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Resolving CYP2D6 Structural Complexity with Long-Read Sequencing: Implications for Tamoxifen Precision Dosing in Thai

Usa Boonyuen1, Sirinyatorn Talukam1, Beatriz Aira C Jacob1

  • 1Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Clinical Pharmacology and Therapeutics
|July 2, 2026
PubMed

Insights

Accurate tamoxifen therapy relies on Cytochrome P450 2D6 (CYP2D6) metabolism. Long-read sequencing precisely identifies complex CYP2D6 variants in Thai breast cancer patients, revealing potential risks of low drug exposure due to misclassification by standard genotyping.

Area of Science:

  • Pharmacogenomics
  • Genetics
  • Oncology

Background:

  • Tamoxifen efficacy in estrogen receptor-positive breast cancer is critically dependent on its bioactivation by Cytochrome P450 2D6 (CYP2D6).
  • Complex CYP2D6 genetic variations are prevalent in Asian populations, posing challenges for accurate genotyping and genotype-phenotype correlation.
  • This can lead to suboptimal tamoxifen dosing and reduced therapeutic benefits.

Purpose of the Study:

  • To investigate the utility of long-read Oxford Nanopore sequencing for resolving complex CYP2D6 structural variations.
  • To evaluate the impact of these complex CYP2D6 genotypes on endoxifen metabolism and tamoxifen efficacy in Thai breast cancer patients.
  • To improve genotype-phenotype correlation for personalized tamoxifen therapy.

Main Methods:

  • Applied long-read Oxford Nanopore sequencing to a cohort of 492 Thai breast cancer patients.
  • Resolved complex CYP2D6 structural variations, including non-identical duplications.
  • Performed multivariable analysis on 361 patients receiving standard-dose tamoxifen to correlate CYP2D6 activity scores with plasma endoxifen concentrations.

Main Results:

  • Identified 82 distinct CYP2D6 diplotypes and successfully resolved complex structural variations.
  • 46.55% of patients exhibited decreased CYP2D6 enzyme function, predominantly as intermediate metabolizers (45.53%).
  • CYP2D6 activity score was the strongest determinant of endoxifen exposure (P < 0.001), with decreased-function genotypes significantly associated with lower endoxifen levels.

Conclusions:

  • Long-read sequencing accurately resolves CYP2D6 structural complexity, capturing rare and complex alleles missed by standard genotyping.
  • Standard genotyping may misclassify a significant proportion of patients, potentially leading to unrecognized risks of low tamoxifen exposure.
  • Precise CYP2D6 genotyping is crucial for optimizing tamoxifen therapy and improving outcomes in breast cancer patients, particularly in populations with complex allele prevalence.

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