Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan‐induced severe toxicity

Abstract

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

“…Our findings support these negative results as we found no associations with severe neutropenia in the 307 patients analyzed. These data, together with the significant association obtained with the UGT1A1*28 marker (P = 0.037) in a previous study by our group (Riera et al, 2018), lead us to infer that UGT1A1 is a more powerful predictor of severe neutropenia than ABCB1.…”

“…A total of 176 patients had been enrolled in clinical trials ( Marcuello et al., 2011 ; Páez et al., 2019 ). The presence of the UGT1A1*28 , UGT1A1*37 , and UGT1A1*36 alleles was determined in a previous study ( Riera et al., 2018 ). Table 1 shows patients’ clinical characteristics along with UGT1A1 genotype status.…”

“…SN-38 is mainly eliminated through glucuronidation by the uridine 5′-diphospho-(UDP)glucuronosyltransferase (UGT) isoform 1A1, which is encoded by the UGT1A1 gene. The presence of seven TA repeats (UGT1A1*28 allele) in the promoter region of this gene reduces enzymatic activity (Bosma et al, 1995) and patients homozygous for this variant have a higher risk of irinotecan-induced toxicity (Innocenti et al, 2004;Marcuello et al, 2004;Rouits et al, 2004;Riera et al, 2018). However, UGT1A1 genetic status does not always explain severe toxicity, suggesting that other mechanisms contribute to the appearance of side effects.…”

The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?

“…CYP3A4 and CYP3A5 are responsible for the oxidation of irinotecan into the inactive metabolites APC, M4 and NPC. Some researchers have studied the possible association of polymorphisms on these genes and chemo-related toxicity but have not found any positive correlation [ 68 , 96 , 112 ], probably because over 80% of variants in CYP genes coding regions are very rare and the sample sizes of these studies were not large enough [ 113 ]. It has also been suggested that their enzymatic function might be altered by non-genetic factors such as diet, concomitant medications, altered liver function or patient’s performance status [ 114 ].…”

Genetics and Adverse Events with Irinotecan Treatment: What do we Know?

“…Even though the risk of severe irinotecan-related toxicity can be significantly decreased if the initial dose in UGT1A1*28 homozygous patients is reduced, not all toxicity can be prevented with this strategy. Factors such as other UGT1A1 variants can also influence UGT1A1 enzyme activity [15]. In the Asian population, where the UGT1A1*28 allele frequency is less than 0.16, a more common variant, UGT1A1*6, can predict irinotecan-induced toxicities better than the UGT1A1*28 polymorphism [16].…”