Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

Background Chemotherapy induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects seen among patients with early stage breast cancer and received taxane-containing regimens. The primary clinical manifestation of CIPN is sensory neuropathy such as numbness, tingling and pain in hands and feet, which negatively affect the patient’s quality of life (QoL). Although in most patients, CIPN improves over time, in a subset of patients, it remains a substantial debilitating problem, significantly affecting QoL. To date, there are no effective prevention strategies- or sufficient treatment due to the limited understanding of CIPN pre-disposing factors or pathophysiology. We hypothesize that a multimodal integration of biomarkers with CIPN progression analysis will be required to understand the pathophysiology and to consistently predict patient susceptibility. Further, we hypothesize that this multimodal approach may be leveraged to identify targets for CIPN treatment and/or prevention. This abstract describes the study protocol used to explore this hypothesis. Objective This study is designed to 1) identify genetic, transcriptional, epigenetic, metabolic, inflammatory biomarkers predictive of CIPN development among patients with early stage breast cancer receiving a taxane containing therapy; 2) With these biomarkers, develop an algorithm to identify patients who are at risk of developing CIPN before or during taxane therapy. Methods This is a longitudinal, multicenter, observational study. Patients with early-stage breast cancer who are receiving a taxane-containing (paclitaxel, docetaxel or nab-paclitaxel) treatment regimen, without preexisting peripheral neuropathy are eligible. Estimated enrollment is 400 patients. Demographic and clinical data are collected after patients consent to participate. Molecular data and patient reported outcomes (PRO) are collected prior to initiation of taxane therapy, the 4th, 8th, and 12th week of taxane therapy, and at 3, 6, and 9 months after completion of taxane therapy. Blood samples are collected for molecular data which include genetic, transcriptional, epigenetic (DNA-methylation), and metabolic data. PRO are assessed using (i) the European Organization for Research and Treatment of Cancer CIPN20 questionnaire, (ii) the Brief Pain Inventory, (iii) the Pain Catastrophizing Scale, and (iv) the PRO Measurement System for anxiety, depression and pain interference. Initial data analysis will characterize the association of biomarkers in each modality (e.g., genetic, epigenetic, etc.) with the presence or absence of CIPN, and machine learning will be used to build candidate biomarker signatures to predict CIPN before and during taxane treatment. Two distinct multi-modal prediction models will be constructed: 1) a pre-treatment model to predict risk of developing CIPN, and 2) an on-treatment model to predict the onset of CIPN. The goal is to develop a parsimonious, clinically translatable model for robust and accurate predictions of taxane-induced CIPN. Trial Status: Active, 135 subjects enrolled. Trial Centers: 1) Cleveland Clinic Foundation (8 regional sites in Ohio and 1 in Florida); 2) Huntsman Cancer Institute, University of Utah Research Funding: National Institute of Neurological Disorder and Stroke. Grant No.: 1R61NS113258-01A1 Citation Format: Mei Wei, Anukriti Sharma, Ken Johnson, Bihua Bie, courtney hershberger, Alper Sen, Emily E. Rhoades, Chi-Fan Hocking, George Budd, N. Lynn Henry, Charis Eng, Joseph Foss, daniel rotroff. Protocol Description of Genetics and Inflammatory Markers to predict Chemotherapy-Induced Peripheral Neuropathy among Early Stage Breast Cancer Patients Receiving Taxane Therapy – GENIE Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-17-01.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

Microorganisms such as coliform-forming bacteria are commonly used to assess freshwater quality for drinking and recreational use. However, such organisms do not exist in isolation; they exist within the context of dynamic, interactive microbial communities which vary through space and time. Elucidating spatiotemporal microbial dynamics is imperative for discriminating robust community changes from ephemeral ecological trends, and for improving our overall understanding of the relationship between microbial communities and ecosystem health. We conducted a seven-year (2013-2019) microbial time-series investigation in the Chicago Area Waterways (CAWS): an urban river system which, in 2016, experienced substantial upgrades to disinfection processes at two wastewater reclamation plants (WRPs) that discharge into the CAWS and improved stormwater capture, to improve river water quality and reduce flooding. Using culture-independent and culture-dependent approaches, we compared CAWS microbial ecology before and after the intervention. Examinations of time-resolved beta distances between WRP-adjacent sites showed that community similarity measures were often consistent with the spatial orientation of site locations to one another and to the WRP outfalls. Fecal coliform results suggested that upgrades reduced coliform-associated bacteria in the effluent and the downstream river community. However, examinations of whole community changes through time suggest that the upgrades did little to affect overall riverine community dynamics, which instead were overwhelmingly driven by yearly patterns consistent with seasonality. Such results emphasize the dynamic nature of microbiomes in open environmental systems such as the CAWS, but also suggest that the seasonal oscillations remain consistent even when perturbed.