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DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine-based protocols
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  • Nada Bozina,
  • Ivan Bilić,
  • Lana Ganoci,
  • Livija Šimičević,
  • Stjepko Pleština,
  • Lucija Lešnjaković,
  • Vladimir Trkulja
Nada Bozina
University of Zagreb School of Medicine
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Ivan Bilić
University Hospital Centre Zagreb
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Lana Ganoci
University Hospital Centre Zagreb Department of Laboratory Diagnostics
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Livija Šimičević
University Hospital Centre Zagreb Department of Laboratory Diagnostics
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Stjepko Pleština
University Hospital Centre Zagreb
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Lucija Lešnjaković
University of Zagreb Faculty of Pharmacy and Biochemistry
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Vladimir Trkulja
University of Zagreb School of Medicine
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Abstract

Aim. Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798, rs56038477). We evaluated relationship between three further DPYD polymorphisms [c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265)] and the risk of severe AEs. Methods. Consecutive FP-treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining three tested polymorphisms). Results. Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n=127) than in controls (n=376) [OR=5.20 (95%CI 1.88-14.3), Bayesian OR=5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in *6 c.2194G>A variant carries (n=58) than in controls (n=432) [OR=1.88 (0.95-3.73), Bayesian OR=1.90 (1.03-3.56)]. *9A c.85T>G did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). Conclusion. DPYD c.496A>G variant might need to be considered for inclusion in the DPYD genotyping panel.
03 Sep 2021Submitted to British Journal of Clinical Pharmacology
06 Sep 2021Submission Checks Completed
06 Sep 2021Assigned to Editor
07 Sep 2021Reviewer(s) Assigned
26 Sep 2021Review(s) Completed, Editorial Evaluation Pending
27 Sep 2021Editorial Decision: Revise Major
08 Oct 20211st Revision Received
09 Oct 2021Assigned to Editor
09 Oct 2021Submission Checks Completed
09 Oct 2021Review(s) Completed, Editorial Evaluation Pending
09 Oct 2021Reviewer(s) Assigned
30 Oct 2021Editorial Decision: Revise Minor
04 Nov 20212nd Revision Received
05 Nov 2021Assigned to Editor
05 Nov 2021Submission Checks Completed
05 Nov 2021Review(s) Completed, Editorial Evaluation Pending
07 Nov 2021Editorial Decision: Accept