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Fluoropyrimidine- and irinotecan-induced toxicity profile associated with mutations in DPYD and UGT1A1 genes
Background
Fluoropyrimidines are a mainstay in the treatment of gastrointestinal tumours (GIT), although they can sometimes produce severe toxicity, usually related to partial or total deficiency of the dihydropyrimidine dehydrogenase enzyme (DPD), so it is recommended to test genotype of DPYD gene before administration. Irinotecan is another drug used in the treatment of GIT whose mechanism of action is the inhibition of DNA topoisomerase by the cytotoxic metabolite SN-38. It is inactivated by the uridine-diphosphoglucuronosyltransferase1A1 enzyme, encoded from UGT1A1 gene. Congenital variants of UGT1A1 gene are associated with reduced activity of the enzyme and increased risk of toxicity. Objectives: to analyse the toxicity profile in patients with GIT treated with fluoropyrimidines and/or irinotecan and its correlation with DPYD/UGT1A1 genotyping, as well as the usefulness of its determination prior to the start of treatment.
Methods
Descriptive and retrospective study of DPYD and UGT1A1 genes mutational status in patients (p) with GIT prior to the beginning of chemotherapy treatment and after the appearance of adverse effects in the University Hospital of Salamanca from January-2018 to February-2022. Extraction and analysis of DNA from peripheral blood and PCR study of DPYD gene [rs3918290(c.1905+1G>A,IVS14+1G>A), rs55886062(c.1679T>G,I560S), rs56038477(c.1236G>A,E412E), rs67376798(c.2846A>T,D949V)] and UGT1A1 gene (c.-55_54insAT(rs8175347,allele*28).
Results
DPYD genotyping 74 patients (p), age (median): 68 years [42-88], males:41%. Tumour distribution: colorectal: 57p, stomach: 7p, cholangiocarcinoma: 3p, pancreas: 3p, oesophagus: 2p and small bowel: 2p. Stage IV at diagnosis: 37.8%. Most used treatment regimen: CAPOX (45.9%) followed by capecitabine (6.8%). Determination of DPYD gene: prior to the start of treatment: 81% (3 pathogenic variants (PV); 1 heterozygosis *2A/A2846T and 2 heterozygosis *1/G1236A, with the use of an alternative chemotherapy scheme in one and a 50% dose reduction in the others). After the presence of toxicity (gastrointestinal grade 4): 19% (2 VP; 1 homozygous *2A IVS14+1A and 1 heterozygous *1/G1236A, with admission of both, one finally died). In patients without mutations, 69 p, there was gastrointestinal toxicity in 17; grade 3-4 in 8p. In 9p; treatment discontinuation and one death. UGT1A1 genotyping 15p, age (median): 81 years [60-85], males:93%. Distribution by tumours: colorectal: 11p, cholangiocarcinoma: 2p, stomach: 1p, pancreas: 1p. Most used regimen: FOLFIRI (46.7%). Determination of UGT1A1 gene: prior to the beginning of treatment: 8p (53%) [4 VP: 2 homozygous *28/28 and 2 heterozygous *1/28 with use of an alternative chemotherapy scheme in 2p] and after the presence of toxicity (grade 4 pancytopenia, grade 3 diarrhea): 7p (47%) [5 VP: 1 homozygous A(TA)7TAA, 1 heterozygous (TA)6/(TA)7 and 3 heterozygous *1/28, with hospital admission of 3p]. In patients without mutations (6p), gastrointestinal toxicity in 3p with dose adjustment in 2p.
Conclusions
Fluoropyrimidines and irinotecan could cause severe toxicity, especially related to deficiency of DPD enzyme activity or genetic alterations of UGT1A1, respectively. Therefore, their prior determination could avoid toxicity in these patients. However, not all cases of severe toxicity are predictable by genotyping the recommended variants. Further investigation of other genes and DPYD and UGT1A1 variants is needed to determine other factors influencing treatment toxicity.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
