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Pinto N, Navarro SL, Rimorin C, et al. Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2021;68(11):e29203doi: 10.1002/pbc.29203.
Pinto, N., Navarro, S. L., Rimorin, C., Wurscher, M., Hawkins, D. S., & McCune, J. S. (2021). Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatric blood & cancer, 68(11), e29203. https://doi.org/10.1002/pbc.29203
Pinto, Navin, et al. "Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group." Pediatric blood & cancer vol. 68,11 (2021): e29203. doi: https://doi.org/10.1002/pbc.29203
Pinto N, Navarro SL, Rimorin C, Wurscher M, Hawkins DS, McCune JS. Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2021 Nov;68(11):e29203. doi: 10.1002/pbc.29203. Epub 2021 Jul 10. PMID: 34245211; PMCID: PMC8719493.
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Pediatr Blood Cancer. 2021 Nov;68(11):e29203. doi: 10.1002/pbc.29203. Epub 2021 Jul 10.

Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

Pediatric blood & cancer

Navin Pinto, Sandi L Navarro, Christine Rimorin, Michelle Wurscher, Douglas S Hawkins, Jeannine S McCune

Affiliations

  1. Seattle Children's Hospital, Seattle, Washington, USA.
  2. Department of Pediatrics, University of Washington, Seattle, Washington, USA.
  3. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  4. Department of Hematologic Malignances Translational Sciences, City of Hope, Duarte, California, USA.

PMID: 34245211 PMCID: PMC8719493 DOI: 10.1002/pbc.29203

Abstract

BACKGROUND: In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting.

PROCEDURES: We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics.

RESULTS: Eight SNPs were associated (p-value < .05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate < 0.05.

CONCLUSIONS: Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.

© 2021 Wiley Periodicals LLC.

Keywords: alklylating agents; biomarkers; cyclophosphamide; pediatric cancer; pharmacogenomics; rhabdomyosarcoma

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