The advantages and challenges of diversity in Pharmacogenomics: Can minority populations bring us closer to implementation?

Clin Pharmacol Ther. 2019 Apr 30;:

Authors: Zhang H, De T, Zhong Y, Perera MA

Abstract
Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explains a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome-wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly European and Asian descent participants, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, the role of genetic variation in pharmacologic pathways and highlight a number of population-specific findings. This article is protected by copyright. All rights reserved.

PMID: 31038731 [PubMed - as supplied by publisher]

Development of the PGx-Passport: A Panel of Actionable Germline Genetic Variants for Pre-emptive Pharmacogenetic Testing.

Clin Pharmacol Ther. 2019 Apr 30;:

Authors: van der Wouden CH, van Rhenen MH, Jama WOM, Ingelman-Sundberg M, Lauschke VM, Konta L, Schwab M, Swen JJ, Guchelaar HJ

Abstract
Pre-emptive pharmacogenetic (PGx) testing of a panel of germline genetic variants represents a new model for personalised medicine. Clinical impact of PGx testing is maximized when all variant alleles for which actionable clinical guidelines are available, are included in the test panel. However, no such standardized method has been presented to date, impeding adoption, exchange and continuity of PGx testing. We, therefore, developed such a panel, hereafter called the PGx-Passport, based on the actionable Dutch Pharmacogenetics Working Group (DPWG) guidelines. Germline variant alleles were systematically selected using pre-defined criteria regarding allele population frequencies, effect on protein functionality and association with drug response. A PGx-Passport of 58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1 and VKORC1) was composed. This PGx-Passport can be used in combination with the DPWG guidelines to optimize drug prescribing for 49 commonly prescribed drugs. This article is protected by copyright. All rights reserved.

PMID: 31038729 [PubMed - as supplied by publisher]

Relationship between warfarin dosage and international normalized ratio: a dose-response analysis and evaluation based on multicenter data.

Eur J Clin Pharmacol. 2019 Apr 29;:

Authors: Xue L, Zhang Y, Xie C, Zhou L, Liu L, Zhang H, Xu L, Song H, Lin M, Qiu H, Zhu J, Zhu Y, Zou J, Zhuang W, Xuan B, Chen Y, Fan Y, Wu D, Shen Z, Miao L

Abstract
PURPOSE: The objectives of the study were to establish a dose-response model for warfarin based on the relationship between daily warfarin dose and international normalized ratio (INR) and to evaluate the stability and reliability of the established model using external data.
METHODS: Clinical data were recorded from 676 outpatients with a steady-state warfarin dosage. Demographic characteristics, concomitant medications, daily dosage of warfarin, CYP2C9 and VKORC1 genotypes, and INR were recorded. Data analysis based on the Michaelis-Menten equation to describe the relationship between daily warfarin dose and INR was performed using NONMEM. The reliability and stability of the final model were evaluated using goodness-of-fit plots, resampling techniques with a nonparametric bootstrap, and external data.
RESULTS: The daily warfarin dose and INR were described by a more pharmacologically expressive model than multivariate linear regression (MLR) model. The population standard value of Km was 3.56 mg, and the Hill coefficient was 0.512, with individual variabilities of 53.1% and 55.9%, respectively. CYP2C9 *1/*3, VKORC1 AA, concomitant amiodarone, and nonheart valve replacement reduced the warfarin Km by 30.4%, 74.3%, 34.5%, and 39.4%, respectively. The Km value decreased with age and increased with fat free mass (FFM). INR prediction error (73.0%) of the external datasets was within ± 20%.
CONCLUSION: A dose-response model of warfarin was established based on the relationship between daily warfarin dose and INR. Expected genotype effects on Km and demographic characteristics were confirmed. The model has the potential to be a powerful tool for individualized warfarin therapy for Chinese outpatients.

PMID: 31037455 [PubMed - as supplied by publisher]

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39.

Ann Rheum Dis. 2019 Apr 29;:

Authors: Spiliopoulou A, Colombo M, Plant D, Nair N, Cui J, Coenen MJ, Ikari K, Yamanaka H, Saevarsdottir S, Padyukov L, Bridges SL, Kimberly RP, Okada Y, van Riel PLC, Wolbink G, van der Horst-Bruinsma IE, de Vries N, Tak PP, Ohmura K, Canhão H, Guchelaar HJ, Huizinga TW, Criswell LA, Raychaudhuri S, Weinblatt ME, Wilson AG, Mariette X, Isaacs JD, Morgan AW, Pitzalis C, Barton A, McKeigue P

Abstract
OBJECTIVES: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response.
METHODS: We studied the relation of TNFi response, quantified by change in swollen joint counts (ΔSJC) and erythrocyte sedimentation rate (ΔESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation.
RESULTS: We detected a statistically significant association between ΔSJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between ΔSJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance.
CONCLUSIONS: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

PMID: 31036624 [PubMed - as supplied by publisher]

Genetic Predispositions of Glucocorticoid Resistance and Therapeutic Outcomes in Polymyalgia Rheumatica and Giant Cell Arteritis.

J Clin Med. 2019 Apr 27;8(5):

Authors: Smutny T, Barvik I, Veleta T, Pavek P, Soukup T

Abstract
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related chronic inflammatory diseases. Glucocorticoids (GCs) are first-choice drugs for PMR and GCA, although some patients show poor responsiveness to the initial GC regimen or experience flares after GC tapering. To date, no valid biomarkers have been found to predict which patients are at most risk for developing GC resistance. In this review, we summarize PMR- and GCA-related gene polymorphisms and we associate these gene variants with GC resistance and therapeutic outcomes. A limited number of GC resistance associated-polymorphisms have been published so far, mostly related to HLA-DRB1*04 allele. Other genes such ICAM-1, TLR4 and 9, VEGF, and INFG may play a role, although discrepancies are often found among different populations. We conclude that more studies are required to identify reliable biomarkers of GC resistance. Such biomarkers could help distinguish non-responders from responders to GC treatment, with concomitant consequences for therapeutic strategy.

PMID: 31035618 [PubMed]

Melatonin Levels in Preterm and Term Infants and Their Mothers.

Int J Mol Sci. 2019 Apr 27;20(9):

Authors: Biran V, Decobert F, Bednarek N, Boizeau P, Benoist JF, Claustrat B, Barré J, Colella M, Frérot A, Garnotel R, Graesslin O, Haddad B, Launay JM, Schmitz T, Schroedt J, Virlouvet AL, Guilmin-Crépon S, Yacoubi A, Jacqz-Aigrain E, Gressens P, Alberti C, Baud O

Abstract
The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin circulating levels would be lower in preterm compared to term infants. We conducted a prospective, longitudinal, multicenter study to assess melatonin, and 6-sulfatoxy-melatonin (aMT6s) concentrations, measured by radioimmunoassay. Among 209 neonates recruited, 110 were born before 34 gestational weeks (GW) and 99 born after 34 GW. Plasma melatonin concentrations, measured at birth and on Day 3 were below detectable levels (≤7 pg/mL) in 78% and 81%, respectively, of infants born before 34 GW compared to 57% and 34%, respectively, of infants born after 34 GW. The distribution of plasma melatonin concentrations was found to be correlated with gestational age at both time-points (p < 0.001). Median urine aMT6s concentrations were significantly lower in infants born before 34 GW, both on Day 1 (230 ng/L vs. 533 ng/L, p < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, p < 0.0001). In conclusion, melatonin secretion appears very low in preterm infants, providing the rationale for testing supplemental melatonin as a neuroprotectant in clinical trials.

PMID: 31035572 [PubMed - in process]

Medical and Dietary Uses of N-Acetylcysteine.

Antioxidants (Basel). 2019 Apr 28;8(5):

Authors: Šalamon Š, Kramar B, Marolt TP, Poljšak B, Milisav I

Abstract
N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.

PMID: 31035402 [PubMed]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/04/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

HLA and immune-mediated adverse drug reactions: another hit with vancomycin.

J Allergy Clin Immunol. 2019 Apr 25;:

Authors: Pirmohamed M

PMID: 31029771 [PubMed - as supplied by publisher]

Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization-Gas Chromatography.

Drug Metab Dispos. 2019 Apr 26;:

Authors: Patrick KS, Rodriquez W

Abstract
A tenable hypothesis is presented which explains disparities between the older oral dl-MPH bioavailability data generated using chiral derivatization gas chromatography versus more recent findings using chiral liquid chromatography. These disparities continue to persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-(R,R)-MPH is 23% and that of l-(S,S)-MPH is 5% (i.e., 82% exists as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. The older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent will yield the (R,R,R)-MPH-prolyl diastereomer from d-MPH which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimating the percent l-MPH at the expense of underestimating d-MPH. Thus, unless compelling reasons exist to justify use of any chiral discriminators, then less complex and less costly achiral analyses of plasma dl-MPH fundamentally allows d-MPH quantitation since 99% exists as d-MPH. However, simultaneous monitoring of both d-MPH and l-MPH appear warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For examples: (a) using transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which especially elevates l-MPH concentrations; (d) in forensic studies of intravenous/intranasal dl-MPH abuse or (e) were dl-MPH to be formulated as a free base sublingual product for direct oral mucosal transport. SIGNIFICANCE STATEMENT: N/A.

PMID: 31028056 [PubMed - as supplied by publisher]

From the beginning to resistance: Study of plasma monitoring and resistance mechanisms in a cohort of patients treated with osimertinib for advanced T790M-positive NSCLC.

Lung Cancer. 2019 May;131:78-85

Authors: Bordi P, Del Re M, Minari R, Rofi E, Buti S, Restante G, Squadrilli A, Crucitta S, Casartelli C, Gnetti L, Azzoni C, Bottarelli L, Petrini I, Cosenza A, Ferri L, Rapacchi E, Danesi R, Tiseo M

Abstract
INTRODUCTION: Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance.
MATERIALS AND METHODS: Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed.
RESULTS: Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [< 2200 copies/mL or allele frequency (AF) < 6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation.
CONCLUSIONS: The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.

PMID: 31027702 [PubMed - in process]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/04/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Precision medicine: a call for increased pharmacogenomic education.

Per Med. 2019 Apr 26;:

Authors: Ta R, Cayabyab MA, Coloso R

Abstract
Precision medicine is an emerging model of care where providers consider patients' genetic profiles, lifestyles and environments to offer more precise therapy. The potential of precision medicine is boundless as interdisciplinary teams utilize genetic technologies to improve patient outcomes. The integration of precision medicine into healthcare faces many barriers, including a lack of standardization and reimbursement concerns. This article argues that increased pharmacogenetics education and system-wide implementation is necessary to overcome some of these challenges. Extensive expansion of pharmacogenomics education is a step toward producing knowledgeable clinicians who are poised to apply its methodology and champion for patient-centered care.

PMID: 31025601 [PubMed - as supplied by publisher]

Estimation of CYP3A4*1B single nucleotide polymorphism in patients with recurrent Major Depressive Disorder.

Mol Genet Genomic Med. 2019 Apr 25;:e669

Authors: Świechowski R, Jeleń A, Mirowski M, Talarowska M, Gałecki P, Pietrzak J, Wodziński D, Balcerczak E

Abstract
BACKGROUND: Major depression is the most common mental illness in the world. Failures in treatment may occur due to the presence of a subtype of depression called TRD (Treatment- Resistant Depression). CYP3A4 polymorphism (rs2740574) can increase the activity of Cytochrome P450 3A4, contributing to faster metabolism of xenobiotics and reduced response to treatment. The aim of the study was to assess the distribution of CYP3A4*1B in study and control group and to estimate the influence of particular genotypes on parameters such as: age at onset, severity of symptoms before treatment and on the effectiveness of therapy.
METHODS: Total of 192 patients were enrolled in this study (102 patients suffering from recurrent Major Depression Disorder, 90 healthy blood donors). PCR Restriction Fragment Length Polymorphism method with MboII enzyme was performed. The presence of CYP3A4*1B allele was evaluated on the basis of agarose gel electrophoresis.
RESULTS: There was a tendency in frequency of genotypes distribution in the study group in comparison with the control group (p = 0.050). There were no statistically significant differences in the distribution mutant allele among these two groups, but there was a tendency for mutant allele to occur more often in the study group (p = 0.050). No significant correlations were found between the specific genotype and the studied parameters: age at onset (p = 0.232), severity of the symptoms (p = 0.946), and efficacy of treatment (p = 0.882).
CONCLUSION: The study suggests that CYP3A4*1B polymorphism have no influence on the predisposition to depression, the severity of depressive symptoms and the efficiency of antidepressant therapy.

PMID: 31025537 [PubMed - as supplied by publisher]

Comparative pharmacokinetic study on three formulations of Astragali Radix by a LC-MS/MS method for determination of formononetin in human plasma.

Biomed Chromatogr. 2019 Apr 26;:e4563

Authors: Rao T, Gong YF, Peng JB, Wang YC, He K, Zhou HH, Zhi-Rong T, Lv LZ

Abstract
Astragali Radix (AR) is a widely used traditional Chinese medicine for healing the cardiovascular, liver and immune systems. Recently, superfine pulverizing technology has been applied to developing novel formulations to improve bioavailability of the active constituents in herbs, such as ultrafine granular powder of AR. In this study, a universal and sensitive quantitative method based on LC-MS/MS was employed for determining formononetin, a main flavonoid in AR, in human plasma for comparative pharmacokinetics of three oral formulations of AR. Formononetin and IS (quercetin) were extracted by ethyl acetate from human plasma and were separated on a C18 column with a mobile phase consisting of acetonitrile and 0.1% formic acid. Positive-ion electrospray- ionization mode was applied in mass spectrometric detection. The quantitative method was validated with regards to selectivity, linearity, accuracy and precision, matrix effect, extraction recovery and stability, and was applied to comparing the pharmacokinetics of ultrafine granular powder (UGP), ultrafine powder (UP) and traditional decoction pieces (TDP) of AR after oral administration. The Cmax , AUC0-48 and AUC0-∞ of formononetin in UGP and UP were significantly higher than those of TDP. UGP and UP could significantly improve the bioavailability of AR in human compared with TDP after oral administration.

PMID: 31025385 [PubMed - as supplied by publisher]

Significant association of DRD2 enhancer variant rs12364283 with heroin addiction in a Pakistani population.

Ann Hum Genet. 2019 Apr 26;:

Authors: Jabeen S, Pinsonneault JK, Sadee W, Lee SH, Zafar MM, Raja MS, Raja GK

Abstract
The dopamine D2 receptor encoded by DRD2 has been implicated in multiple psychiatric disorders, mediated at least in part by two intronic variants affecting mRNA splicing, rs1076560 and rs2283265, and a less frequent enhancer variant, rs12364283, which increases DRD2 mRNA expression. This study tests whether these functionally validated variants confer susceptibility toward heroin addiction in a Pakistani population. A total of 540 heroin addicts and 467 healthy controls were genotyped, basic allele and genotype tests were performed. Neither rs1076560 nor rs2283265 significantly associated with heroin addiction. The enhancer rs12364283 occurs more frequently in heroin-dependent cases than controls (MAF 13% vs. 7%, respectively), revealing significant association with heroin addiction (p = 3.0E-06, OR 2.1). This study identifies rs12364283 of DRD2 as a potential risk factor for heroin addiction in the Pakistani study population. This enhancer variant had been shown to increase DRD2 mRNA expression, a possible factor in increased vulnerability to heroin addiction. Further studies are needed to validate this association of rs12364283.

PMID: 31025317 [PubMed - as supplied by publisher]

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.

Cell Res. 2019 Apr 25;:

Authors: Mugoni V, Panella R, Cheloni G, Chen M, Pozdnyakova O, Stroopinsky D, Guarnerio J, Monteleone E, Lee JD, Mendez L, Menon AV, Aster JC, Lane AA, Stone RM, Galinsky I, Zamora JC, Lo-Coco F, Bhasin MK, Avigan D, Longo L, Clohessy JG, Pandolfi PP

Abstract
Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.

PMID: 31024166 [PubMed - as supplied by publisher]

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

Oncologist. 2019 Apr 25;:

Authors: Ciruelos E, Apellániz-Ruiz M, Cantos B, Martinez-Jáñez N, Bueno-Muiño C, Echarri MJ, Enrech S, Guerra JA, Manso L, Pascual T, Dominguez C, Gonzalo JF, Sanz JL, Rodriguez-Antona C, Sepúlveda JM

Abstract
BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity.
MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated.
RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy.
CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

PMID: 31023863 [PubMed - as supplied by publisher]

Journal of Translational Medicine advances in Translational Genomics and Genetics Era.

J Transl Med. 2019 Apr 25;17(1):134

Authors: Liu W

Abstract
We are delighted to announce the launch of a new section in the Journal of Translational Medicine, 'Translational Genomics and Genetics'. Central to translational medicine trend is the ability to sequence, annotate and interpret the genomic variants in a given patient to guide precision diagnosis and personalized treatment. This new section intends to promote the translation of emerging genomic technologies into clinical applications. The coverage extends to basic, translational and clinical studies related to human genomics and genetics. The manuscripts in following categories are welcome, but not limited to: Application of next generation sequencing in clinical diagnosis, including but not limited to rare genetic disease, complex inherited disease, prenatal/perinatal screening, oncology, organ transplantation and pathogen identification; Novel bioinformatics approaches in human genomics; Single cell sequencing, liquid biopsy and other emerging genomic assays in molecular genetics, pharmacogenomics, oncology and immuno-oncology; Integration of genomics with other "omics" technology in genetic medicine.

PMID: 31023327 [PubMed - in process]

Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy.

Nat Genet. 2018 10;50(10):1399-1411

Authors: Lee JK, Liu Z, Sa JK, Shin S, Wang J, Bordyuh M, Cho HJ, Elliott O, Chu T, Choi SW, Rosenbloom DIS, Lee IH, Shin YJ, Kang HJ, Kim D, Kim SY, Sim MH, Kim J, Lee T, Seo YJ, Shin H, Lee M, Kim SH, Kwon YJ, Oh JW, Song M, Kim M, Kong DS, Choi JW, Seol HJ, Lee JI, Kim ST, Park JO, Kim KM, Song SY, Lee JW, Kim HC, Lee JE, Choi MG, Seo SW, Shim YM, Zo JI, Jeong BC, Yoon Y, Ryu GH, Kim NKD, Bae JS, Park WY, Lee J, Verhaak RGW, Iavarone A, Lee J, Rabadan R, Nam DH

Abstract
Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.

PMID: 30262818 [PubMed - indexed for MEDLINE]