Real-world analysis of genotype-guided treatment for carriers of actionable DPYD and UGT1A1 variants.

DPYD, UGT1A1

Reduced dihydropyrimidine dehydrogenase (DPYD) activity and impaired glucuronidation (UGT1A1) leading to increased toxicity

This retrospective matched case-control study compared rates of severe adverse events during the first three treatment cycles in DPYD and UGT1A1 variant carriers receiving genotype-guided treatment versus standard treatment with fluoropyrimidines and irinotecan. Matching was on at-risk phenotype, chemotherapy regimen and age. Sixteen subjects received genotype-guided treatment, 12 of them on fluoropyrimidines, matched to 75 subjects receiving standard treatment. The primary endpoint, a severe adverse event attributed to the fluoropyrimidine or irinotecan, was significantly less frequent in the guided group (12.5% vs. 50.7%; odds ratio 0.15; 95% CI 0.03-0.68), as were treatment modifications (12.5% vs. 54.6%; p < 0.05). Six subjects in the guided group (37.5%) received and tolerated dose escalation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The effect size is striking but the sample makes it fragile: 16 guided patients, only 12 of them on fluoropyrimidines, against 75 controls — the odds ratio confidence interval spans 0.03 to 0.68, and the result rests on a handful of events. The study is retrospective and non-randomized: pre-emptively genotyped patients may differ from others in ways not captured by matching on phenotype, regimen and age. Its value lies elsewhere: it is a reminder that DPYD genotyping is not only about dose reduction, since more than a third of guided patients could be escalated without toxicity.

Analysis by Dr Thibaut Benquey