Dataset Information

Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study.

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10^-8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10^-8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10^-8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

SUBMITTER: Adjei AA

PROVIDER: S-EPMC7959452 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:Despite the success of immune checkpoint and targeted therapy, many patients with melanoma ultimately require further treatment. The combination of carboplatin, paclitaxel, and bevacizumab (CPB) has demonstrated promising activity in a single-arm study. In the current study, the authors performed a randomized phase 2 study to confirm efficacy and to determine whether adding everolimus would increase the activity of the combination. METHODS:Through the North Central Cancer Treatment Group, a total of 149 patients with unresectable AJCC 6th edition stage IV melanoma were randomized from May 2010 to May 2014 to either CPB or CPB with everolimus (CPBE). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate, and tolerability. RESULTS:The CPB and CPBE treatment arms were balanced with regard to age (median age: 59 years vs 58 years) and high lactate dehydrogenase (48% vs 51%), but were unbalanced with regard to sex (male sex: 72% vs 55%; P = .03). Overall, there was no difference noted with regard to PFS, with a median PFS of 5.6 months for CPB versus 5.1 months for CPBE (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.81-1.62 [P = .44]), or for OS, with a median OS of 14.5 months for CPB versus 10.8 months for CPBE (HR, 1.16; 95% CI, 0.84-1.84). The confirmed response rate was 13% for CPB and 23% for CPBE (P = .13). Toxicity was higher for CPBE compared with CPB (83% for grade 3 + and 14% for grade 4 + vs 63% for grade 3 + and 11% for grade 4+, respectively) (toxicities were graded using the Cancer Therapy Evaluation Program of the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Common grade 3 + toxicities were neutropenia, leukopenia, and fatigue, which occurred in both treatment arms with comparable frequency. CONCLUSIONS:Both experimental arms demonstrated activity, with a PFS of >5 months. However, the addition of everolimus to CPB failed to improve outcomes, with increased toxicity noted. These findings replicate the moderate antitumor activity of CPB, with future development possibly in combination with targeted or immunotherapy. Cancer 2018;124:537-45. © 2017 American Cancer Society.

Project description:ImportanceChemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development.ObjectiveTo identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin.Design, setting, and participantsThis cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020.ExposuresPaclitaxel or oxaliplatin chemotherapy.Main outcomes and measuresCIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development.ResultsThe study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (β = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (β = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (β = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (β = -1.08; 95% CI, -1.76 to -0.16; P = .01).Conclusions and relevanceThe results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.

Dataset Information

Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets