Pharmacogenetic Results Research Articles

Open-label pilot study of psychiatric pharmacogenetic testing in an adult psychiatric inpatient population

IntroductionTreatment outcomes for depression and anxiety disorders remain suboptimal. Pharmacogenetic-guided medication treatment may be one way to improve outcomes. However, feasibility of pharmacogenetic testing in inpatient psychiatric settings has not been explored. This pilot study investigated the feasibility of collection and potential efficacy of pharmacogenetic testing three months after psychiatric hospitalization for severe depression and anxiety-related symptoms. MethodsParticipants (n = 75) in this open-labeled study were inpatients on a short-term acute care unit for severe depression and anxiety. Participants were assigned to control and experimental conditions. The experimental group completed a psychiatric pharmacogenetic assay while inpatient. Results were returned prior to discharge, allowing prescribers to adjust medication regimens as clinically indicated. The control group received pharmacogenetic results three months later. At admission and three months later, participants completed self-report measures to address psychiatric symptoms, quality of life, and satisfaction with the pharmacogenetic assay. ResultsReductions on primary outcome measures were not significantly different between study groups. The experimental group did not report significantly greater reductions than the control group on primary study outcomes of anxiety, depression, frequency of medication changes following discharge or on some secondary study measures. Participants in the experimental group did report significantly greater reductions than controls on quality of life impairment (X2 = 8.51, p=.004) after corrections for multiple comparisons. ConclusionsThis open-label pilot study provides preliminary support for the feasibility of psychiatric pharmacogenetic testing in an inpatient setting. Future studies should investigate psychiatric pharmacogenetic testing efficacy in larger inpatient samples and account for medication changes resulting directly from test results.

Current state assessment survey of challenges of pharmacogenomics within oncology pharmacy practice.

The goal of this survey was to identify opportunities for health systems to increase implementation and adoption of oncology-focused pharmacogenomics services. An online survey assessing respondent demographics, baseline knowledge and training in pharmacogenomics, comfort level with pharmacogenomic data, and challenges of implementing clinical pharmacogenomic platforms was distributed to professional colleagues and over national oncology pharmacy listservs. Pharmacists were grouped based on their comfort level with pharmacogenomic data. Results were analyzed utilizing Pearson chi-square test. A p value of <0.05 was considered significant. A total of 84 participants from 58 cancer centers participated in the survey. Most participants were post-graduate year 2 trained and a majority reported being comfortable assessing oncology pharmacogenomic data. Respondents indicated that pharmacogenomics reported within the electronic medical record was the most common institutional process to support pharmacogenomics for oncology patients. Despite this, poor visibility of pharmacogenomics within the electronic medical record was the most challenging aspect of implementing a pharmacogenomic program. Additional challenges included lack of resources for pharmacogenomic programs, insurance denials for pharmacogenomic-driven testing and medication, and prolonged turnaround time of pharmacogenetic results. Length of practice, post-graduate year 2 residency training, institutions with pharmacist involvement on hematology/oncology molecular tumor board, and institutions where a pharmacist helped create local pharmacogenomic policies were significantly associated with respondents' comfortability in assessing pharmacogenomics. Oncology pharmacists reported substantial challenges in implementing a pharmacogenomic program. Future efforts to assist in developing pharmacogenomic efforts should focus on increasing pharmacist involvement, expanding education and training, and improving clinical decision support tools.

Description of an Innovative Pediatric Individualized Therapeutics Clinic: Working toward Precision Drug Therapy.

The GOLDILOKs® (Genomic and Ontogeny-Linked Dose Individualization and cLinical Optimization for KidS) Clinic aims to provide families and physicians with data to make more informed decisions with regard to pharmacological therapy by using innovative therapy and genomic technologies. The objectives are two-fold: (1) To describe the utility of the GOLDILOKs® Clinic to referring prescribers by evaluating the type of referrals made to the GOLDILOKs® Clinic and (2) to assess the most often utilized technologies (e.g., genotyping) completed to formulate therapy recommendations. Patient data from July 2010 to June 2016 was retrospectively reviewed following Institutional Review Board (IRB) approval. The GOLDILOKs® Clinic evaluated 306 patients and had increases in annual referrals from 14 in 2010–2011 to 84 in 2016–2017. The children that were referred were predominately Caucasian (82%) and male (59%) with an average age of 12.4 ± 5.9 years. Subspecialty versus primary care referrals accounted for 82% and 18% of referrals, respectively. Adverse drug reactions (n = 166) and poor medication response (n = 179) were the major reasons for referral. However, it must be noted that patients could have multiple reasons for referral. Pharmacogenetic results were extensively used to provide guidance for future therapy in patients with medication-related problems. Genotyping of drug metabolizing enzymes and drug target receptors was performed in 221 patients (72.2%). Recommendations were fully accepted by 63% and partially accepted by 22% of internal provider referrals.

Abstract P1-14-05: Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Abstract Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD ≥ 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (&amp;gt; 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A &amp;gt;G and FGD4 2044236G&amp;gt;A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A&amp;gt;C, RRM1 2455 A&amp;gt;G, and CYP2C8 416G&amp;gt;A SNPs were associated with poorer overall survival by Cox proportional hazards model. Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity. Citation Format: Musolino A, Cavanna L, Boggiani D, Zamagni C, Frassoldati A, Caldara A, Rocca A, Gori S, Piacentini F, Berardi R, Brandes AA, Foglietta J, Villa F, Pellegrino B, Todeschini R, Tognetto M, Naldi N, Bortesi B, Boni L, Montemurro F, Ardizzoni A. Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-05.

The use of pharmacogenetic testing in patients with schizophrenia or bipolar disorder: A systematic review.

Introduction:Pharmacogenetic testing may assist in identifying an individual's risk of developing a mental illness as well as predict an individual's response to treatment. The objective of this study is to report published outcomes of pharmacogenetic testing in patients with schizophrenia or bipolar disorder.Methods:A systematic review using PubMed and EBSCOhost through April 2017 was performed to identify articles that reported pharmacogenetic testing in adult patients with either bipolar disorder or schizophrenia using the keywords pharmacy, pharmacogenomics, pharmacogenetics, psychiatry, bipolar disorder, schizophrenia, mood stabilizer, and antipsychotic.Results:A total of 18 articles were included in the final literature review. A wide variety of genes amongst adult patients with varying ethnicities were found to be correlated with the development of schizophrenia or bipolar disorder as well as response to antipsychotics and mood stabilizers.Discussion:While current studies show a correlation between genetic variations and medication response or disease predisposition for patients with schizophrenia and bipolar disorder, research is unclear on the type of therapeutic recommendations that should occur based on the results of the pharmacogenetic testing. Hopefully interpreting pharmacogenetic results will one day assist with optimizing medication recommendations for individuals with schizophrenia and bipolar disorder.

Lack of response to quinidine in KCNT1-related neonatal epilepsy.

To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings. Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine. Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.

Primary Care Clinicians Attitudes and Knowledge of Pharmacogenetics in a Large, Multi-state, Healthcare System.

Considerable progress has been made in the way of pharmacogenetic research and the development of clinical recommendations; however, its implementation into clinical practice has been slower than anticipated. We sought to better understand its lack of clinical uptake within primary care. The primary objective of this survey was to ascertain primary care clinicians' perceptions of pharmacogenetic use and implementation in an integrated health system of metropolitan and rural settings across several states. Primary care clinicians (including MDs, DOs, NPs, and PAs) were invited to participate in a survey via email. Questions about pharmacogenetics knowledge and perceptions were presented to assess current understanding and usage of pharmacogenetics in practice. The rate of response for the survey was 17%. Of the 90 respondents, 58% were female, 69% were MDs/DOs, 20% were NPs, and 11% were PAs. Fifty-eight percent of respondents received their clinical degree in or after 2000. Ninety percent of respondents noted that they were uncomfortable ordering a pharmacogenetics test, with 76% stating they were uncomfortable applying the results of a pharmacogenetic test. Notably, 78% of respondents were interested in having pharmacogenetic testing available through Medication Therapy Management (MTM) services, although PAs were significantly less interested as compared to NPs and MD/DOs. Ninety-five percent of respondents were interested in a clinical decision support tool relevant to pharmacogenetic results. As a whole, prescribing clinicians in primary care clinics are uncomfortable in the ordering, interpreting, and applying pharmacogenetic results to individual patients. However, favorable attitudes towards providing pharmacogenetic testing through existing MTM clinics provides the opportunity for pharmacists to advance existing practices.

Systematic evaluation of commercial pharmacogenetic testing in psychiatry: a focus on CYP2D6 and CYP2C19 allele coverage and results reporting.

The aim of this study was to systematically assess commercial pharmacogenetic tests relevant to prescribing in psychiatry, with specific attention on CYP2D6 and CYP2C19 star allele coverage as well as compliance with consensus recommendations for pharmacogenetic test result reporting. The CYP2D6 and CY2C19 star (*) allele contents of 20 pharmacogenetic test panels were compared and their test results reports were evaluated on the basis of consensus reporting recommendations published by The Centers for Disease Control and Prevention as well as the Clinical Pharmacogenetics Implementation Consortium. Most test panels included the major CYP2D6 (*2, *4, *5, *10, *17) and CYP2C19 (*2, *3, *17) alleles, but no two test panels contained the same combination of CYP2D6 and CYP2C19 alleles. Of the 20 pharmacogenetic reports that we evaluated, none fulfilled all the recommendations and no recommendation was fulfilled by all tests. Consensus has yet to be reached on which CYP2D6 and CYP2C19 star alleles to include on pharmacogenetic testing panels and pharmacogenetic results reporting could be considerably improved. Collaboration between test manufacturers and end-users is required to narrow the gap between the availability and integration of these pharmacogenetic-based decision-support tools into routine practice.

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

Background and purposeThe 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 settingThird-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. FindingsResponse 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 summaryThe simulation gave students an opportunity to apply pharmacogenetics knowledge and allowed them to gain an appreciation of pharmacists’ roles within the pharmacogenetics field.

Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility

The objective of this study was to evaluate the effect of pharmacogenetics-guided treatment on patients diagnosed with depression and/or anxiety, in a diverse set of clinical settings, as compared to the standard of care. The trial design followed a prospective, randomized, subject- and rater-blinded approach enrolling 685 patients from clinical providers specializing in Psychiatry, Internal Medicine, Obstetrics & Gynecology, and Family Medicine. The NeuroIDgenetix® test uses a genetic variant panel of ten genes, along with concomitant medications, to make medication management recommendations based on gene-drug and drug-drug interactions for over 40 medications used in the treatment of depression and anxiety. Pharmacogenetic testing was performed at the initial screening visit and baseline patient assessments were determined using the 17-item Hamilton Rating Scale for Depression (HAM-D17) and the Hamilton Rating Scale for Anxiety (HAM-A). Following enrollment and randomization, pharmacogenetic results for subjects assigned to the experimental group were provided to physicians to guide treatment selection, while control subjects were treated according to the usual standard of care. HAM-D17 and HAM-A assessments were collected at 4 weeks, 8 weeks, and 12 weeks after baseline to assess the efficacy of therapeutic selection. In patients diagnosed with depression, response rates (p = 0.001; OR: 4.72 [1.93–11.52]) and remission rates (p = 0.02; OR: 3.54 [1.27–9.88]) were significantly higher in the pharmacogenetics-guided group as compared to the control group at 12 weeks. In addition, patients in the experimental group diagnosed with anxiety showed a meaningful improvement in HAM-A scores at both 8 and 12 weeks (p = 0.02 and 0.02, respectively), along with higher response rates (p = 0.04; OR: 1.76 [1.03–2.99]). From these results, we conclude that pharmacogenetic-guided medication selection significantly improves outcomes of patients diagnosed with depression or anxiety, in a variety of healthcare settings.

Move Over Person-Centered Care, Make Way for Precision Medicine

Move Over Person-Centered Care, Make Way for Precision Medicine

Ethical perspectives on translational pharmacogenetic research involving children.

Children represent a special population characterized by dynamic changes which may affect drug safety and efficacy. The interplay of pharmacogenetics with physiological alterations that occur throughout development is an area of increasing research focus. Given the translational nature of pharmacogenetic research, it is possible that pharmacogenetic research results may possess clinically actionable information. The potential long-term implications of pharmacogenetic test results throughout the lifespan of the child, and the potential impact of the results for other members of the family need to be considered. Comprehensive counselling and communication strategies may need to be integrated as part of pharmacogenetic research studies in children.

519P - Folfoxiri + Bevacizumab (Bev) in Patients (Pts) with Previously Untreated Metastatic Colorectal Cancer (Mcrc): Final Survival and Pharmacogenomic Profiling Results from the Opal Study

ABSTRACT Aim: The addition of BEV to standard doublet chemotherapy (CT) improves outcomes vs CT alone in pts with mCRC. Use of more intensive triplet CT may prolong overall survival (OS), progression-free survival (PFS), increase response rates and improve resectability rates but at the expense of greater toxicity. The OPAL study examined the effect of BEV + FOLFOXIRI on PFS in pts with previously untreated unresectable mCRC. Here we report final survival and pharmacogenetic results. Methods: Eligible pts had histologically confirmed mCRC, ECOG PS ≤1 and were 18–70 years old. Pts received ≤12 cycles of FOLFOXIRI (infusional 5-fluorouracil [FU] 3200 mg/m2, folinic acid [FA] 200 mg/m2, oxaliplatin 85 mg/m2 and irinotecan 165 mg/m2) + BEV 5 mg/kg q2w (induction phase) followed by ≤40 cycles of 5-FU/FA + BEV q2w (maintenance phase). PFS was the primary endpoint; secondary endpoints included OS, proportion of pts achieving resectability, safety, and prognostic value of pharmacogenetic profiling (single nucleotide polymorphisms (SNP) for VEGF-A, VEGFR 1-3, PDGFR beta, HIF 1 alpha, Neuropilin). Results: 96 pts were enrolled. Of these, 90 received study medication and formed the safety population: 64 male, 26 female; median age 58 (range 28–71) years; ECOG performance status 0/1 in 49/41 pts; liver only disease in 35 pts. During induction phase a median number of 9.5 cycles FOLFOXIRI and BEV was administered. Relative dose intensities were 81-86% for all 4 drugs. The incidence of adverse events (AEs) was as previously reported and there were no new safety signals. during induction phase. In total, 61 serious AEs occurred in 34 pts (38%). AEs resulting in death occurred in 3 pts (3%); these were not considered treatment-related by the investigators. Median PFS was 11.1 months (m) (95% CI 9.4-12.0) and OS was 32.2m (95% CI 22.6-36.9). 52 pts were pharmacogenetically profiled and VEGFR 2 SNP 305 was associated with OS (CC–12.4m, CT–18.7m, and TT–30.1m; p = 0.038). Conclusions: FOLFOXIRI + BEV was feasible in this mCRC pt population. Survival was relevantly increased compared to standard three drug combinations in a molecularly unstratified pt population. VEGFR 2 SNPs might be prognostic for treatment with FOLFOXIRI + BEV. Disclosure: A. Stein: Roche: membership on an advisory board, corporate-sponsored research. C. Bokemeyer: Roche: corporate-sponsored research. All other authors have declared no conflicts of interest.

No Significant Association between the Alpha-2A-Adrenergic Receptor Gene and Treatment Response in Combined or Inattentive Subtypes of Attention-Deficit Hyperactivity Disorder

Given the shortage of pharmacogenetic studies on treatment response according to subtype of attention-deficit hyperactivity disorder (ADHD), we investigated the associations between the MspI and DraI polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD. We enrolled 115 medication-naïve children with ADHD into an open label 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical -Global Impression (CGI), ADHD rating scale, and Continuous Performance Test (CPT) pre- and post-treatment. There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGI-improvement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045). The results of this study do not support the association between the the MspI or DraI genotypes and treatment response to methylphenidate in ADHD. However, our results -suggest that subtypes might influence pharmacogenetic results in ADHD.·available online at http://www.thieme-connect.de/ejournals/toc/pharmaco.

A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric cancer: Clinical and pharmacogenetic results.

4114 Background: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 + docetaxel (DS) in locally advanced gastric cancer (LAGC), and to investigate the association between CYP2A6 genotypes and treatment outcomes. Methods: Eligibility criteria included 18-70 yrs, PS 0-1, measurable lesion(s), and LAGC (clinical stage III-IV (M0) by Japanese staging system). Pts were given each 3 cycles of pre- and post-operative chemotherapy (S-1 40 mg/m2 bid on D1-14, docetaxel 35 mg/m2iv on D1, 8 q 3 wks), and underwent surgery (≥D2). Results: From Oct 2006 to June 2008, 44 pts entered into the study, and 43 pts were eligible. Median age=53 yrs (range, 33-69); PS 0/1=2/41; M/F=29/14; and stage IIIA/IIIB/IV (M0)=20/18/5. All 43 eligible pts completed preoperative DS and 40 pts (93%) completed postoperative DS. The most common G3/4 toxicities during pre- and post-operative DS were neutropenia (28% vs. 65%), stomatitis (19% vs. 5%), and abdominal pain (5% vs. 18%). The clinical response rate was 74.4% (95% CI, 61.4-87.4%) with 1 CR (2.3%) and 31 (72.1%) PRs. R0 resection rate was 97.7%, major pathologic response rate was 48.8% with 1 CR, and pathologic stage was 0/1/2/3/4 (%) = 2.3/44.2/20.9/20.9/11.6. With a median follow-up of 66.6 months, 3-yr PFS and 5-yr OS was 62.8% and 69.6%, respectively. Survival differed according to clinical response, clinical downstaging, and CYP2A6 genotypes (Table). Pts with two CYP2A6 variant alleles (V/V) had higher Cmax (27.7±4.6 vs. 20.3±1.2; p=0.045) and AUCinf (220.4±43.1 vs. 172.5±12.5; p=0.187) of tegafur, and lower Cmax (1.4±0.2 vs. 1.8±0.1; p=0.178) and AUCinf (8.4±1.2 vs. 9.7±0.5; p=0.308) of 5-FU than those with no or one variant allele (W/W or W/V). Conclusions: DS is active with a manageable toxicity profile in the perioperative setting in pts with LAGC. CYP2A6 genotype may be predictive of efficacy (S-1 and docetaxel was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively). Clinical trial information: NCT00587145. [Table: see text]

Abstract LB-172: A randomized phase II study of S-1 versus capecitabine as first-line chemotherapy in the elderly metastatic gastric cancer patients with/without poor performance status: clinical and pharmacogenetic results.

Abstract Introduction: This study investigated the efficacy and safety of S-1 vs. capecitabine in elderly patients (pts) with metastatic gastric cancer (MGC) with/without poor performance status (PS), and examined the association between CYP2A6 polymorphisms and treatment outcomes. Methods: Eligibility criteria included MGC, measurable lesion(s), no prior chemotherapy for MGC, and age of 70-85 yrs with ECOG PS 0-2 or age ≥ 65 and &amp;lt; 70 yrs with PS 2. Pts were randomized to receive S-1 40 mg/m2 bid or capecitabine 1250 mg/m2 bid on days 1-14 every 3 weeks. The primary endpoint was overall response rate (ORR) with time to progression (TTP), overall survival (OS), quality of life (QOL), safety, and the association between CYP2A6 genotypes (*1, *4, *7, *9, *10) and treatment outcomes as secondary endpoints. Results: From May 2007 to July 2010, 107 pts were randomized to receive either S-1 (n=53) or capecitabine (n=54). Baseline characteristics were well balanced between the two arms (S-1:capecitabine): median age, 72 yrs (range, 64-81):71 yrs (65-78); male, 74%:81%; and PS 0/1, 85%:83%. The median number of cycles was 4 (range, 1-26) in S-1 arm and 5 (1-32) in capecitabine arm. The incidence of G3/4 neutropenia was 3.8% in each arm, and the most common G3/4 non-hematological toxicities included anorexia (21.2% with S-1 vs. 7.5% with capecitabine), fatigue (13.5% vs. 15.1%), and nausea (7.7% vs. 1.9%). S-1 arm had higher incidences of vomiting (40.4% vs. 17.0%; P=0.010) and tearing (51.9% vs. 28.3%; P=0.017), and lower incidence of HFS (25.0% vs. 58.5%; P=0.001) than capecitabine arm. Of the 49 pts assessable for response in each arm, the ORR was 28.6% (95% CI, 15.9-41.3%) in S-1 arm and 26.5% (95% CI, 14.1-38.9%) in capecitabine arm. The median TTP was 3.2 months (95% CI, 1.6-4.8 months) in S-1 arm and 3.4 months (95% CI, 2.5-4.3 months) in capecitabine arm (P=0.825), and median OS was 8.5 months (95% CI, 6.1-10.9 months) and 10.3 months (95% CI, 7.1-13.5 months), respectively (P=0.691). CYP2A6 polymorphisms were associated with the efficacy of S-1. Pts having two variant alleles (V/V) had inferior efficacy to those having no or one variant allele (W/W or W/V): median TTP 2.3 vs. 4.1 months (P=0.062), and median OS 6.4 vs. 11.5 months (P=0.034). However, the efficacy of capecitabine did not differ according to CYP2A6 genotypes: median TTP was 3.6 months in V/V pts vs. 3.3 in W/W or W/V (P=0.257), and median OS was 11.6 vs. 10.2 months (P=0.756), respectively. In pts with V/V genotype, capecitabine arm had better TTP (median, 3.6 vs. 2.3 months; P=0.062) and OS (median, 11.6 vs. 6.5 months; P=0.090) than S-1 arm. Conclusions: Both S-1 and capecitabine were active and tolerable for elderly MGC pts with/without poor PS with different toxicity profiles. Genotyping for CYP2A6 might provide useful information for treatment selection. Citation Format: Sook Ryun Park, Sun-Young Kong, Mi-Jung Kim, Min Kyeong Kim, Byung-Ho Nam, Mihee Choi, Young-Iee Park. A randomized phase II study of S-1 versus capecitabine as first-line chemotherapy in the elderly metastatic gastric cancer patients with/without poor performance status: clinical and pharmacogenetic results. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-172. doi:10.1158/1538-7445.AM2013-LB-172

Strengths and Weaknesses of Pharmacogenetic Studies of Antipsychotic Drugs: The Potential Value of the PEPs Study

The successful application of pharmacogenetics in routine clinical practice is still a long way from becoming a reality. In order to favor the transfer of pharmacogenetic results to clinical practice, especially in psychiatry, these studies must be optimized. This article reviews the strengths and weaknesses that characterize pharmacogenetic studies in psychiatry and condition their implementation in clinical practice. We also include recommendations for improving the design of pharmacogenetic studies, which may convert their limitations into strengths and facilitate the implementation of their results into clinical practice. Finally, we discuss the potential value of naturalistic, prospective, multicenter and coordinated projects such as the 'Phenotype-genotype and environmental interaction. Application of a predictive model in first psychotic episodes' (known as the PEPs study, from the Spanish abbreviation) in pharmacogenetic studies.

Current State and Future Prospects of Direct-to-Consumer Pharmacogenetics

Direct-to-consumer (DTC) DNA testing has grown from contentious beginnings into a global industry, by providing a wide range of personal genomic information directly to its clients. These companies, typified by the well-established 23andMe, generally carry out a gene-chip analysis of single-nucleotide polymorphisms (SNPs) using DNA extracted from a saliva sample. These genetic data are then assimilated and provided direct to the client, with varying degrees of interpretation. Although much debate has focused on the limitations and ethical aspects of providing genotypes for disease risk alleles, the provision of pharmacogenetic results by DTC companies is less studied. We set out to evaluate current DTC pharmacogenetics offerings, and then to consider how these services might best evolve and adapt in order to play a potentially useful future role in delivery of personalized medicine.

Relevance of germ-line genetic variations for treatment response in pediatric osteosarcoma patients.

9518 Background: Osteosarcoma comprises 5% of all pediatric malignancies and only 50% of the patients will survive. A poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can help to understand the mechanism of drug response in these patients and offers the possibility to optimise treatment and improve outcome. Therefore, we applied a pathway-based approach to evaluate the cumulative effect of genes involved in the transport and metabolism of cisplatin and doxorubicin in relationship to clinical outcome of patients with osteosarcoma. Methods: We used a two stage approach to comprehensively evaluate the role of polymorphisms in genes involved in the cisplatinum and doxorubicin pathway. For the first stage we included 107 patients with osteosarcoma, 31 with good histologic respons (huvos III/IV) following neoadjuvant treatment and 76 patients with bad histologic respons (huvos I/II). A total of 54 candidate genes were selected by a pathway-driven approach based on literature, using databases from NCBI (PubMed, Gene, and SNP) and the Pharmacogenomics Knowledge Base. In order to comprehensively assess common genetic variation in the genes selected, a linkage disequilibrium (LD) based tag-SNP strategy was employed. A final set of 384 SNPs were typed using Illumina Beadarray platform. Results: Of the 384 SNPs genotyped, 353 SNPs passed our initial quality control criteria, and of these, two were excluded by PLINK default thresholds. Another 20 SNPs of the remaining 351 SNPs failed to meet Hardy-Weinberg equilibrium (HWE) criteria (PHWE<0.05). Of the remaining 331 SNPs analyzed in the discovery stage, a total of 24 SNPs with PTrend<0.05 in the cisplatina doxorubicine pathway were associated with histological response. In addition, a clear associations betweenthe development of acute cardiotoxicity and the presence of SNPs in the doxorubicine pathway were observed. Conclusions: This pharmacogenetic results might be useful to stratify treatment of patients immediately after diagnosis and offer the possibility to improve treatment and disease free survival of pediatric patients with osteosarcoma.

Phase II study of a triplet regimen of S-1 combined with irinotecan and oxaliplatin in patients with metastatic gastric cancer: clinical and pharmacogenetic results

BackgroundThe aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. Patients and methodsPatients with previously untreated MGC received S-1 40 mg/m2 b.i.d. on days 1–14 and irinotecan 150 mg/m2 plus oxaliplatin 85 mg/m2 on day 1 every 3 weeks. ResultsForty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). ConclusionsThe TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.