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.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes.

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

Evaluation of pharmacy students' knowledge and perceptions of pharmacogenetics before and after a simulation activity.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate students' knowledge and perceptions of the clinical application of pharmacogenetics through a simulation activity and to assess communication of pharmacogenetic-guided treatment recommendations utilizing standardized patients. EDUCATIONAL ACTIVITY AND SETTING: Third-year students in the four-year doctor of pharmacy (PharmD) program at University of South Florida College of Pharmacy completed a pharmacogenetics simulation involving a patient case review, interpretation of pharmacogenetic test results, completion of a situation, background, assessment, recommendation (SBAR) note with drug therapy recommendations, and patient counseling. Voluntary assessments were completed before and after the simulation, which included demographics, knowledge, and perceptions of students' ability to interpret and communicate pharmacogenetic results. FINDINGS: Response rates for the pre- and post-simulation assessments were 109 (98%) and 104 (94%), respectively. Correct responses in application-type questions improved after the simulation (74%) compared to before the simulation (44%, p < 0.01). Responses to perception questions shifted towards "strongly agree" or "agree" after the simulation (p < 0.01). DISCUSSION AND SUMMARY: The simulation gave students an opportunity to apply pharmacogenetics knowledge and allowed them to gain an appreciation of pharmacists' roles within the pharmacogenetics field.

Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned.

Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme). TPMT tests were most commonly ordered for gastroenterology, rheumatology, dermatology, and hematology/oncology patients (661 of 834 patients (79.2%); 580 outpatient vs. 293 inpatient; P < 0.0001). Thirty-nine patients had both genotype and enzyme tests (n = 2 discordant results). We observed significant differences between TPMT test use and characteristics in a diverse, multispecialty environment vs. a pediatric cancer setting, which led to unique implementation needs. As pharmacogenetic implementations expand, disseminating lessons learned in diverse, real-world environments will be important to support routine adoption.

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.

Role of Cytochrome P450 2B6 Pharmacogenomics in Determining Efavirenz-Mediated Central Nervous System Toxicity, Treatment Outcomes, and Dosage Adjustments in Patients with Human Immunodeficiency Virus Infection.

For treatment-naive patients with human immunodeficiency virus infection, efavirenz (EFV), together with tenofovir and emtricitabine, was once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system (CNS) toxicities from EFV prompted the U.S. Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and often the mainstay of treatment outside the United States because newer antiretroviral treatments are more expensive. CNS toxicity occurring with the recommended standard dose of EFV remains a challenge and may in part be attributable to polymorphisms in cytochrome P450 (CYP) 2B6, the enzyme involved in the major metabolic pathway for converting EFV to inactive metabolites. Functionally deficient alleles of CYP2B6 such as CYP2B6*6, *18, and *22 may be responsible for significantly higher therapeutic concentrations of EFV at a standard dose of 600 mg/day. We conducted a thorough review of the reported studies to elucidate the relationship between polymorphisms in CYP2B6 with adverse events and treatment response, including virologic suppression, immunologic response, resistance, and discontinuation of treatment. Compelling evidence exists to support the case for CYP2B6 genotype-guided EFV therapy while acknowledging the need for prospective controlled clinical trials to evaluate its clinical utility.

Anti-VEGF-Induced Hypertension: a Review of Pathophysiology and Treatment Options.

OPINION STATEMENT: Abnormal intracellular signaling has been implicated in the development of many different types of cancer. Therapies targeting these abnormal pathways have revolutionized the treatment of many malignancies leading to significantly improved outcomes and survival. Despite these advances, cardiovascular toxicity is a frequently reported complication. Angiogenesis is the physiologic process of new blood vessel development and can be dysregulated in some forms of cancer. VEGF inhibitors are the pharmaceutical agents targeting this pathway; however hypertension is a commonly observed toxicity which can have significant adverse consequences including premature cessation of therapy if adequate blood pressure control cannot be achieved. This review will provide a comprehensive discussion about hypertension due to VEGF inhibition, focusing on pathophysiology, frequently used agents, and available treatment options for VEGF-induced hypertension.