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Purpose <p>Standard dosing of infusional 5-FU results in subtherapeutic drug exposure for up to half of all patients. We evaluated plasma uracil concentration and <i>DPYD</i> rs4294451 genotype as candidate predictors of individual-level 5-FU exposure.</p> Methods <p>We conducted a prospective study of drug exposure in patients with gastrointestinal cancer receiving infusional 5-FU. Participants were evaluated by measurement of fasting pretreatment plasma uracil concentration, <i>DPYD</i> gene sequence (including genotyping of rs4294451) and 5-FU area under the curve (5-FU AUC). We used a linear mixed-effects model to evaluate the association of 5-FU AUC with uracil concentration and rs4294451 genotype, adjusting for cycle number, sex, serum creatinine, and 5-FU dose.</p> Results <p>There were 29 evaluable participants with a median age of 64 years (range 41–81); nine (31%) were female. The median plasma uracil concentration was 10.4 ng/mL (IQR 7.2, 12.6). Nine participants carried the <i>DPYD</i> rs4294451 T-allele (7 with T/A, 2 with T/T.) Among all participants the median 5-FU AUC was 22.0&#xa0;mg*h/L in cycle 1 and 19.3&#xa0;mg*h/L in cycle 2. In the mixed-effects model, higher rs4294451 T-allele count (0, 1, or 2) was significantly associated with lower 5-FU AUC (-4.0&#xa0;mg*h/L per T-allele [95% CI -8.0, 0.0], <i>p</i> = 0.049), as was male sex (-7.5&#xa0;mg*h/L [95% CI -13.8, -1.3], <i>p</i> = 0.021). Pretreatment plasma uracil concentration was not significantly associated with 5-FU AUC (<i>p</i> = 0.57). The subject with the highest uracil concentration (23.1 ng/mL) had a rare <i>DPYD</i> missense variant (c.2185G &gt; A [p.A729T]) and experienced early 5-FU-related toxicity.</p> Conclusions <p><i>DPYD</i> rs4294451 T-allele count and male sex were significantly associated with reduced 5-FU drug exposure. <i>DPYD</i> rs4294451 and male sex merit further evaluation as candidate biomarkers to inform initial dosing of infusional 5-FU.</p>

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Association of DPYD rs4294451, plasma uracil concentration, and sex with 5-fluorouracil exposure in patients with gastrointestinal cancer

  • 期刊论文

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  • 发表日期：

    2025年12月4日

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  • Gabriel A. Brooks,
  • Dylan B. Ness,
  • Kathryn C. Hourdequin,
  • Gregory H. Ripple,
  • Manik Amin,
  • Sierra Lord-Halvorson,
  • Wahab A. Khan,
  • Sophie J. Deharvengt,
  • Vincent Busque,
  • Konstantin H. Dragnev,
  • Wenyan Zhao,
  • Tor D. Tosteson,
  • Lionel D. Lewis

摘要

Purpose

Standard dosing of infusional 5-FU results in subtherapeutic drug exposure for up to half of all patients. We evaluated plasma uracil concentration and DPYD rs4294451 genotype as candidate predictors of individual-level 5-FU exposure.

Methods

We conducted a prospective study of drug exposure in patients with gastrointestinal cancer receiving infusional 5-FU. Participants were evaluated by measurement of fasting pretreatment plasma uracil concentration, DPYD gene sequence (including genotyping of rs4294451) and 5-FU area under the curve (5-FU AUC). We used a linear mixed-effects model to evaluate the association of 5-FU AUC with uracil concentration and rs4294451 genotype, adjusting for cycle number, sex, serum creatinine, and 5-FU dose.

Results

There were 29 evaluable participants with a median age of 64 years (range 41–81); nine (31%) were female. The median plasma uracil concentration was 10.4 ng/mL (IQR 7.2, 12.6). Nine participants carried the DPYD rs4294451 T-allele (7 with T/A, 2 with T/T.) Among all participants the median 5-FU AUC was 22.0 mg*h/L in cycle 1 and 19.3 mg*h/L in cycle 2. In the mixed-effects model, higher rs4294451 T-allele count (0, 1, or 2) was significantly associated with lower 5-FU AUC (-4.0 mg*h/L per T-allele [95% CI -8.0, 0.0], p = 0.049), as was male sex (-7.5 mg*h/L [95% CI -13.8, -1.3], p = 0.021). Pretreatment plasma uracil concentration was not significantly associated with 5-FU AUC (p = 0.57). The subject with the highest uracil concentration (23.1 ng/mL) had a rare DPYD missense variant (c.2185G > A [p.A729T]) and experienced early 5-FU-related toxicity.

Conclusions

DPYD rs4294451 T-allele count and male sex were significantly associated with reduced 5-FU drug exposure. DPYD rs4294451 and male sex merit further evaluation as candidate biomarkers to inform initial dosing of infusional 5-FU.