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Background: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor., Methods: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet., Results: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05)., Conclusions: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The causes of variation in toxicity to the same treatment regimen among seemingly similar patients remain largely unknown. There was tremendous optimism that the patient's germline genome would be strongly predictive of treatment-related toxicity and could be used to personalize treatment and improve therapeutic outcomes. However, there has been limited success in discovering robust pharmacogenetic predictors of treatment-related toxicity and even less progress in translating the few validated predictors into clinical practice. It is apparent that identification of toxicity predictors that can be used to predict and prevent treatment-related toxicity will require thinking beyond germline genomics. To that end, we propose an integrated biomarker discovery approach that recognizes that a patient's toxicity risk is determined by the cumulative effects of a broad range of "omic" and non-omic factors. This commentary describes the limited success in discovering and translating clinical and pharmacogenetic toxicity predictors into clinical practice. We illustrate the evolution of cancer toxicity biomarker discovery and translation through studies of taxane-induced peripheral neuropathy, which is one of the most common and debilitating side effects of cancer treatment. We then discuss the opportunities for discovering non-genomic (e.g., metabolomic, lipidomic, transcriptomic, proteomic, microbiomic, medical, behavioral, environmental) and integrated biomarkers that may be more strongly predictive of toxicity risk and the potential challenges with translating integrated biomarkers into clinical practice. This integrated biomarker discovery approach may circumvent some of the major limitations in toxicity biomarker science and move precision oncology treatment forward so that patients receive maximum treatment benefit with minimal toxicity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

Precision medicine has revolutionized clinical care for patients with cancer through the development of targeted therapy, identification of inherited cancer predisposition syndromes and the use of pharmacogenetics to optimize pharmacotherapy for anticancer drugs and supportive care medications. While germline (patient) and somatic (tumor) genomic testing have evolved separately, recent interest in paired germline/somatic testing has led to an increase in integrated genomic testing workflows. However, paired germline/somatic testing has generally lacked the incorporation of germline pharmacogenomics. Integrating pharmacogenomics into paired germline/somatic genomic testing would be an efficient method for increasing access to pharmacogenomic testing. In this perspective, the authors argue for the benefits of implementing a comprehensive approach integrating somatic and germline testing that is inclusive of pharmacogenomics in clinical practice.

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx-relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx-informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research-only genetic data repositories to expand the number of patients who benefit from PGx-informed treatment while we continue to work toward wide-scale adoption of PGx testing and implementation., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many common anti-cancer agents that can lead to dose reduction or treatment discontinuation, which decrease chemotherapy efficacy. Long-term CIPN can interfere with activities of daily living and diminish the quality of life. The mechanism of CIPN is not yet fully understood, and biomarkers are needed to identify patients at high risk and potential treatment targets. Metabolomics can capture the complex behavioral and pathophysiological processes involved in CIPN. This chapter is to review the CIPN metabolomics studies to find metabolic pathways potentially involved in CIPN. These potential CIPN metabolites are then investigated to determine whether there is evidence from studies of other neuropathy etiologies such as diabetic neuropathy and Leber hereditary optic neuropathy to support the importance of these pathways in peripheral neuropathy. Six potential biomarkers and their putative mechanisms in peripheral neuropathy were reviewed. Among these biomarkers, histidine and phenylalanine have clear roles in neurotransmission or neuroinflammation in peripheral neuropathy. Further research is needed to discover and validate CIPN metabolomics biomarkers in large clinical studies., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies., (© 2022 Peripheral Nerve Society.)

Objective: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations., Methods: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk., Results: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10 -8 ), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts., Conclusions: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment., Methods: Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity., Results: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p > 0.05)., Conclusion: The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is the major treatment-limiting toxicity of paclitaxel, which predominantly presents as sensory symptoms, with motor symptoms in some patients. Differentiating CIPN into subtypes has been recommended to direct CIPN research. The objective of this study was to investigate whether sensory and motor CIPN are distinct subtypes with different predictive biomarkers in patients with breast cancer receiving paclitaxel., Methods: Data were from a prospective cohort of 60 patients with breast cancer receiving up to 12 weekly infusions of 80 mg/m 2 paclitaxel (NCT02338115). European Organisation for Research and Treatment of Cancer Quality of Life questionnaire CIPN20 was used to evaluate CIPN. Clusters of the time course of sensory (CIPN S ), motor (CIPN M ), and the difference between sensory and motor (CIPN S -CIPN M ) were identified using k-means clustering on principal component scores. Predictive metabolomic biomarkers of maximum CIPN S and CIPN M were investigated using linear regressions adjusted for baseline CIPN, paclitaxel pharmacokinetics, and body mass index., Results: More sensory than motor CIPN was found (CIPN S change: mean = 10.8, ranged [-3.3, 52.1]; CIPN M change: mean = 3.5, range: [-7.5, 35.0]). Three groups were identified with No CIPN, Mixed CIPN, and Sensory-dominant CIPN (maximum CIPN S : mean = 12.7 vs. 40.9 vs. 74.3, p < 0.001; maximum CIPN M : mean = 5.4 vs. 25.5 vs. 36.1, p < 0.001; average CIPN S -CIPN M : mean = 2.8 vs. 5.8 vs. 24.9, p < 0.001). Biomarkers of motor CIPN were similar to previously identified biomarkers of sensory CIPN, including lower serum histidine (p = 0.029)., Conclusion: Our findings suggest that sensory and motor CIPN co-occur and may not have differentiating metabolic biomarkers. These findings need to be validated in larger cohorts of patients treated with paclitaxel and other neurotoxic agents to determine the optimal approach to predict, prevent, and treat CIPN and improve patients' outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Patients with low muscle mass have increased risk of paclitaxel-induced peripheral neuropathy, which is dependent on systemic paclitaxel exposure. Dose optimization may be feasible through the secondary use of radiologic data for body composition. The objective of this study was to interrogate morphomic parameters as predictors of paclitaxel pharmacokinetics to identify alternative dosing strategies that may improve treatment outcomes., Methods: This was a secondary analysis of female patients with breast cancer scheduled to receive 80 mg/m 2 weekly paclitaxel infusions. Paclitaxel was measured at the end of initial infusion to estimate maximum concentration (C max ). Computed tomography (CT) scans were used to measure 29 body composition features for inclusion in pharmacokinetic modelling. Monte Carlo simulations were performed to identify infusion durations that limit the probability of exceeding C max  > 2885 ng/mL, which was selected based on prior work linking this to an unacceptable risk of peripheral neuropathy., Results: Thirty-nine patients were included in the analysis. The optimal model was a two-compartment pharmacokinetic model with T11 skeletal muscle area as a covariate of paclitaxel volume of distribution (Vd). Simulations suggest that extending infusion of the standard paclitaxel dose from 1 hour to 2 and 3 hours in patients who have skeletal muscle area 4907-7080 mm 2 and <4907 mm 2 , respectively, would limit risk of C max  > 2885 ng/mL to <50%, consequently reducing neuropathy, while marginally increasing overall systemic paclitaxel exposure., Conclusion: Extending paclitaxel infusion duration in ~25% of patients who have low skeletal muscle area is predicted to reduce peripheral neuropathy while maintaining systemic exposure, suggesting that personalizing paclitaxel dosing based on body composition may improve treatment outcomes., (© 2022 British Pharmacological Society.)

Competing Interests: Daniel L. HertzResearch Funding: Disarm TherapeuticsOther Relationship: Advocates for Universal DPD/DPYD Testing (AUDT)Uncompensated Relationships: PEPID, Saladax Biomedical Lisa M. McShaneThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Daniel F. HayesStock and Other Ownership Interests: InBiomotionHonoraria: TempusConsulting or Advisory Role: Cepheid, Freenome, Epic Sciences, Cellworks, BioVica, Oncocyte, Turnstone Bio, Predictus Biosciences, Guardant Health, L-Nutra, MacroGenics, TempusResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Merrimack (Inst), Menarini Silicon Biosystems (Inst)Patents, Royalties, Other Intellectual Property: Royalties from licensed technology, Diagnosis and Treatment of Breast Cancer. Patent No. US 8,790,878 B2. Date of Patent: July 29, 2014. Applicant Proprietor: University of Michigan. Dr Daniel F. Hayes is designated as an inventor/coinventor, Circulating Tumor Cell Capturing Techniques and Devices. Patent No.: US 8,951,484 B2. Date of Patent: February 10, 2015. Applicant Proprietor: University of Michigan. Dr Daniel F. Hayes is designated as an inventor/coinventor, Title: A method for predicting progression-free and overall survival at each follow-up timepoint during therapy of metastatic breast cancer patients using circulating tumor cells. Patent No. 05725638.0-1223-US2005008602Travel, Accommodations, Expenses: Menarini Silicon BiosystemsOther Relationship: Menarini, UpToDateUncompensated Relationships: UpToDateNo other potential conflicts of interest were reported.

Purpose: Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing., Methods: Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses., Results: Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%)., Conclusion: Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines., Competing Interests: N. Lynn HenryResearch Funding: Blue Note Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/27894/summary Vaibhav SahaiConsulting or Advisory Role: Celgene, Halozyme, Newlink Genetics, Ipsen, Incyte, QED Therapeutics, Klus Pharma, AstraZeneca, GlaxoSmithKline, Rafael Pharmaceuticals, HistosonicsResearch Funding: Celgene (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Agios (Inst), Incyte (Inst), Clovis Oncology (Inst), Debiopharm Group (Inst), FibroGen (Inst), Halozyme (Inst), MedImmune (Inst), Rafael Pharmaceuticals (Inst), Ipsen (Inst), Exelixis (Inst), Syros Pharmaceuticals (Inst), Relay Therapeutics (Inst), Pancreatic Cancer Action Network (Inst), Actuate Therapeutics (Inst)Travel, Accommodations, Expenses: ASCO, FibroGen, FibroGen Daniel L. HertzResearch Funding: Disarm TherapeuticsUncompensated Relationships: PEPID, Saladax BiomedicalNo other potential conflicts of interest were reported.

CYP3A5 and CYP3A4 are the predominant enzymes responsible for tacrolimus metabolism; however only a proportion of the population expresses CYP3A5 secondary to genetic variation. CYP3A5 is expressed in both the intestine and the liver and has been shown to impact both the bioavailability and metabolism of orally administered tacrolimus. Increasing the initial tacrolimus dose by 50% to 100% is recommended in patients who are known CYP3A5 expressers; however, whether this dose adjustment is appropriate for i.v. tacrolimus administration is unclear. The objective of this study was to evaluate the impact of CYP3A5 genotype as well as other pharmacogenes on i.v. tacrolimus exposure to determine whether the current genotype-guided dosing recommendations are appropriate for this formulation. In addition, this study aimed to investigate dose conversion requirements among CYP3A5 genotypes when converting from i.v. to p.o. tacrolimus. This study is a retrospective chart review of all patients who underwent allogeneic stem cell transplantation at Michigan Medicine between June 1, 2014, and March 1, 2018, who received i.v. tacrolimus at the time of their transplantation. Secondary use samples were obtained for genotyping CYP3A5, CYP3A4, and ABCB1. Patient demographic information, tacrolimus dosing and trough levels, and concomitant medications received at the time of tacrolimus trough were collected retrospectively from the patients' medical records. The i.v. dose-controlled concentration (C/D) and the i.v.:p.o. exposure ratio was calculated for all tacrolimus doses and patients, respectively. The impact of CYP3A5, CYP3A4, and ABCB1 genotypes on the i.v. C/D were evaluated with linear mixed modeling. The impact of CYP3A5 genotype on the i.v.:p.o. ratio was evaluated while controlling for age and concomitant use of an azole inhibitor. CYP3A5 and CYP3A4 genotypes were significantly associated with the i.v. C/D, with CYP3A5 expressers and CYP3A4 rapid metabolizers having 20% lower tacrolimus exposure. Neither genotype remained significant in the multivariable model, although age, hematocrit, and concomitant use of strong azole inhibitors were associated with increased i.v. C/D. When controlling for patient age and sex, CYP3A5 expressers had significantly higher i.v.:p.o. ratios than CYP3A5 nonexpressers (3.42 versus 2.78; P = .04). Post hoc analysis showed that the i.v.:p.o. ratio may differ among different CYP3A5 genotypes and azole inhibitor combinations. This study demonstrates that the current genotype-guided tacrolimus dose adjustment recommendations are inappropriate for CYP3A5 expressers receiving i.v. tacrolimus. Although CYP3A5 genotype is likely a minor contributor to i.v. tacrolimus exposure, genotype, in addition to capturing concomitant CYP3A inhibitors, would likely improve i.v.:p.o. dose conversion selection. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Clinical guidelines recommend altering chemotherapy treatment by decreasing, delaying, or discontinuing dosing in patients who are experiencing chemotherapy-induced peripheral neuropathy. There are few data available on the clinical use of treatment alteration including the severity of CIPN at the time of treatment alteration., Methods: This was a retrospective analysis of patients receiving oxaliplatin on the NCCTG N08CB trial. Neuropathy severity was assessed at each cycle by clinicians and patients. Patients were classified as (1) completed treatment without alteration, (2) dose reduction or delay due to neuropathy, (3) discontinuation due to neuropathy, (4) discontinuation for other toxicity, or (5) discontinuation for another reason (5). Comparisons focused primarily on patients with alteration due to neuropathy (groups 2 and/or 3) compared with patients who completed treatment without alteration (group 1)., Results: In 350 participants, 135 (39%) completed treatment without alteration, 70 (20%) had a dose reduction or delay due to neuropathy, and 35 (10%) discontinued early due to neuropathy. Clinician-assessed neuropathy severity was greater in patients at the time of dose reduction or delay compared with severity at the end of treatment in patients without alteration (p < 0.0001). Patient-reported neuropathy severity at cycle 4 was worse in patients who eventually had a reduction or delay as compared with patients who completed treatment without alteration (p = 0.017)., Conclusions: Treatment alterations due to neuropathy are common in patients receiving oxaliplatin for colon cancer and are associated with clinician-assessed neuropathy severity. Rapid increases in patient-reported neuropathy severity indicate a potential need for monitoring and intervention., Trial Registration: Clinicaltrials.gov Identifier: NCT01099449 (NCCTG N08CB)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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 < 0.001). Users reported the tool highly usable, with >90% 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., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel., Methods: Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN., Results: Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06-76.15), had lower income (OR = 7.04, 95%CI 1.5-32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03-1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms., Conclusions: This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors., Competing Interests: Declaration of competing interest Syverson owns stock in Pfizer Inc. and AbbVie Inc. Loprinzi received personal fees from Pled Pharma, Metys, Disarm Therapeutics, and Asahi Kasei. Farris is a consultant and received remuneration from Quio Technologies. All other authors declare that they have no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown., Methods: We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables., Results: 25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20 ng/mL) for analysis (15/37 = 41%). Vitamin D-deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8 ± SD, 36 ± 23 vs. 16 ± 16, p = 0.003) and a non-significant, approximately threefold increase in risk of treatment disruption (OR 2.98, 95% CI [0.72, 12.34], p = 0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (β = - 0.04, p = 0.02)., Conclusion: Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.

Cytochrome P450 enzyme variant alleles have shown evidence that functional consequences differ between substrates. A systematic effort has not yet been made to confirm substrate-dependent activity. This review will discuss the challenges of assessing three examples (CYP2C8*3, CYP2D6*10, and CYP2C9*2) where substrate-dependent activity has been hypothesized with differing levels of evidence and their potential clinical implications. Data supports bidirectional substrate-dependent activity for CYP2C8*3. Although some data suggests CYP2D6*10 causes differences in the magnitude of effect across substrates, confirmatory studies are needed. Convincing evidence for CYP2C9*2 was lacking likely due to compensatory CYP450 metabolism or experimental variability. Confirmed substrate-dependent activity has the potential to impact clinical use of pharmacogenomics, and must be taken into consideration to ensure the goal of improving treatment through personalization is met. It is important for the pharmacogenomics community to begin thinking about this important topic and how it can be best accommodated in clinical practice.

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.

Purpose: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer., Methods: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2., Results: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05)., Conclusion: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.

Purpose: The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations., Methods: Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures., Results: Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05)., Conclusions: Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumor-infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy., Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy., Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10 -8 , adjusted P = 5.88 × 10 -7 ). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001)., Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR., Competing Interests: The authors declare the following relevant conflicts of interest., (©2016 American Association for Cancer Research.)

Aims: In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n = 349) was superior to anastrozole alone (n = 345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant., Methods: Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6 and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model., Results: A total of 483 anastrozole concentration measurements were included, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the combination arm. The mean anastrozole concentration in the combination arm was significantly lower than that in the anastrozole alone arm at each sample collection time (all P < 0.01) and in the mixed effects model (an estimated difference of 9.85 ng ml(-1) (95% CI 5.69, 14.00 ng ml(-1) ), P < 0.001)., Conclusion: A significant pharmacokinetic drug interaction was detected, in which the addition of fulvestrant to anastrozole treatment decreased the trough anastrozole concentration. Further research is needed to verify whether this interaction affects treatment efficacy and to determine the pharmacological mechanism by which this interaction occurs., (© 2016 The British Pharmacological Society.)

Pharmacogenetics attempts to predict treatment response using a patient's "germline" genome as the biomarker of interest. This chapter on pharmacogenetic predictors of breast cancer response is divided into four sections. The first introduces readers to genetic variation and describes how variation in the germline genome can affect biology or pharmacology. The second section introduces the translational pathway for pharmacogenetic research and discusses the specific challenges to identifying pharmacogenetic predictors of breast cancer response. The third section is divided into three subsections, each of which discusses a distinct category of pharmacogenetic response predictors; pharmacokinetics, cancer cell sensitivity, and effector cell activation. Within each subsection a specific pharmacogenetic association is described in detail; CYP2D6-tamoxifen, BRCA-PARP inhibitors, and FCGRA-trastuzumab, respectively, followed by a general discussion of other less well-established examples or areas for further research. The chapter concludes with a summary of the current status of pharmacogenetic predictors of breast cancer response and a few predictions for the future of this field.

Cardiomyopathy is a known complication of anthracycline-based adjuvant chemotherapy and is more commonly reported in population-based studies of breast cancer survivors than in clinical trials. This study prospectively evaluated the prevalence of elevated cardiac biomarkers in unselected patients who had been treated with doxorubicin for early-stage breast cancer and the prevalence of reduced LVEF in patients with an elevated biomarker. All participants underwent an examination, symptom inventory, medical record review, and biomarker analysis for BNP, troponin, and plasma and urine NT-proBNP. Patients who had one or more elevated biomarkers were referred for echocardiogram; systolic dysfunction was defined as LVEF less than 55 %. Multivariable logistic regression was used to determine the associations between age, BMI, cumulative dose of doxorubicin, diabetes, hypertension, and left-sided radiation therapy and the risk of reduced LVEF. Among the 269 patients who underwent lab testing (mean age 56 years, mean time since completion of doxorubicin-based chemotherapy 6 years), 192 (72 %) had one or more elevated biomarker. Among the 166 patients who completed an echocardiogram, 11.5 % had a LVEF < 55 %. After adjusting for covariates known to affect cardiac function, multivariable logistic regression revealed plasma NT-proBNP to be the only measured cardiac biomarker associated with systolic dysfunction. There is a relationship between NT-proBNP and the frequency of reduced LVEF in women treated with doxorubicin for curative intent; further study of NT-proBNP as a potential biomarker for subclinical cardiac dysfunction after exposure to anthracyclines is warranted.

Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity., Patients and Methods: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1., Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival., Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival., (©2013 AACR.)