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Characteristics and Clinical Implication of UGT1A1 Heterozygous Mutation in Tumor
Qian Li1, Tao Sun2, Hua Zhang3
1Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing 100191, China.
Background:
The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.
Methods:
A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization.
Results:
There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.
Conclusions:
In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.
Insights
Heterozygous UGT1A1*6 and UGT1A1*28 mutations increase the risk of CPT-11 related adverse events like vomiting and neutropenia in cancer patients. However, these genetic variations do not impact treatment efficacy or prognosis.
Area of Science:
- Pharmacogenomics
- Oncology
- Clinical Pharmacology
Background:
- Reduced CPT-11 dosage is recommended for UGT1A1 homozygous mutations.
- The impact of UGT1A1 heterozygous mutations on CPT-11 adverse reactions remains unclear.
Purpose of the Study:
- To investigate the association between UGT1A1 heterozygous mutations (UGT1A1*6, UGT1A1*28) and CPT-11-related adverse reactions.
- To evaluate the influence of these mutations on treatment efficacy and prognosis in cancer patients.
Main Methods:
- Retrospective analysis of 107 patients treated with CPT-11.
- Genotyping for UGT1A1*6 and UGT1A1*28 mutations using digital fluorescence molecular hybridization.
- Adverse reactions assessed by NCI-CTCAE 5.0 and efficacy by RECIST 1.1.
Main Results:
- UGT1A1*28 heterozygous mutations correlated with vomiting and mucositis.
- UGT1A1*6 heterozygous mutations correlated with vomiting severity and neutropenia.
- In colorectal cancer, UGT1A1*6 was linked to diarrhea; efficacy and prognosis were similar across genotypes.
Conclusions:
- UGT1A1*6 and UGT1A1*28 heterozygous mutations are associated with increased risk and severity of adverse reactions to CPT-11.
- Treatment outcomes and prognosis are not significantly affected by UGT1A1 genotype variations or CPT-11 dosage adjustments.
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