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Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical 5-fluorouracil (5-FU) treatment in these patients, leading to inconsistent guideline recommendations for pretreatment testing and topical 5-FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary end point) and 1+ (secondary end point) toxicity was compared between DPYD variant carriers vs. wild-type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40, 95% confidence interval: 0.10-2.53, P = 0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5-FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5-FU treatment should be avoided in these patients., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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.)

Background: Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401., Methods: Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥ 3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses., Results: Of 1008 randomized patients, the odds of experiencing grade ≥ 3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥ 3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE., Conclusions: Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care., (© 2014 American Cancer Society.)