The review concludes with the roles that the UGT1A1*28 and UGT1A1*6 alleles play in adverse drug reactions (decreased glucuronidation of irinotecan, belinostat, atazanavir, pegvisomant) leading to increased exposure, reduced clearance and neutropenia (irinotecan, belinostat), increased risk for jaundice and hyperbilirubinaemia (atazanavir) and liver toxicity (pegvisomant) before discussing the future role of UGT1A1 in personalised medicine.
In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.
However, in lung cancer patients administered a low dose of CPT-11, <i>UGT1A1*6</i>/<i>*28</i> variants were not significantly associated with severe neutropenia or delayed diarrhea.
Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients.
These data suggest that the UGT1A1*28 polymorphism may not be a suitable biomarker to predict IRI-induced toxicities and chemotherapy TR in Asians, while UGT1A*6 polymorphism is associated with a higher risk of IRI-induced neutropenia and diarrhea, but not IRI-based chemotherapy TR.
No significant difference in grade 3/4 neutropenia was found between patients with the wild-type genotype and those with variant genotypes for UGT1A1*28 or UGT1A1*6.
All data were collected by a physician.The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated.
However, analysis of UGT1A1(*)28 and (*)6 in combination revealed an association with severe neutropenia in the first and second cycles (P = 0.044, P = 0.017, respectively).
The most common grade 4 adverse event in patients with the UGT1A1*6 genotypes was neutropenia (88.9%), but there were no gastrointestinal adverse events or treatment-related deaths.
In contrast, carriers of one protective marker (UGT1 rs11563250G) but none of these risk alleles experienced significantly less severe neutropenia (8.2 vs. 34.0%; P<0.0001).
The incidence of grade III-IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022).
By characterizing the UGT1 sequence from a cohort of 167 Canadian metastatic colorectal cancer (mCRC) patients and a validation cohort of 250 Italian mCRC patients, we found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; P=0.043 and OR=0.27; P=0.036, respectively, and OR=0.31 when combined; P=0.001), which remained significant upon correction for multiple testing in the combined cohort (P=0.041).
The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan.