Dataset Information

Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors.

ABSTRACT: BACKGROUND:Paclitaxel is one of the most commonly used drugs to treat breast cancer. Its major dose-limiting toxicity is paclitaxel-induced peripheral neuropathy (PIPN). PIPN persists into survivorship and has a negative impact on patient's mood, functional status, and quality of life. No interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. Mitochondrial dysfunction has been evaluated in preclinical studies as a hypothesized mechanism for PIPN, but clinical data to support this hypothesis are limited. The purpose of this pilot study was to evaluate for differential gene expression and perturbed pathways between breast cancer survivors with and without PIPN. METHODS:Gene expression in peripheral blood was assayed using RNA-seq. Differentially expressed genes (DEG) and pathways associated with mitochondrial dysfunction were identified between survivors who received paclitaxel and did (n?=?25) and did not (n?=?25) develop PIPN. RESULTS:Breast cancer survivors with PIPN were significantly older; more likely to be unemployed; reported lower alcohol use; had a higher body mass index and poorer functional status; and had a higher number of lower extremity sites with loss of light touch, cold, and pain sensations and higher vibration thresholds. No between-group differences were found in the cumulative dose of paclitaxel received or in the percentage of patients who had a dose reduction or delay due to PIPN. Five DEGs and nine perturbed pathways were associated with mitochondrial dysfunction related to oxidative stress, iron homeostasis, mitochondrial fission, apoptosis, and autophagy. CONCLUSIONS:This study is the first to provide molecular evidence that a number of mitochondrial dysfunction mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors with persistent PIPN and suggest genes for validation and as potential therapeutic targets.

SUBMITTER: Kober KM

PROVIDER: S-EPMC6293373 | biostudies-other | 2018 Jan-Dec

REPOSITORIES: biostudies-other

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Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors.

Kober Kord M KM Olshen Adam A Conley Yvettte P YP Schumacher Mark M Topp Kimberly K Smoot Betty B Mazor Melissa M Chesney Margaret M Hammer Marilyn M Paul Steven M SM Levine Jon D JD Miaskowski Christine C

Molecular pain 20180101

<h4>Background</h4>Paclitaxel is one of the most commonly used drugs to treat breast cancer. Its major dose-limiting toxicity is paclitaxel-induced peripheral neuropathy (PIPN). PIPN persists into survivorship and has a negative impact on patient's mood, functional status, and quality of life. No interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. Mitochondrial dysfunction ...[more]

PMID: 30426838

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Project description:Chemotherapy is a common treatment for breast cancer (BrCa) and can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN contributes to falls, and is thus a potential risk factor for nontraumatic fractures (NTFx); yet, the effect of CIPN on NTFx risk has not been examined for BrCa survivors. We therefore investigated the association between CIPN and NTFx in BrCa survivors. Data were extracted from Optum's Deidentified Clinformatics® Data Mart Database years 2010-2015 in this retrospective cohort study. Among women, three groups were derived based on BrCa and CIPN status: BrCa+/CIPN+ (primary group of interest), BrCa+/CIPN- (first comparison group), and BrCa-/CIPN- (second comparison group). After propensity score matching the comparison groups to BrCa+/CIPN+ at a ratio of 1:11 (BrCa:control) for demographics, osteoporosis, glucocorticoid medication, comorbidities, and cancer-related variables for BrCa+/CIPN-, 1-year incidence rate (IR) of NTFx was determined for each group. The incident rate ratio (IRR) determined if the IR for NTFx was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. Cox proportional hazards regression models estimated the hazard ratios (HRs) after adjusting for covariates that were unable to be matched for. The crude IR (95% confidence interval [CI]) of NTFx was 4.54 (2.32-6.77) for BrCa+/CIPN+ (n = 359), 2.53 (2.03-3.04) for BrCa+/CIPN- (n = 3949), and 1.76 (1.35-2.18) for BrCa-/CIPN- (n = 3949). The crude IRR of NTFx was significantly elevated for BrCa+/CIPN+ as compared to BrCa+/CIPN- (IRR = 1.80; 95% CI, 1.06-3.05) and BrCa-/CIPN- (IRR = 2.58; 95% CI, 1.50-4.44). The elevated rate of NTFx for BrCa+/CIPN+ remained unchanged after adjusting for aromatase inhibitors compared to BrCa+/CIPN- (HR = 1.79; 95% CI, 1.06-3.04). Female BrCa survivors have an increased 1-year IR of NTFx after the onset of CIPN, suggesting that CIPN is an additive burden on NTFx risk among BrCa survivors. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dataset Information

Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors.

Publications

Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors.

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