthesis of major pharmacogenomics pretest counseling themes: a multisite comparison.

The accessibility of pharmacogenomic (PGx) testing has grown substantially over the last decade and with it has arisen a demand for patients to be counseled on the use of these tests. While guidelines exist for the use of PGx results; objective determinants for who should receive PGx testing remain incomplete. PGx clinical services have been created to meet these screening and education needs and significant variability exists between these programs. This article describes the practices of four PGx clinics during pretest counseling sessions. A description of the major tenets of the benefits, limitations and risks of testing are compiled. Additional tools are provided to serve as a foundation for those wishing to begin or expand their own counseling service.

Implementing pharmacogenetic testing in rural primary care practices: a pilot feasibility study.

Aim: Assess feasibility and perspectives of pharmacogenetic testing/PGx in rural, primary care physician (PCP) practices when PCPs are trained to interpret/apply results and testing costs are covered. Methods: Participants included PCPs who agreed to training, surveys and interviews and eligible patients who agreed to surveys and testing. 51 patients from three practices participated. Results: Prestudy, no PCP had ever ordered a PGx test. Test results demonstrated gene variations in 30% of patients, related to current medications, with PCPs reporting changes to drug management. Poststudy, test cost was still a concern, but now PCPs reported practical barriers, including the utilization of PGx results over time. PCPs and patients had favorable responses to testing. Summary: PGx testing is feasible in rural PCP practices.

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

Implementing a personalized medicine program in a community health system.

The implementation of a de novo personalized medicine program in a rural community health system serving an underserved population is described. Focusing on the safe use of drugs impacted by genetic variations in the non-oncology setting, we first addressed drug-gene pairs designated by the US FDA in black-box warnings (codeine, clopidogrel, abacavir, carbamazepine). The program's first success was a policy change to remove codeine from the pediatric formulary, rather than a testing recommendation. Pilot studies were then conducted with primary care providers to get them familiar with pharmacogenetic testing, and a consultative outpatient clinic for patients was developed. The assessment, planning, implementation, challenges, successes and lessons learned are described.

Prediction of chemotherapy-induced nausea and vomiting from patient-reported and genetic risk factors.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is common among cancer patients. Early identification of patients at risk for CINV may help to personalize anti-emetic therapies. To date, few studies have examined the combined contributions of patient-reported and genetic risk factors to CINV. The goal of this study was to evaluate these risk factors. METHODS: Prior to their first chemotherapy infusion, participants completed demographic and risk factor questionnaires and provided a blood sample to measure genetic variants in ABCB1 (rs1045642) and HTR3B (rs45460698) as well as CYP2D6 activity score. The M.D. Anderson Symptom Inventory was completed at 24 h and 5-day post-infusion to assess the severity of acute and delayed CINV, respectively. RESULTS: Participants were 88 patients (55% female, M = 60 years). A total of 23% experienced acute nausea and 55% delayed nausea. Younger age, history of pregnancy-related nausea, fewer hours slept the night prior to infusion, and variation in ABCB1 were associated with more severe acute nausea; advanced-stage cancer and receipt of highly emetogenic chemotherapy were associated with more severe delayed nausea (p values < 0.05). In multivariable analyses, ABCB1 added an additional 5% predictive value beyond the 13% variance explained by patient-reported risk factors. CONCLUSIONS: The current study identified patient-reported and genetic factors that may place patients at risk for acute nausea despite receipt of guideline-consistent anti-emetic prophylaxis. Additional studies examining other genetic variants are needed, as well as the development of risk prediction models including both patient-reported and genetic risk factors.

Pharmacogenomics Implementation: Considerations for Selecting a Reference Laboratory.

One of the initial steps for implementing pharmacogenomics into routine patient care is selecting an appropriate clinical laboratory to perform the testing. With the rapid advances in genotyping technologies, many clinical laboratories are now performing pharmacogenomic testing. Selection of a reference laboratory depends on whether a particular genotype assay is already performed by an internal health care organization laboratory or only available externally. Other factors for consideration are coverage of genomic variants important for the patient population, technical support, and cost. In some instances, the decision to select a particular reference laboratory may be the responsibility of the clinician who is recommending genomic interrogation. Only limited guidance is available that describes the laboratory characteristics to consider when selecting a reference laboratory. We provide practical considerations for selecting a clinical laboratory for pharmacogenomic testing broadly categorized into four domains: pharmacogene and variant selection; logistics; reporting of results; and test costs along with reimbursement.

Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience.

BACKGROUND: The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice. MATERIALS AND METHODS: In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine. RESULTS: Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting-edge practice merged with individualized preferences in treatment and care. CONCLUSIONS: Genomic-driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence-based translation of observed molecular alterations into patient-centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards. The Oncologist 2017;22:144-151Implications for Practice: It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards.

Implementation of a multidisciplinary pharmacogenomics clinic in a community health system.

PURPOSE: The development and implementation of a multidisciplinary pharmacogenomics clinic within the framework of an established community-based medical genetics program are described. SUMMARY: Pharmacogenomics is an important component of precision medicine that holds considerable promise for pharmacotherapy optimization. As part of the development of a health system-wide integrated pharmacogenomics program, in early 2015 Northshore University Health-System established a pharmacogenomics clinic run by a multidisciplinary team including a medical geneticist, a pharmacist, a nurse practitioner, and genetic counselors. The team identified five key program elements: (1) a billable-service provider, (2) a process for documentation of relevant medication and family histories, (3) personnel with the knowledge required to interpret pharmacogenomic results, (4) personnel to discuss risks, benefits, and limitations of pharmacogenomic testing, and (5) a mechanism for reporting results. The most important program component is expert interpretation of genetic test results to provide clinically useful information; pharmacists are well positioned to provide that expertise. At the Northshore University HealthSystem pharmacogenomics clinic, patient encounters typically entail two one-hour visits and follow a standardized workflow. At the first visit, pharmacogenomics-focused medication and family histories are obtained, risks and benefits of genetic testing are explained, and a test sample is collected; at the second visit, test results are provided along with evidence-based pharmacotherapy recommendations. CONCLUSION: A multidisciplinary clinic providing genotyping and related services can facilitate the integration of pharmacogenomics into clinical care and meet the needs of early adopters of precision medicine.

Detection of a PDGFRB fusion in refractory CMML without eosinophilia: A case for broad spectrum tumor profiling.

In this case report, we describe a refractory CMML case without eosinophilia harboring a PDGFRB rearrangement leading to a favorable response with imatinib. We believe this case demonstrates the utility of broad spectrum genomic profiling in refractory CMML cases as an opportunity to uncover additional treatment options.

Clinical Implications of Opioid Pharmacogenomics in Patients With Cancer.

BACKGROUND: Pain can be a significant burden for patients with cancer and may have negative effects on their quality of life. Opioids are potent analgesics and serve as a foundation for pain management. The variation in response to opioid analgesics is well characterized and is partly due to genetic variability. METHODS: We reviewed the results of clinical studies to evaluate the relationships between genetic variants and select genes involved in the pharmacokinetics and pharmacodynamics of opioids, with an emphasis on patients with cancer. RESULTS: In patients with cancer-related pain, genetic variation in OPRM1, COMT, and ABCB1 is associated with response to morphine, which is the most well-studied opioid. Although it has not been studied in patients with cancer-related pain, the effect of CYP2D6 variation is well characterized with codeine and tramadol. Evidence is limited for associating the genetic variation and pain response of oxycodone, hydrocodone, and fentanyl in patients with cancer. CONCLUSION: The clinical availability of pharmacogenomic testing and research findings related to these polymorphic genes suggest that genotyping patients for these genetic variants may allow health care professionals to better predict patient response to pain and, thus, personalize pain treatment.

Budget impact analysis of CYP2C19-guided voriconazole prophylaxis in AML.

OBJECTIVES: The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML. METHODS: An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with voriconazole and (ii) CYP2C19 genotyping of all AML patients to guide voriconazole dosing and prescribing. RESULTS: Based on the model, genotype-guided dosing of voriconazole conservatively spares 2.3 patients per year from invasive fungal infections. Implementing proactive genotyping of all AML patients in a simulated 100 patient cohort is expected to save a total of $41467 or $415 per patient. CONCLUSIONS: The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection.

Development and use of active clinical decision support for preemptive pharmacogenomics.

BACKGROUND: Active clinical decision support (CDS) delivered through an electronic health record (EHR) facilitates gene-based drug prescribing and other applications of genomics to patient care. OBJECTIVE: We describe the development, implementation, and evaluation of active CDS for multiple pharmacogenetic test results reported preemptively. MATERIALS AND METHODS: Clinical pharmacogenetic test results accompanied by clinical interpretations are placed into the patient's EHR, typically before a relevant drug is prescribed. Problem list entries created for high-risk phenotypes provide an unambiguous trigger for delivery of post-test alerts to clinicians when high-risk drugs are prescribed. In addition, pre-test alerts are issued if a very-high risk medication is prescribed (eg, a thiopurine), prior to the appropriate pharmacogenetic test result being entered into the EHR. Our CDS can be readily modified to incorporate new genes or high-risk drugs as they emerge. RESULTS: Through November 2012, 35 customized pharmacogenetic rules have been implemented, including rules for TPMT with azathioprine, thioguanine, and mercaptopurine, and for CYP2D6 with codeine, tramadol, amitriptyline, fluoxetine, and paroxetine. Between May 2011 and November 2012, the pre-test alerts were electronically issued 1106 times (76 for thiopurines and 1030 for drugs metabolized by CYP2D6), and the post-test alerts were issued 1552 times (1521 for TPMT and 31 for CYP2D6). Analysis of alert outcomes revealed that the interruptive CDS appropriately guided prescribing in 95% of patients for whom they were issued. CONCLUSIONS: Our experience illustrates the feasibility of developing computational systems that provide clinicians with actionable alerts for gene-based drug prescribing at the point of care.

Faculty and student perceptions of effective study strategies and materials.

OBJECTIVES: To evaluate faculty members' and students' perceptions of study strategies and materials. METHODS: Focus groups were conducted with course directors and first- and second-year students to generate ideas relating to use of course materials, technology, class attendance, and study strategies for mastering class concepts. RESULTS: Students and faculty members differed in their opinions about the utility of textbooks and supplemental resources. The main learning method recommended by students and faculty members was repeated review of course material. Students recommended viewing classroom lectures again online, if possible. Course directors reported believing that class attendance is important, but students based their opinions regarding the importance of attendance on their perceptions of lecture and handout quality. Results did not differ by campus or by student group (first-year vs. second-year students). CONCLUSIONS: Students and faculty members have differing opinions on the process that could influence learning and course design. Faculty members should understand the strategies students are using to learn course material and consider additional or alternative course design and delivery techniques based on student feedback.