Paclitaxel exposure, specifically the maximum concentration () and amount of time the concentration remains above 0.05 μmol/L (), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy. Patients with breast cancer receiving paclitaxel 80 mg/m × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate and Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Secondary analyses were conducted using as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption. In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity ( < 0.05), but neither ( = 0.27) nor ( = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; = 0.0008) and (OR = 1.79; 95% CI, 1.06-3.01; = 0.029) or (OR = 2.74; 95% CI, 1.45-5.20; = 0.002) were associated with peripheral neuropathy-induced treatment disruption. Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. .

Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis.

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Aims: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). Methods:Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption.Results: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (β-coefficient: −0.42, 95% confidence interval −0.72 to −0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. Conclusion:Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment. K E Y W O R D Sbreast cancer, genetic polymorphism, pharmacodynamics, pharmacogenomics, pharmacokinetics Principal statement: The authors confirm that the PI for this paper is D.L. Hertz and that the coinvestigator N. Lynn Henry had direct clinical responsibility for patients.

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.