UGT1A1 genotyping before irinotecan

What it measures. Irinotecan is converted to its active metabolite SN-38, which is cleared by the liver enzyme UGT1A1. The *28 variant, a longer repeat in the gene's promoter, roughly halves expression; about ten per cent of Europeans and Africans carry two copies. In East Asian populations the *6 variant plays the same role. People with two reduced-function copies have higher SN-38 exposure and more severe neutropenia and diarrhoea, especially at doses of 180 mg per square metre and above or when irinotecan is given as a single agent every three weeks.

Evidence and guidelines. The FDA added the UGT1A1*28 warning and a recommendation to consider a lower starting dose for homozygous patients to the irinotecan label in 2005, the first pharmacogenomic label change in oncology. The Dutch Pharmacogenetics Working Group recommends a 30 per cent starting dose reduction for *28 or *6 homozygotes, and the French GPCO-Unicancer group recommends testing before high-dose regimens. The Clinical Pharmacogenetics Implementation Consortium has not issued its own irinotecan guideline, and testing is less consistently mandated than DPYD testing, partly because carriers can often tolerate standard doses at the lower intensities used in FOLFIRI and FOLFIRINOX. The same enzyme variant matters for the antibody-drug conjugate sacituzumab govitecan, whose payload is also SN-38, and its label carries a UGT1A1*28 warning.

Who should have it and what changes. Patients about to receive irinotecan at higher doses or in intensive combinations, and those with a history of unexplained jaundice suggesting Gilbert syndrome. A homozygous result lowers the starting dose by around a third with escalation if tolerated; heterozygotes are usually treated at full dose with closer monitoring. The test costs tens of pounds and is available from most pharmacogenomic laboratories; it can be run on the same sample as DPYD genotyping.