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| 2. |
- Apellániz-Ruiz, Maria, et al.
(författare)
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Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.
- 2017
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Ingår i: Clinical Cancer Research. - : American Association of Cancer Research. - 1078-0432 .- 1557-3265. ; 23:5, s. 1227-1235
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.EXPERIMENTAL DESIGN: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/ gene-based analyses were used to compare variant frequencies among neuropathy groups and Cox regression models were used to analyze neuropathy evolution along treatment.RESULTS: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low frequency non-synonymous variants in EPHA6 were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, 95%CI=2.33-91.62, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10(-4)).CONCLUSION: This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.
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| 3. |
- Engvall, Kristina, et al.
(författare)
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Impact of persistent peripheral neuropathy on health-related quality of life among early-stage breast cancer survivors : a population-based cross-sectional study
- 2022
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Ingår i: Breast Cancer Research and Treatment. - : Springer. - 0167-6806 .- 1573-7217. ; 195, s. 379-391
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Tidskriftsartikel (refereegranskat)abstract
- Background We explored the impact of persistent sensory and motor taxane-induced peripheral neuropathy (TIPN) symptoms on health-related quality of life (HRQL) among early-stage breast cancer survivors (ESBCS). Methods A population-based cohort of 884 residual-free ESBCS received a postal questionnaire, including the EORTC chemotherapy-induced PN (CIPN20) and the EORTC QLQ-C30 instruments. Mean scores of QLQ-C30 scales among ESBCS with and without TIPN were calculated and adjusted for confounding factors (age, lifestyle factors, co-morbidities; linear regression analyses). Interpretation of QLQ-C30 results were based on guidelines. Results Response rate was 79%, and 646 survivors were included in the analysis. In median, 3.6 (1.5-7.3) years had elapsed post-taxane treatment. All TIPN symptoms had a significant impact on global QoL, which worsened with increased severity of TIPN. Between 29.5% and 93.3% of ESBCS with moderate-severe TIPN reported a clinical important impairment of functioning and personal finances, 64.3-85.7% reporting "difficulty walking because of foot drop," and 53.1-81.3% reporting "problems standing/walking because of difficulty feeling ground under feet" had impaired functioning/finances. The difference in mean scores between affected and non-affected survivors was highest for "numbness in toes/feet" and "difficulty walking because of foot drop." Moderate-severe "difficulty climbing stairs or getting out of chair because of weakness of legs" and "problems standing/walking because of difficulty feeling ground under feet" were associated with the largest clinically important differences on all scales. Conclusion Persistent sensory and motor TIPN is associated with clinically relevant impairment of global QoL, functioning, and personal finances among ESBCS, which increased with level of TIPN severity.
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| 4. |
- Engvall, Kristina, et al.
(författare)
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Persistent neuropathy among early-stage breast cancer survivors in a population-based cohort
- 2021
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 125:3, s. 445-457
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Tidskriftsartikel (refereegranskat)abstract
- Background The prevalence of persistent peripheral neuropathy (PN) in early-stage breast cancer (ESBC) survivors is largely unknown. We explored the occurrence and risk factors of PN among long-term ESBC survivors treated with taxane chemotherapy. Methods A population-based cohort of 884 recurrence-free ESBC survivors diagnosed 2010-2015 in the South East Health Care region, Sweden and 1768 control women without prior cancer received a postal questionnaire that included the European Organisation for Research and Treatment of Cancer chemotherapy-induced peripheral neuropathy (CIPN20) items. Prevalence, relative risks (RRs) (Poisson regression) and risk factors (binomial regression) were calculated. Adjustments were made for confounding factors (e.g. age, body mass index, comorbidities). Results The response rate was 79% for survivors and 59% for controls. The median time post taxane was 3.6 years (1.5-7.3 years). The adjusted RR was highest (RR 1.8) for "tingling/numbness of toes/feet". Individual sensory symptoms occurred in 8.9-48.4% and motor symptoms in 7.2-61.3% of survivors; the most prevalent symptoms were "difficulty opening jar" and "cramps in feet". Paclitaxel, older age, overweight, diabetes mellitus, vibrating hand tools, autoimmune disease and smoking were independent risk factors. Conclusions PN was more common among ESBC survivors than control women and many symptoms persisted over time. Risk factors should be considered when treatment decisions are made.
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| 5. |
- Engvall, Kristina, 1978-
(författare)
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Taxane-Induced Peripheral Neuropathy among Early-Stage Breast Cancer Survivors : Prevalence, Risk Factors, Quality of Life and Genetic Prediction Models
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Taxane-induced peripheral neuropathy (TIPN) is a common and distressful side effect. Little is known on how long TIPN persist and its effect on health-related quality of life (HRQL). The overall aim of this thesis was to study the prevalence and severity of persistent TIPN, to investigate its impact on HRQL and to explore the clinical and genetic risk factors for TIPN among early-stage breast cancer survivors (ESBCS). Methods: A population-based cohort of 884 recurrence-free ESBCS diagnosed 2010-2015 in the Southeast Health Care region, Sweden and 1768 control women without prior cancer, who received a postal questionnaire including EORTC chemotherapy-induced peripheral neuropathy (CIPN20) and QLQ-C30 instruments. Prevalence of TIPN symptoms and clinical risk factors were explored. Adjusted relative risks (RR) were estimated for ESBCS compared to control women. For impact on HRQL, adjusted mean scores of QLQ-C30 scales among ESBCS with and without TIPN were calculated. Blood samples from 362 ESBCS were whole-exome sequenced. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training and test cohort. Results: The response rate was 79% for ESBCS and 59% for controls. The median time post-taxane was 3.6 years. The adjusted RR for ESBCS vs. controls was highest (RR 1.8) for tingling in feet and numbness in feet. Individual sensory symptoms occurred in 9%-48% and motor symptoms in 7%-61% of ESBCS. The most prevalent symptoms were difficulty opening jar and cramps in feet. Paclitaxel, older age, overweight, diabetes mellitus, vibrating hand tools, smoking and autoimmune disease were independent risk factors (Study I). All 13 sensory and motor TIPN symptoms at increased risks among ESBCS had a significant impact on global health status, which worsened with increased severity of TIPN. Between 30%-93% of ESBCS with moderate-severe TIPN reported a clinically important impairment of functioning and personal finances. Moderate-severe difficulty climbing stairs and problems standing/walking were associated with medium-large clinically important differences (Study II). In the explorative sub-study, two of five prediction models based on genetic and clinical risk factors obtained AUC results above 60% in the test cohort. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted (Study III).Conclusions: Most sensory and motor symptoms are more common among taxane-treated ESBC survivors than in women from the general population, many symptoms persist ≥3.6 years. Persistent TIPN symptoms are associated with clinically relevant impairment of HRQL. Polygenic prediction models including clinical risk factors may be used to estimate the risk of persistent taxane-induced numbness in feet and tingling in feet.
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| 6. |
- Green, Henrik, et al.
(författare)
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Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer
- 2011
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 100:10, s. 4205-4209
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Tidskriftsartikel (refereegranskat)abstract
- The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8(*)3, CYP2C8-HapC, and CYP3A5(*)3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5(*)3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p andlt; 0.05) than patients with the wild-type genotype. CYP3A5(*)3/(*)1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than (*)3/(*)3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.
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| 7. |
- Green, Henrik, et al.
(författare)
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Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer
- 2009
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley-Blackwell Publishing Inc.. - 1742-7835 .- 1742-7843. ; 104:2, s. 130-137
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
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| 9. |
- Isaksson, Jenny, et al.
(författare)
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Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer
- 2021
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Ingår i: World Journal of Clinical Oncology. - : Baishideng Publishing Group Inc. - 2218-4333. ; 12:11, s. 1009-1022
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDThe majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting.AIMTo assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODSA multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linkoping, Jonkoping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed.RESULTSNinety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66-84) and 58% (46-70), respectively. OS at 12 and 24 mo was 93% (87-99) and 86% (76-96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m(2) every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m(2) every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39-5.87, P = 0.0041 and 3.36, 95%CI: 1.03-10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21-5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78-8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSIONResults from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.
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| 10. |
- Leandro-Garcia, Luis J., et al.
(författare)
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Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy
- 2013
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group Ltd. - 0022-2593 .- 1468-6244. ; 50:9, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- Background Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. less thanbrgreater than less thanbrgreater thanMethods A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. less thanbrgreater than less thanbrgreater thanResults The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0x10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4x10(-5) and rs1159057, p=6.8x10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4x10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1x10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0x10(-7)). less thanbrgreater than less thanbrgreater thanConclusions This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.
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