Showing papers in "Pharmacogenomics in 2017"

Triple-negative breast cancer and the potential for targeted therapy.

Abstract: Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.

Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing.

Abstract: CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.

Pharmacogenetics of drug–drug interaction and drug–drug–gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6

Abstract: Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

Institutional profile: University of Florida Health Personalized Medicine Program.

Abstract: The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.

Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population

Abstract: Aim: To systematically investigate the genetic polymorphisms of the CYP3A4 gene in a Han Chinese population. Materials & methods: The promoter and exons of CYP3A4 gene in 1114 unrelated, healthy Han Chinese subjects were amplified and genotyped by direct sequencing. Results: In total, five previously reported alleles (*1G, *4, *5, *18B and *23) were detected, of which one allele (*23) was reported for the first time in Han Chinese population. Additionally, seven novel exonic variants were also identified and designated as new alleles CYP3A4*28–*34. Conclusion: This study provides the most comprehensive data of CYP3A4 polymorphisms in Han Chinese population and detects the largest number of novel CYP3A4 alleles in one ethnic group.

MiRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma

Abstract: Cholangiocarcinoma (CCA) is a lethal malignancy originating from the biliary tract epithelium. Most patients are diagnosed at an advanced stage. Even after resection with curative intent, prognosis remains poor. Previous studies have reported the evolving role of miRNAs as novel biomarkers in cancer diagnosis, prognostication and chemotherapy response. Various miRNAs, such as miR-21, miR-26, miR-122 and miR-150, have been identified as possible blood-based biomarkers for noninvasive diagnosis of CCA. Moreover, epithelial-mesenchymal transition (EMT)- and angiogenesis-associated miRNAs have been implicated in tumor cell dissemination and are able to determine clinical outcome. In fact, miRNAs involved in cell survival might even determine chemotherapy response. This review provides an overview of known miRNAs as CCA-specific biomarkers.

Healthcare provider education to support integration of pharmacogenomics in practice: the eMERGE Network experience

Abstract: Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

Pharmacogenetics of drug-induced ototoxicity caused by aminoglycosides and cisplatin.

Abstract: Aminoglycosides and the anticancer drug cisplatin can cause permanent hearing loss, which impacts patients' quality of life and results in considerable subsequent costs. Since patients' individual susceptibility to aminoglycoside- and cisplatin-induced ototoxicity varies considerably, strategies are needed to identify patients at risk, who may require alternative treatments or specific protection strategies. For both drugs, various genetic variants were linked to an increased or decreased risk for ototoxicity. Except for the association between the A1555G mitochondrial DNA mutation and aminoglycoside ototoxicity, their evidence is considered low because study cohorts were often small and replication studies either missing or contradictory. This review summarizes the pharmacogenetic markers linked to aminoglycoside- or cisplatin-induced ototoxicity and discusses reasons for replication failure and future perspective.

CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients

Abstract: Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for Cmax, p = 0.016 for AUC0–6 and p = 0.026 for AUC0–24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM ...

Pharmacogenomics testing in a community pharmacy: patient perceptions and willingness-to-pay

Abstract: Aim: To determine patient knowledge, interest and willingness-to-pay for pharmacogenomics testing in a community pharmacy. Patients & methods: The link to a cross-sectional, anonymous online survey was distributed to a convenience sample of patients. The contingent valuation method was used to assess willingness-to-pay. Results: Twenty seven surveys were completed. Eighty one percent of patients were interested in the service, but patients felt that they would be more likely to use the service if insurance covered the cost. Conclusion: Patients indicated interest in a pharmacogenomics test, but varying levels of willingness-to-pay. Patients may not be able to connect the benefits of testing to their health, justifying further patient education in order to increase the viability of pharmacogenomics testing as a pharmacy service.

Clinicians' perceptions of pharmacogenomics use in psychiatry.

Abstract: Aim: This study aims to assess the attitudes and opinions of clinicians practicing in psychiatry toward pharmacogenomic testing, and in so doing elicits possible barriers and risks to employ this technology in patient care. Materials & methods: Doctors and pharmacists presently practicing in psychiatry were invited to participate in an anonymous web-based survey. Besides information on participant characteristics and experience in psychiatry, specific themes on pharmacogenomics including self-assessed competency, perceived usefulness in clinical situations, perceived risks and preferred mode of education were evaluated. Results: A total of 81% of respondents believed that pharmacogenomic testing would be useful for identifying suitable treatments and 71% believed that pharmacogenomic testing would be useful for medication intolerance. However, only 46.4% felt competent to order these tests. There were significant differences in responses for gender, doctors versus pharmacists and seniority in position. A ...

A nationwide survey of pharmacists’ perception of pharmacogenetics in the context of a clinical decision support system containing pharmacogenetics dosing recommendations

Abstract: Aim: To benchmark Dutch pharmacists knowledge, experience and attitudes toward pharmacogenetics (PGx) with a specific focus on the effects of awareness of the Dutch Pharmacogenetics Working Group guidelines. Methods: A web-based survey containing 41 questions was sent to all certified Dutch pharmacists. Results: A total of 667 pharmacists completed the survey (18.8%). Virtually all responders believed in the concept of PGx (99.7%). However, only 14.7% recently ordered a PGx test (≤6 months), 14.1% felt adequately informed and 88.8% would like to receive additional training on PGx. Being aware of the Dutch Pharmacogenetics Working Group guidelines did not have any significant effect on knowledge or adoption of PGx. Conclusion: Dutch pharmacists are very positive toward PGx. However, test adoption is low and additional training is warranted.

Genetic variation in the glucocorticoid pathway involved in interindividual differences in the glucocorticoid treatment.

Abstract: Glucocorticoids (GCs) are widely used for treating asthma, rheumatoid arthritis, nephrotic syndrome, acute lymphoblastic leukemia and other autoimmune diseases. However, in a subgroup of patients, failure to respond to GCs is known as GC resistance or GC insensitivity. This represents an important barrier to effective treatment and a clinical problem requiring an urgent solution. Genetic variation in the GC pathway is a significant factor in interindividual differences in GC treatment. This article reviews the pharmacogenetics of GCs in diverse diseases based on the GC pathway.

OCT1 genetic variants are associated with postoperative morphine-related adverse effects in children

Abstract: Aim: Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African–American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine’s PK and clinically important postoperative morphine-related adverse outcomes. Methods: After obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6–15 years, American Society of Anesthesiologists’ physical status 1 or ...

Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients.

Abstract: The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1)-mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer.

Trough concentration and ABCG2 polymorphism are better to predict imatinib response in chronic myeloid leukemia: a meta-analysis.

Abstract: Aim: The present study aimed to conduct a series of meta-analyses to investigate the influence of imatinib trough concentration (C0), as well as ABCB1 and ABCG2 polymorphisms, on the clinical response in patients with chronic myeloid leukemia (CML). Methods: A literature search was conducted using the PubMed and Cochrane electronic databases to locate relevant papers from 2003 onward. Then, an initial meta-analysis of 14 studies involving 2184 patients was conducted to understand the effect of imatinib mesylate (IM) C0 on clinical outcome in CML patients. Subsequently, a series of meta-analyses were performed, including up to 23 studies with 2577 patients, on the effect of genetic polymorphisms of ABCB1 and ABCG2 on the clinical response to IM. Results: Meta-analysis revealed that patients who achieved a major molecular response (MMR) have a significantly higher IM C0 than those who failed to achieve an MMR. We also found that the patients who achieved a complete cytogenic response (CCyR) have a significa...

Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium

Abstract: Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

CYP2C19-guided antiplatelet therapy: a cost–effectiveness analysis of 30-day and 1-year outcomes following percutaneous coronary intervention

Abstract: Aim Determine whether using CYP2C19 genotype to optimize antiplatelet therapy selection is cost effective over the initial 30 days and 1-year following percutaneous coronary intervention. Materials & methods A cost-effectiveness analysis compared 30-day and 1-year outcomes and cost across three treatment strategies (universal clopidogrel, universal prasugrel, genotype-guided) in a hypothetical cohort. Results Base-case scenario results at 30 days indicated that the incremental cost per major cardiovascular or bleeding event avoided for genotype-guided treatment was US$8525 and US$42,198 compared with universal clopidogrel and prasugrel, respectively. Probabilistic sensitivity analysis demonstrated that genotype-guided treatment was cost effective over 30 days and 1 year in 62 and 70% of simulations, respectively. Conclusion Implementing a CYP2C19 genotype-guided approach to antiplatelet therapy could have a positive economic impact by preventing readmissions following percutaneous coronary intervention.

HLA-associated drug hypersensitivity and the prediction of adverse drug reactions.

Abstract: Adverse drug reactions are an important cause of morbidity and mortality and constitute the leading reason of drug withdrawal from the market. Besides classical reactions that are related to pharmacologic activity of the drug, some reactions are unpredictable, not dose dependent, and seem to occur in genetically predisposed individuals. The majority of this reaction is immunologically driven and they are referred to as hypersensitivity reactions. A growing number of studies provided evidences that specific HLA alleles increase the risk of developing hypersensitivity drug reactions. In this context, drug hypersensitivities that have more robust pharmacogenetic data include abacavir hypersensitivity syndrome and severe cutaneous adverse reactions induced by allopurinol and carbamazepine.

The nuclear factor-kappa B pathway and response to treatment in breast cancer.

Abstract: The nuclear factor-kappa B (NF-κB) pathway is known to contribute to critical signaling in cancer biology, including breast cancer, through promotion of proliferation, angiogenesis, metastasis, tumor progression, inflammation and cell survival. In this review, in vivo and in vitro studies of the NF-κB pathway in breast cancer are discussed, focusing on DNA damage and the epithelial-mesenchymal transition associated with breast cancer stem cell properties. The relationships between NF-κB signaling and conventional cancer treatments in terms of response to chemo- and radiotherapy will also be discussed. Then contribution and involvement of immune system in the NF-κB pathway will be covered. Furthermore, the future perspective of NF-κB targeting as an innovative strategy to overcome refractory breast cancer, including recent updates on out-receptor activator of NF-κB (RANKing), will be covered.

Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype.

Abstract: Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2-33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96-23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90-75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83-40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.

Pharmacogenetic dosing of warfarin in the Han-Chinese population: a randomized trial.

Abstract: Aim: This study aimed to determine clinical utility of genotype-guided dosing for warfarin in Han-Chinese. Methods: A total of 320 patients were randomly assigned International Warfarin Pharmacogenetic Consortium algorithm, Taiwan algorithm and optimal clinical care arms. The primary outcome of the study was the percentage of time in the therapeutic range during the first 90 days of treatment. Results: The percentage of time in the therapeutic range of the clinical care group in the first 2 weeks was significantly higher than the algorithm groups. This difference was no longer observed after 4 weeks. No difference in excessive anticoagulation (international normalized ratio ≥4.0) and adverse events was observed. Conclusion: Genotype-guided dosing did not provide significant benefit. Loading dose with frequent international normalized ratio monitoring could provide sufficient control of anticoagulation.

Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis.

Abstract: Aim: Identifying the predictors of responsiveness and adverse events in methotrexate (MTX) treated patients with rheumatoid arthritis (RA) has been the focus of most concern, but still without consistent consensus. Methods: PubMed and OVID EMBASE were searched to collect relevant studies that addressed correlations between gene polymorphisms and efficacy and/or toxicity in MTX-treated RA patients. Allelic, recessive, dominant and over-dominant model were applied. Results: A total of 68 studies were included. For associations with efficacy, AMPD1 34C>T polymorphism was related to responsiveness in dominant model (odds ratio [OR]: 1.77; 95% CI: 1.19–2.63) and over-dominant model (OR: 1.59; 95% CI: 1.04–2.45). ATIC T675C polymorphism had association with responsiveness in recessive model (OR: 2.54; 95% CI: 1.23–5.26). For associations with toxicity, polymorphisms in TYMS 1494 del6 and FPGS rs10106 were correlated to absenting overall adverse events in recessive model (OR: 0.68; 95% CI: 0.49–0.95) and dominan...

The influences of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin, in relation to CYP3A4 inhibition.

Abstract: Aim: To investigate the combined effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin and its active metabolite simvastatin acid, in relation to CYP3A4 inhibition. Methods: We conducted a single-dose pharmacokinetic study of simvastatin in 26 healthy volunteers screened for their SLCO1B1 c.521T>C and ABCB1 c.1236C>T–2677G>T–3435C>T genotypes, with and without amlodipine pretreatment. The genetic effects and drug-interaction effect on simvastatin pharmacokinetic parameters were analyzed using a linear-mixed model. Results: The SLCO1B1 c.521T>C variant significantly increased exposure to simvastatin acid by around 40% (p < 0.05), similar to that caused by the amlodipine pretreatment. The ABCB1 gene showed no influence on exposure to simvastatin or simvastatin acid. Conclusion: Only SLCO1B1, not ABCB1 genotype, is likely to be associated with simvastatin-induced myopathy. SLCO1B1 genotyping may be particularly beneficial in simvastatin users who are co-administered CYP3A4 inhibitors.

Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis

Abstract: Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). Results/Conclusion: The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine.

Polymorphisms associated with etanercept response in moderate-to-severe plaque psoriasis

Abstract: Aim: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with etanercept. Materials & methods: We evaluated the association between 124 polymorphisms with the response to etanercept in patients with moderate-to-severe plaque psoriasis at 3 months (n = 78) and 6 months of treatment (n = 68). Results: The results of the multivariate analysis showed an association between polymorphisms rs13437088 (HLA-B/MICA), rs96844 (MAP3K1), rs2431697 (PTTG1), rs9304742 (ZNF816A) and the response to etanercept at 3 months. Besides polymorphisms rs928655 (GBP6) and rs2546890 (IL12B) were associated to response at 6 months. Conclusions. Nevertheless, these biomarkers should be validated in large-scale studies before its implementation in clinical practice.

Precision oncology: neither a silver bullet nor a dream.

Abstract: Precision oncology is not an illusion, nor is it the magic bullet that will eradicate all cancers. Precision oncology is simply another weapon in our growing armament against cancer. Rather than honing in on the failures of a relatively young field, one should advocate for integrating its successes into widespread clinical practice, especially for indications, such as: ABL, ALK, BRAF, BRCA1, BRCA2, EGFR, KIT, KRAS, PDGFRA, PDGFRB, ROS1, BCR-ABL, FLT3 and ROS1, where aberrations have been shown to alter responses to US FDA approved drugs - that is, level 1 data. Moreover, to truly assess the promise of precision oncology, we must first begin by defining our expectations for this field. Importantly, we must recognize that the conception of precision oncology arose as an antithesis of the 'one-size fits all' cancer therapeutics approach. Consequently, tools used for evaluating these conventional, large-scale trials, are not directly transferable for assessing nonconventional, smaller-scale trials needed for evaluating precision oncology. Hence, a thorough vetting of precision oncology as another tool of the trade, must first begin by reassessing our expectations for this field, as well as current clinical trial designs and end point measurements. Importantly, we must recognize that most targeted therapy approaches are in their infancy, with only monotherapy approaches being assessed and combination therapies likely being necessary to fulfill the promise of precision oncology.

Advanced cancer pain: the search for genetic factors correlated with interindividual variability in opioid requirement.

Abstract: Aim: To assess association between genetic variants and opioid requirement in cancer patients. Materials & methods: A prospective observational trial of 243 advanced cancer patients with inadequate analgesia treated by the palliative care team was analyzed for ABCB1, ARRB2, COMT, GCH1, IL1RN, KCNJ6, OPRM1, RHBDF2, SCN9A and Stat6 polymorphisms. Results: For patients carrying OPRM1 118AG/GG and COMT 472GG (Val158Val) or these genotypes alone, a significant higher median percentage dose increase was observed (95.2% [32.8-345]) compared with OPRM1 118AA and COMT 472GA/AA (158Met allele carriers; 48.5% [0-98.8]; p = 0.0016). No associations were found with morphine equivalent dose after consultation palliative care team or ketamine use. Conclusion: Patients with the combined OPRM1 118AG/GG and COMT 472GG genotype required 50% higher dose increase for sufficient analgesia.

Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population

Abstract: Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patient ...

Primary care providers' use of pharmacist support for delivery of pharmacogenetic testing.

Abstract: Aim: To investigate provider utilization of pharmacist support in the delivery of pharmacogenetic testing in a primary care setting. Methods: Two primary care clinics within Duke University Health System participated in the study between December 2012 and July 2013. One clinic was provided with an in-house pharmacist and the second clinic had an on-call pharmacist. Results: Providers in the in-house pharmacist arm consulted with the pharmacist for 13 of 15 cases, or about one of every four patients tested compared with one of every 7.5 patients in the on-call pharmacist arm. A total of 63 tests were ordered, 48 by providers in the pharmacist-in-house arm. Conclusion: These findings suggest that the availability of an in-house pharmacist increases the likelihood of pharmacogenetic test utilization.