Pharmacogenetic Predictors of Taxane-Induced Peripheral Neuropathy

Peripheral neuropathy is an adverse event of taxane treatment that is related both to the patient's cumulative drug exposure and their inherent sensitivity to neurotoxicity. Discovery and validation of genetic loci that determine neuropathy risk is an important first step towards individualization of taxane treatment with the ultimate goal of maximizing treatment efficacy and minimizing the risk of severe adverse events. Paclitaxel exposure is regulated by enzymes and transporters that have common variants known to influence protein expression or activity. Paclitaxel is primarily metabolized by the CYP2C8 enzyme, and prior research from our group and others suggests that patients who carry a common low-activity variant, CYP2C8*3, may be at increased risk of neuropathy. Using a cohort of paclitaxel-treated breast cancer patients, I was able to confirm the association between CYP2C8*3 and increased risk of paclitaxel-induced peripheral neuropathy. I then attempted to use a genotyping platform that interrogates thousands of variants in hundreds of genes relevant to drug metabolism, elimination, and transport to identify polymorphisms that influence risk of neurotoxicity after accounting for the CYP2C8*3 variant. Surprisingly, I discovered a polymorphism in a gene not thought to be relevant to paclitaxel pharmacokinetics, ABCG1, which was associated with neuropathy risk. Less is known about the clinical or genetic factors that modulate docetaxel-induced neuropathy risk. I performed genome-wide association in a large cohort of docetaxel-treated patients to discover genetic loci that modulate risk of neuropathy. I discovered several candidates, one of which was an intergenic polymorphism that surpassed genome-wide significance after adjustment for relevant clinical covariates. I then attempted, unsuccessfully, to replicate these discoveries in independent cohorts of taxane-treated patients. This inability to replicate indicates that either the associations of these variants are limited to the cohort in which they were discovered or that they were merely spurious discoveries. Replication should be attempted in independent patient cohorts that are more similar to those in which these discoveries were made to validate the influence of these variants on neuropathy risk, enabling translation into routine clinical practice.Doctor of Philosoph

Drug-Drug Interactions in Subjects Enrolled in SWOG Trials of Oral Chemotherapy

Background Patients with cancer are at increased risk of drug-drug interactions (DDI), which can increase treatment toxicity or decrease efficacy. It is especially important to thoroughly screen DDI in oncology clinical trial subjects to ensure trial subject safety and data accuracy. This study determined the prevalence of potential DDI involving oral anti-cancer trial agents in subjects enrolled in two SWOG clinical trials. Methods Completed SWOG clinical trials of commercially available agents with possible DDI that had complete concomitant medication information available at enrollment were included. Screening for DDI was conducted through three methods: protocol-guided screening, Lexicomp® screening, and pharmacist determination of clinical relevance. Descriptive statistics were calculated. Results SWOG trials S0711 (dasatinib, n = 83) and S0528 (everolimus/lapatinib, n = 84) were included. Subjects received an average of 6.6 medications (standard deviation = 4.9, range 0–29) at enrollment. Based on the clinical trial protocols, at enrollment 18.6% (31/167) of subjects had a DDI and 12.0% (20/167) had a DDI that violated a protocol exclusion criterion. According to Lexicomp®, 28.7% of subjects (48/167) had a DDI classified as moderate or worse, whereas pharmacist review indicated that 7.2% of subjects (12/167) had a clinically relevant interaction. The majority of clinically relevant DDI identified were due to the coadministration of acid suppression therapies with dasatinib (83.3%, 10/12). Conclusions The high DDI prevalence in subjects enrolled on SWOG clinical trials, including a high prevalence that violate trial exclusion criteria, support the need for improved processes for DDI screening to ensure trial subject safety and trial data accuracy

Pharmacogenetics, enzyme probes and therapeutic drug monitoring as potential tools for individualizing taxane therapy

The taxanes are a class of chemotherapeutic agents that are widely used in the treatment of various solid tumors. Although taxanes are highly effective in cancer treatment, their use is associated with serious complications attributable to large interindividual variability in pharmacokinetics and a narrow therapeutic window. Unpredictable toxicity occurrence necessitates close patient monitoring while on therapy and adverse effects frequently require decreasing, delaying or even discontinuing taxane treatment. Currently, taxane dosing is based primarily on body surface area, ignoring other factors that are known to dictate variability in pharmacokinetics or outcome. This article discusses three potential strategies for individualizing taxane treatment based on patient information that can be collected before or during care. The clinical implementation of pharmacogenetics, enzyme probes or therapeutic drug monitoring could enable clinicians to personalize taxane treatment to enhance efficacy and/or limit toxicity

Prevalence of drug-drug interactions in oncology patients enrolled on National Clinical Trials Network oncology clinical trials

Abstract Background Drug-drug interactions (DDIs) in subjects enrolling in clinical trials can impact not only safety of the patient but also study drug outcomes and data validity. This makes it critical to adequately screen and manage DDIs. The study objective was to determine the prevalence of DDIs involving study medications in subjects enrolling in National Clinical Trials Network (NCTN) clinical trials at a single institution. DDIs were evaluated based on study protocol recommendations for concomitant medication use (i.e. exclude, avoid or use caution), screening via DDI tool, and pharmacist review. Methods Subjects enrolled in NCTN trials of commercially available agents between January 2013 and August 2017 were included if a complete medication list was available. Complete medication lists were collected from the date of enrollment or the next available date then screened utilizing protocol guidance and the DDI screening tool, Lexicomp® Drug Interactions (Wolters Kluwer, Hudson, OH). Interactions were reviewed for clinical relevance: defined as a DDI that would require a medication change to ensure study agent safety and efficacy at enrollment. Results One hundred and twenty-eight subjects enrolled in 35 clinical trials were included. Protocol guidance detected 15 unique DDI pairs that should be avoided or used with caution in 10.2% (13/128) of subjects. The majority of these subjects did not have a clinically relevant DDI (69.2%, 9/13) based on pharmacist review. Lexicomp® detected moderate to major DDIs in 24.2% (31/128) of subjects, with 9.4% (12/128) having a clinically relevant DDI. Conclusions This study confirms a high prevalence of DDIs present in subjects enrolling in oncology clinical trials. Further efforts should be made to improve methods to detect and manage DDIs in patients enrolling on clinical trials to ensure patient safety and trial data validity.https://deepblue.lib.umich.edu/bitstream/2027.42/146516/1/12885_2018_Article_5076.pd

Operationalizing ambiguity in sustainability science: embracing the elephant in the room

Ambiguity is often recognized as an intrinsic aspect of addressing complex sustainability challenges. Nevertheless, in the practice of transdisciplinary sustainability research, ambiguity is often an ‘elephant in the room’ to be either side-stepped or reduced rather than explicitly mobilized in pursuit of solutions. These responses threaten the salience and legitimacy of sustainability science by masking the pluralism of real-world sustainability challenges and how research renders certain frames visible and invisible. Critical systems thinking (CST) emerged from the efforts of operational researchers to address theoretical and practical aspects of ambiguity. By adapting key concepts, frameworks, and lessons from CST literature and case studies, this paper aims to establish (1) an expansive conceptualization of ambiguity and (2) recommendations for operationalizing ambiguity as a valuable means of addressing sustainability challenges. We conceptualize ambiguity as an emergent feature of the simultaneous and interacting boundary processes associated with being, knowing, and intervening in complex systems, and propose Reflexive Boundary Critique (RBC) as a novel framework to help navigate these boundary processes. Our characterization of ambiguity acknowledges the boundary of a researcher’s subjective orientation and its influence on how ambiguity is exposed and mediated in research (being), characterizes knowledge as produced through the process of making boundary judgments, generating a partial, contextual, and provisional frame (knowing), and situates a researcher as part of the complexity they seek to understand, rendering any boundary process as a form of intervention that reinforces or marginalizes certain frames and, in turn, influences action (intervening). Our recommendations for sustainability scientists to operationalize ambiguity include (1) nurturing the reflexive capacities of transdisciplinary researchers to navigate persistent ambiguity (e.g., using our proposed framework of RBC), and (2) grappling with the potential for and consequences of theoretical incommensurability and discordant pluralism. Our findings can help sustainability scientists give shape to and embrace ambiguity as a fundamental part of rigorous sustainability science

Improvement Initiative to Develop and Implement a Tool for Detecting Drug-Drug Interactions During Oncology Clinical Trial Enrollment Eligibility Screening

Objectives Screening subjects for drug-drug interactions (DDIs) before enrollment in oncology clinical trials is integral to ensuring safety, but standard procedures or tools are not readily available to screen DDI in this setting. Our objectives were to develop a DDI screening tool for use during oncology clinical trial enrollment and to test usability in single-center and multicenter pilot studies. Methods A multistage approach was used for this quality improvement intervention. Semistructured interviews with individuals responsible for DDI screening were conducted to develop a prototype tool. The tool was used for screening DDI in subjects enrolling in National Clinical Trials Network trials of commercially available agents during a single-center 3-month pilot. Improvements were made, and a 3-month multicenter pilot was conducted at volunteer SWOG Cancer Research Network sites. Participants were surveyed to determine tool usability and efficiency. Results A tool was developed from semistructured interviews. A critical feature was reporting which medications had specific pharmacokinetic and pharmacodynamic characteristics including transporter and cytochrome P450 substrates, inhibitors, or inducers and QT prolongation. In the 12-site study, average (SD) DDI screening time for each patient decreased by 15.7 (10.2) minutes (range, 3–35 minutes; P \u3c 0.001). Users reported the tool highly usable, with \u3e90% agreeing with all positive usability characterizations and disagreeing with all negative complexity characterizations. Conclusions A DDI screening tool for oncology clinical trial enrollment was created and its usability confirmed. Further testing with more diverse investigator sites and study drugs during eligibility screening is warranted to improve safety and data accuracy within clinical trials

Genotyping concordance in DNA extracted from formalin‐fixed paraffin embedded (FFPE) breast tumor and whole blood for pharmacogenetic analyses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135708/1/mol22015991868.pd

Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154957/1/bcp14192.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154957/2/bcp14192_am.pd

Disordered Bosons: Condensate and Excitations

The disordered Bose Hubbard model is studied numerically within the Bogoliubov approximation. First, the spatially varying condensate wavefunction in the presence of disorder is found by solving a nonlinear Schrodinger equation. Using the Bogoliubov approximation to find the excitations above this condensate, we calculate the condensate fraction, superfluid density, and density of states for a two-dimensional disordered system. These results are compared with experiments done with ${}^4{\rm He}$ adsorbed in porous media.Comment: RevTeX, 26 pages and 10 postscript figures appended (Figure 9 has three separate plots, so 12 postcript files altogether

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field