J Clin Pharmacol. 2024 May 20. doi: 10.1002/jcph.2461. Online ahead of print.

ABSTRACT

Tacrolimus metabolism is heavily influenced by the CYP3A5 genotype, which varies widely among African Americans (AA). We aimed to assess the performance of a published genotype-informed tacrolimus dosing model in an independent set of adult AA kidney transplant (KTx) recipients. CYP3A5 genotypes were obtained for all AA KTx recipients (n = 232) from 2010 to 2019 who met inclusion criteria at a single transplant center in Philadelphia, Pennsylvania, USA. Medical record data were used to calculate predicted tacrolimus clearance using the published AA KTx dosing equation and two modified iterations. Observed and model-predicted trough levels were compared at 3 days, 3 months, and 6 months post-transplant. The mean prediction error at day 3 post-transplant was 3.05 ng/mL, indicating that the model tended to overpredict the tacrolimus trough. This bias improved over time to 1.36 and 0.78 ng/mL at 3 and 6 months post-transplant, respectively. Mean absolute prediction error-a marker of model precision-improved with time to 2.33 ng/mL at 6 months. Limiting genotype data in the model decreased bias and improved precision. The bias and precision of the published model improved over time and were comparable to studies in previous cohorts. The overprediction observed by the published model may represent overfitting to the initial cohort, possibly limiting generalizability.

PMID:38766706 | DOI:10.1002/jcph.2461

medRxiv [Preprint]. 2024 May 9:2024.05.06.24306379. doi: 10.1101/2024.05.06.24306379.

ABSTRACT

BACKGROUND: Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden.

METHODS: We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on systematic assessment of the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary finding genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals.

RESULTS: The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance from samples in the 1000 Genomes Project revealed ~6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 0.9% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min.

CONCLUSIONS: A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives.

PMID:38766118 | PMC:PMC11100944 | DOI:10.1101/2024.05.06.24306379

Psychiatry Clin Psychopharmacol. 2021 Jun 1;31(2):148-156. doi: 10.5152/pcp.2021.20176. eCollection 2021 Jun.

ABSTRACT

BACKGROUND: Schizophrenia is a serious mental illness affecting 0.3-0.7% of the world's population. It is a classic quantitative genetic disease and is affected by a variety of common and rare genetic variants.

METHODS: To facilitate personalized and precise medicine for schizophrenia treatment, we designed a program by genotyping a panel of related genes for schizophrenic patients using MassARRAY time-of-flight mass spectrometry. The program was tested in an observational clinical study conducted at the Hulunbuir Mental Health Center of China. In the study, a total of 254 patients diagnosed with schizophrenia were recruited and genotyped. The genotyping results were used to generate reports listing where the 16 included antipsychotics should be placed: "Use as directed," "Use with caution," or "Use with caution and with frequent blood concentration monitoring" categories. Seventy-two of the patients completed the 24-week follow-up observation, during which their PANSS scores were assessed at eight time points.

RESULTS: For all of the subjects who completed the study, the PANSS scores dropped significantly, showing the effectiveness of the treatment. During the 24-week study, PANSS scores of patients whose medications were consistent (N = 48) with their genetic test results dropped from 84.3 (SD = 12.4) to 58.8 (SD = 15.3), and average PANSS change rate reached 56.1% after 24 weeks. In contrast, PANSS scores of patients with genetic tests reported as "Use with caution" or "Use with caution and with frequent blood concentration monitoring" (N = 24) dropped from 81.1 (SD = 10.5) to 63.8 (SD = 10.1), and their average PANSS change rate was 37.6%.

CONCLUSIONS: This research indicates that our pharmacogenomic-based program could be a suitable and effective tool to facilitate precise medication in schizophrenia treatment.

PMID:38765225 | PMC:PMC11079651 | DOI:10.5152/pcp.2021.20176

World J Gastrointest Oncol. 2024 May 15;16(5):2233-2240. doi: 10.4251/wjgo.v16.i5.2233.

ABSTRACT

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with dispiriting survival data. Immunotherapy is a promising approach to many cancer types, but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment. We describe a case of metastatic PDAC effectively treated with pembrolizumab.

CASE SUMMARY: We report the case of a 67-year-old woman with unresectable locally advanced PDAC, treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine. At nine months, pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary, confirmed by left lung biopsy. Systemic immunotherapy was then initiated with pembrolizumab, an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types. The patient showed a complete metabolic response that was maintained throughout the treatment. The patient continues to be disease-free at 5.6 years since the start of immunotherapy.

CONCLUSION: These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC. To our knowledge, this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery. Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.

PMID:38764840 | PMC:PMC11099454 | DOI:10.4251/wjgo.v16.i5.2233

Front Oncol. 2024 May 3;14:1395618. doi: 10.3389/fonc.2024.1395618. eCollection 2024.

ABSTRACT

Despite multiple recent advances in systemic therapy for metastatic breast cancer, cases which display suboptimal response to guideline-driven treatment are frequently seen in the clinic. Effective options for such patients are limited, particularly in later line of therapy, and selection of optimal treatment options is essentially empirical and based largely on considerations of previous regimens received. Comprehensive cancer profiling includes detection of genetic alterations in tissue and circulating tumor DNA (ctDNA), immunohistochemistry (IHC) from re-biopsied metastatic disease, circulating tumor cells (CTCs), gene expression analysis and pharmacogenomics. The advent of this methodology and application to metastatic breast cancer, facilitates a more scientifically informed approach to identification of optimal systemic therapy approaches independent of the restrictions implied by clinical guidelines. Here we describe a case of metastatic breast cancer where consecutive comprehensive tumor profiling reveals ongoing tumor evolution, guiding the identification of novel effective therapeutic strategies.

PMID:38764581 | PMC:PMC11099277 | DOI:10.3389/fonc.2024.1395618

J Am Heart Assoc. 2024 May 21;13(10):e032248. doi: 10.1161/JAHA.123.032248. Epub 2024 May 18.

ABSTRACT

BACKGROUND: Carriers of CYP2C19 loss-of-function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention.

METHODS AND RESULTS: The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel-based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3-year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all-cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3-year clinical outcomes.

CONCLUSIONS: In older patients, the presence of any CYP2C19 loss-of-function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients.

REGISTRATION: URL: https://clinicaltrials.gov. Identifier: NCT04734028.

PMID:38761068 | DOI:10.1161/JAHA.123.032248

J Affect Disord. 2024 May 16:S0165-0327(24)00799-7. doi: 10.1016/j.jad.2024.05.063. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacotherapy is one of the primary treatment modalities for depression. However, there is considerable variability in the individual response to antidepressant medications. Personalized medicine guided by pharmacogenomic testing may hold promise in addressing this issue.

METHODS: In this study, 665 depressive patients were randomly enrolled into two groups: the pharmacogenomic testing group (n = 333) and the control group (n = 332). In the testing group, participants underwent pharmacogenomic testing, and clinicians customized the treatment plan with the result, while the control group relied solely on clinicians' experience. The primary outcomes were the proportion of remission and response, assessed with Hamilton Depression Rating Scale (HDRS). The secondary outcomes included changes in HDRS scores over time and frequency of adverse drug reactions by the participants.

RESULTS: At week 8, the pharmacogenomic testing group showed significantly higher remission rates (24.0 % v.s. 15.1 %; RR = 1.117; P = 0.007) and response rates (39.3 % v.s. 25.7 %; RR = 1.225; P < 0.001) compared to the control group. By week 12, the pharmacogenomic testing group continued to demonstrate significant advantages in remission (31.0 % v.s. 20.0 %; RR = 1.159; P = 0.003) and response (48.7 % v.s. 37.3 %; RR = 1.224; P = 0.006). Additionally, adverse drug reactions were less frequent in the pharmacogenomic testing group.

LIMITATIONS: This study is not blind to clinicians and it's a single-center study.

CONCLUSIONS: Pharmacogenomic testing-guided drug therapy can provide greater assistance in the treatment of depression.

PMID:38762035 | DOI:10.1016/j.jad.2024.05.063

BMJ Open. 2024 May 16;14(5):e085115. doi: 10.1136/bmjopen-2024-085115.

ABSTRACT

INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.

METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.

ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.

TRIAL REGISTRATION NUMBER: NCT05667766.

PMID:38760050 | DOI:10.1136/bmjopen-2024-085115

Hum Genomics. 2024 May 17;18(1):47. doi: 10.1186/s40246-024-00621-9.

ABSTRACT

Association between genomic variants and athletic performance has seen a high degree of controversy, as there is often conflicting data as far as the association of genomic variants with endurance, speed and strength is concerned. Here, findings from a thorough meta-analysis from 4228 articles exploring the association of genomic variants with athletic performance in power and endurance sports are summarized, aiming to confirm or overrule the association of genetic variants with athletic performance of all types. From the 4228 articles, only 107 were eligible for further analysis, including 37 different genes. From these, there were 21 articles for the ACE gene, 29 articles for the ACTN3 gene and 8 articles for both the ACE and ACTN3 genes, including 54,382 subjects in total, from which 11,501 were endurance and power athletes and 42,881 control subjects. These data show that there is no statistically significant association between genomic variants and athletic performance either for endurance or power sports, underlying the fact that it is highly risky and even unethical to make such genetic testing services for athletic performance available to the general public. Overall, a strict regulatory monitoring should be exercised by health and other legislative authorities to protect the public from such services from an emerging discipline that still lacks the necessary scientific evidence and subsequent regulatory approval.

PMID:38760851 | DOI:10.1186/s40246-024-00621-9

Ther Drug Monit. 2024 May 14. doi: 10.1097/FTD.0000000000001225. Online ahead of print.

ABSTRACT

BACKGROUND: Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM.

METHODS: The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach.

RESULTS: Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3.

CONCLUSIONS: This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.

PMID:38758634 | DOI:10.1097/FTD.0000000000001225

Front Pharmacol. 2024 May 2;15:1373007. doi: 10.3389/fphar.2024.1373007. eCollection 2024.

ABSTRACT

Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.

PMID:38756376 | PMC:PMC11096557 | DOI:10.3389/fphar.2024.1373007

J Natl Compr Canc Netw. 2024 May;22(4):e247022. doi: 10.6004/jnccn.2024.7022.

ABSTRACT

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

PMID:38754463 | DOI:10.6004/jnccn.2024.7022

JAMA Netw Open. 2024 May 1;7(5):e2411726. doi: 10.1001/jamanetworkopen.2024.11726.

ABSTRACT

IMPORTANCE: Disparities in outcomes exist between Black and White patients with acute myeloid leukemia (AML), with Black patients experiencing poorer prognosis compared with their White counterparts.

OBJECTIVE: To assess whether varying intensity of induction therapy to treat pediatric AML is associated with reduced disparities in treatment outcome by race.

DESIGN, SETTING, AND PARTICIPANTS: A comparative effectiveness analysis was conducted of 86 Black and 359 White patients with newly diagnosed AML who were enrolled in the AML02 trial from 2002 to 2008 or the AML08 trial from 2008 to 2017. Statistical analysis was conducted from July 2023 through January 2024.

INTERVENTIONS: Patients in AML02 were randomly assigned to receive standard low-dose cytarabine-based induction therapy or augmented high-dose cytarabine-based induction therapy, whereas patients in AML08 received high-dose cytarabine-based therapy.

MAIN OUTCOMES AND MEASURES: Cytarabine pharmacogenomic 10-single-nucleotide variant (ACS10) scores were evaluated for association with outcome according to race and treatment arm.

RESULTS: This analysis included 86 Black patients (mean [SD] age, 8.8 [6.5] years; 54 boys [62.8%]; mean [SD] leukocyte count, 52 600 [74 000] cells/µL) and 359 White patients (mean [SD] age, 9.1 [6.2] years; 189 boys [52.6%]; mean [SD] leukocyte count, 54 500 [91 800] cells/µL); 70 individuals with other or unknown racial and ethnic backgrounds were not included. Among all patients without core binding factor AML who received standard induction therapy, Black patients had significantly worse outcomes compared with White patients (5-year event-free survival rate, 25% [95% CI, 9%-67%] compared with 56% [95% CI, 46%-70%]; P = .03). By contrast, among all patients who received augmented induction therapy, there were no differences in outcome according to race (5-year event-free survival rate, Black patients, 50% [95% CI, 38%-67%]; White patients, 48% [95% CI, 42%-55%]; P = .78). Among patients who received standard induction therapy, those with low ACS10 scores had a significantly worse 5-year event-free survival rate compared with those with high scores (42.4% [95% CI, 25.6%-59.3%] and 70.0% [95% CI, 56.6%-83.1%]; P = .004); however, among patients who received augmented induction therapy, there were no differences in 5-year event-free survival rates according to ACS10 score (low score, 60.6% [95% CI, 50.9%-70.2%] and high score, 54.8% [95% CI, 47.1%-62.5%]; P = .43).

CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study of pediatric patients with AML treated in 2 consecutive clinical trials, Black patients had worse outcomes compared with White patients after treatment with standard induction therapy, but this disparity was eliminated by treatment with augmented induction therapy. When accounting for ACS10 scores, no outcome disparities were seen between Black and White patients. Our results suggest that using pharmacogenomics parameters to tailor induction regimens for both Black and White patients may narrow the racial disparity gap in patients with AML.

PMID:38753328 | DOI:10.1001/jamanetworkopen.2024.11726

Breast Cancer Res Treat. 2024 May 15. doi: 10.1007/s10549-024-07355-1. Online ahead of print.

ABSTRACT

PURPOSE: HER2-positive breast cancer (BC) accounts for 20-30% of all BC subtypes and is linked to poor prognosis. Trastuzumab (Tz), a humanized anti-HER2 monoclonal antibody, is a first-line treatment for HER2-positive breast cancer which faces resistance challenges. This study aimed to identify the biomarkers driving trastuzumab resistance.

METHODS: Differential expression analysis of genes and proteins between trastuzumab-sensitive (TS) and trastuzumab-resistant (TR) cells was conducted using RNA-seq and iTRAQ. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used to study their functions. The prognostic significance and protein levels of ARFIP2 and MSN were evaluated using online tools and immunohistochemistry. Sensitivity of MSN and ARFIP2 to other therapies was assessed using public pharmacogenomics databases and the R language.

RESULTS: Five genes were up-regulated, and nine genes were down-regulated in TR cells at both transcriptional and protein levels. Low ARFIP2 and high MSN expression linked to poor BC prognosis. MSN increased and ARFIP2 decreased in TR patients, correlating with shorter OS. MSN negatively impacted fulvestrant and immunotherapy sensitivity, while ARFIP2 had a positive impact.

CONCLUSION: Our findings suggest that MSN and ARFIP2 could serve as promising biomarkers for predicting response to Tz, offering valuable insights for future research in the identification of diagnostic and therapeutic targets for BC patients with Tz resistance.

PMID:38750271 | DOI:10.1007/s10549-024-07355-1

Pharmacogenomics J. 2024 May 15;24(3):14. doi: 10.1038/s41397-024-00334-1.

ABSTRACT

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

PMID:38750044 | DOI:10.1038/s41397-024-00334-1

Pharmacogenet Genomics. 2024 May 15. doi: 10.1097/FPC.0000000000000536. Online ahead of print.

ABSTRACT

OBJECTIVES: Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients.

METHODS: A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (Css-min) in overall patients and in age subgroups was analyzed.

RESULTS: Voriconazole Css-min correlated positively with age, and mean voriconazole Css-min was significantly higher in the elderly group (P < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole Css-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole Css-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole Css-min (>5.5 mg/l) was higher in the elderly patients. When the average Css-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole Css-min in the young group, while the influence of age on voriconazole Css-min exceeded CYP2C19 genotypes in the elderly.

CONCLUSION: CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

PMID:38747453 | DOI:10.1097/FPC.0000000000000536

Clin Transl Sci. 2024 May;17(5):e13816. doi: 10.1111/cts.13816.

ABSTRACT

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.

PMID:38747311 | DOI:10.1111/cts.13816

Nat Ment Health. 2024;2(5):616-626. doi: 10.1038/s44220-024-00240-2. Epub 2024 Apr 17.

ABSTRACT

Pharmacogenomics could optimize antipsychotic treatment by preventing adverse drug reactions, improving treatment efficacy or relieving the cost burden on the healthcare system. Here we conducted a systematic review to investigate whether pharmacogenetic testing in individuals undergoing antipsychotic treatment influences clinical or economic outcomes. On 12 January 2024, we searched MEDLINE, EMBASE, PsycINFO and Cochrane Centrale Register of Controlled Trials. The results were summarized using a narrative approach and summary tables. In total, 13 studies were eligible for inclusion in the systematic review. The current evidence base is either in favor of pharmacogenetics-guided prescribing or showed no difference between pharmacogenetics and treatment as usual for clinical and economic outcomes. In the future, we require randomized controlled trials with sufficient sample sizes that provide recommendations for patients who take antipsychotics based on a broad, multigene panel, with consistent and comparable clinical outcomes.

PMID:38746691 | PMC:PMC11088993 | DOI:10.1038/s44220-024-00240-2

Explor Target Antitumor Ther. 2024;5(2):374-383. doi: 10.37349/etat.2024.00223. Epub 2024 Apr 24.

ABSTRACT

Fluoropyrimidines, crucial in cancer treatment, often cause toxicity concerns even at standard doses. Toxic accumulation of fluoropyrimidine metabolites, culminating in adverse effects, can stem from impaired dihydropyrimidine dehydrogenase (DPYD) enzymatic function. Emerging evidence underscores the role of single nucleotide polymorphisms (SNPs) in DPYD gene, capable of inducing DPYD activity deficiency. Consequently, DPYD genotyping's importance is on the rise in clinical practice before initiating fluoropyrimidine treatment. Although polymerase chain reaction (PCR) followed by Sanger sequencing (SS; PCR-SS) is a prevalent method for DPYD genotyping, it may encounter limitations. In this context, there is reported a case in which a routine PCR-SS approach for genotyping DPYD SNP rs55886062 failed in a proband of African descent. The Clinical Pharmacogenetics Implementation Consortium (CPIC) categorizes the guanine (G) allele of this SNP as non-functional. The enforcement of whole genome sequencing (WGS) approach led to the identification of two adenine (A) insertions near the PCR primers annealing regions in the proband, responsible for a sequence frameshift and a genotyping error for rs55886062. These SNPs (rs145228578, 1-97981199-T-TA and rs141050810, 1-97981622-G-GA) were extremely rare in non-Finnish Europeans (0.05%) but prevalent in African populations (16%). Although limited evidence was available for these SNPs, they were catalogued as benign variants in public databases. Notably, these two SNPs exhibited a high linkage disequilibrium [LD; squared correlation coefficient (R2) = 0.98]. These findings highlighted the importance to consider the prevalence of genetic variants within diverse ethnic populations when designing primers and probes for SNP genotyping in pharmacogenetic testing. This preventive measure is essential to avoid sequence frameshifts or primer misalignments arising from SNP occurrences in the genome, which can compromise PCR-SS and lead to genotyping failures. Furthermore, this case highlights the significance of exploring alternative genotyping approaches, like WGS, when confronted with challenges associated with conventional techniques.

PMID:38745766 | PMC:PMC11090686 | DOI:10.37349/etat.2024.00223

JCO Oncol Pract. 2024 May 14:OP2400255. doi: 10.1200/OP.24.00255. Online ahead of print.

NO ABSTRACT

PMID:38743915 | DOI:10.1200/OP.24.00255