Dataset Information

A narrative review of genetic factors affecting fluoropyrimidine toxicity.

ABSTRACT:

Objective

Our objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation.

Background

FPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0.5-1% of patients. While serious systemic toxicities may occur in any patient, patients with polymorphisms in DPYD, which encodes the rate-limiting enzyme for pyrimidine degradation are at very high risk. Other genetic factors affecting risk for 5-FU toxicity, including miR-27a, are under investigation.

Methods

Literature used to inform the text of this article was selected from PubMed.gov from the National Library of Medicine while regulatory documents were identified via Google search.

Conclusions

Clinical studies to date have validated four DPYD polymorphisms (DPYD*2A, DPYD*13, c.2846A>T, HapB3) associated with serious toxicities in patients treated with 5-FU. Genetic screening for these is being implemented in the Netherlands and the UK and has been shown to be a cost-effective way to improve outcomes. Factors other than DPYD polymorphisms (e.g., miR-27a, TYMS, ENOSF1, p53) also affect 5-FU toxicity. Functional testing for deficient pyrimidine catabolism {defined as [U] >16 ng/mL or [UH2]:[U] <10} is being implemented in France and has demonstrated utility in identifying patients with elevated risk for 5-FU toxicity. Therapeutic drug monitoring (TDM) from plasma levels of 5-FU during first cycle treatment also is being used to improve outcomes and pharmacokinetic-based dosing is being used to increase the percent of patients within optimal area under the curve (AUC) (18-28 mg*h/L) values. Patients maintained in the optimal AUC range experienced significantly reduced systemic toxicities. As understanding the genetic basis for increased risk of 5-FU toxicity becomes more refined, the development of functional-based methods to optimize treatment is likely to become more widespread.

SUBMITTER: Gmeiner WH

PROVIDER: S-EPMC8664072 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Type 2 diabetes is impacting millions of people globally; however, many future cases can be prevented through lifestyle changes and interventions. Primary care is an important setting for diabetes prevention, for at-risk populations, because it is a patient's primary point of contact with the health care system and professionals can provide lifestyle counselling and support, as well as monitoring health outcomes. These are all essential elements for diabetes prevention for at-risk adults.To understand the factors related to the delivery and uptake of type 2 diabetes prevention interventions within primary care in higher income countries.For this narrative systematic review, we combined qualitative and quantitative studies of diabetes prevention within a primary care setting for patients at-risk of developing the condition. We used an iterative approach for evidence collection, which included using several databases (MEDLINE, Embase, Pysch info, BNI, SSCI, CINAHL, ASSIA), where we combined diabetes terms with primary care terms. Narrative and thematic synthesis were utilised to identify the prominent themes emerging from the data.A database of 6646 records was screened by the research team, and 18 papers were included. Three major themes were identified in this review. The first theme of context and setting of diabetes progression includes the risk and progression of diabetes, primary care as a setting, and where the responsibility for change is thought to lie. This review also found mixed views on the value of preventative services within primary care. The second theme focused on the various patient factors associated with diabetes prevention such as a patient's motivation to modify their current lifestyle, perceptions and knowledge (or lack thereof) of the impacts of diabetes, lack of follow-up in healthcare settings, and trust in healthcare professionals. The third theme was centred on professional factors impacting on diabetes prevention which included workload, time constraints, resources, self-efficacy and knowledge as well as professionals' perception of patient motivations towards change.This review explored the factors influencing diabetes prevention in primary care, and identified the context of prevention, as well as patient and professional factors related to preventative services being offered in primary care. This systematic review complements previous reviews of real-world settings by exploring the significant factors in prevention, and the findings are relevant to academics, policymakers, patients and practitioners interested in understanding the factors associated with the delivery and uptake of diabetes prevention interventions.

Project description:Background: Fluoropyrimidine is widely used owing to its clinical efficacy, however, patients with dihydropyrimidine dehydrogenase (DPD) deficiency can experience fluoropyrimidine-associated toxicity. The dihydropyrimidine dehydrogenase (DPYD) gene encodes DPD, and studies suggest that DPYD polymorphisms can result in DPD deficiency. Since there is not a complete consistency of how much the risk of complication is elevated, we aimed to conduct a systematic literature review and a meta-analysis to provide the risk of fluoropyrimidine-associated toxicity in patients with DPYD rs1801160 polymorphism. Methods: We searched for qualifying studies published before October 2021 from PubMed, Web of Science, and EMBASE based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between rs1801160 polymorphism and toxicities. A sensitivity analysis using the leave-one-out method was performed on the overall toxicity. Results: The pooled OR for overall toxicity in the patients with A allele was elevated 1.73 times higher than those with the GG genotype (95% CI 1.44-2.07). Sensitivity analysis yielded similar results, showing the robustness of the result. Subjects with variants showed a 2.37-fold increased hematological toxicity (95% CI 1.48-3.81); especially a 1.87-fold increased neutropenia compared to patients with wildtype (95% CI 1.49-2.34). Patients with A allele revealed 1.22 times higher gastrointestinal toxicity compared to those with GG genotype (95% CI 0.93-1.61), and among gastrointestinal toxicity, the risk of diarrhea was elevated 1.43 times higher in those with variants than patients with wildtype (95% CI 1.12-1.83). Conclusions: rs1801160 polymorphism is associated with elevated fluoropyrimidine-associated toxicity. Therefore, rs1801160 can be a potential candidate for DPD deficiency screening prior to fluoropyrimidine-based regimen.

Project description:Background and objectiveRadiation therapy (RT) is one of the important components of comprehensive treatment for breast cancer and has important value in improving the control rate of local areas, reducing the chance of recurrence and metastasis after breast cancer surgery, delaying disease progression, and improving the survival of breast cancer patients. The factors that affect the RT sensitivity of breast cancer are important. The above potential predictors of radiation efficacy can provide patients with a predictive method and therefore have significant value in clinical therapy. In this paper, we have summarised the predictive factors of radiotherapy sensitivity by reviewing recent research on breast cancer and focused on the following areas: tumor immune microenvironment (TIME), cancer stem cells, noncoding RNAs, signal transduction pathways, genes, etc. This review aims to provide theoretical basis and reference for improving the efficacy of radiotherapy and experimental individualized treatment of breast cancer.MethodsWe searched the Web of Science database to identify clinical studies published between 2010 and January 2024 that investigated radiotherapy sensitivity. The main findings of the validated studies were summarised.Key content and findingsImproving the radiosensitivity of breast cancer is essential in the treatment of breast cancer. The radiosensitivity can be improved by modulating immune cells or immunomodulatory factors in the TIME, modulating signal transduction pathways, and other innovative combination therapy strategies. And we also summarized the predictive markers of breast cancer radiosensitivity.ConclusionsIn this paper, we reviewed the literature and summarized the newest research advances on the radiosensitivity of breast cancer patients. This review paper includes the following six aspects: the immune microenvironment, tumor stem cells, signaling pathways, regulation of gene/protein expression, small molecule drugs, and predictive markers for radiosensitivity.

Project description:BackgroundMobile health (mHealth) tools have emerged as a promising health care technology that may contribute to cost savings, better access to care, and enhanced clinical outcomes; however, it is important to ensure their acceptance and adoption to harness this potential. Patient adoption has been recognized as a key challenge that requires further exploration.ObjectiveThe aim of this review was to systematically investigate the literature to understand the factors affecting patients' adoption of mHealth tools by considering sociotechnical factors (from technical, social, and health perspectives).MethodsA structured search was completed following the participants, intervention, comparators, and outcomes framework. We searched the MEDLINE, PubMed, Cochrane Library, and SAGE databases for studies published between January 2011 and July 2021 in the English language, yielding 5873 results, of which 147 studies met the inclusion criteria. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the Cochrane Handbook were followed to ensure a systematic process. Extracted data were analyzed using NVivo (QSR International), with thematic analysis and narrative synthesis of emergent themes.ResultsThe technical factors affecting patients' adoption of mHealth tools were categorized into six key themes, which in turn were divided into 20 subthemes: usefulness, ease of use, data-related, monetary factors, technical issues, and user experience. Health-related factors were categorized into six key themes: the disease or health condition, the care team's role, health consciousness and literacy, health behavior, relation to other therapies, integration into patient journey, and the patients' insurance status. Social and personal factors were divided into three key clusters: demographic factors, personal characteristics, and social and cultural aspects; these were divided into 19 subthemes, highlighting the importance of considering these factors when addressing potential barriers to mHealth adoption and how to overcome them.ConclusionsThis review builds on the growing body of research that investigates patients' adoption of mHealth services and highlights the complexity of the factors affecting adoption, including personal, social, technical, organizational, and health care aspects. We recommend a more patient-centered approach by ensuring the tools' fit into the overall patient journey and treatment plan, emphasizing inclusive design, and warranting comprehensive patient education and support. Moreover, empowering and mobilizing clinicians and care teams, addressing ethical data management issues, and focusing on health care policies may facilitate adoption.

Project description:BackgroundThe Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity.MethodsBiospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS.ResultsTwenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10-8), however, five variants were suggestive of association (P < 5 × 10-6) with severe toxicity.ConclusionsResults from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.