Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in
Silvia Cantara1,2, Cristina Dalmiglio1, Carlotta Marzocchi1
1Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy.
Abstract:
Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (CYP3A4 rs2242480 and rs2687116 and CYP3A5 rs776746) genes and to ATP-binding cassette transporters (ABCB1 rs1045642, rs2032582 and rs2235048 and ABCG2 rs2231142). Our results suggest that the GG genotype for rs2242480 in CYP3A4 and CC genotype in rs776746 for CYP3A5 were both associated with the presence of hypertension. Being heterozygous for SNPs in the ABCB1 gene (rs1045642 and 2235048) implicated a higher grade of weight loss. The ABCG2 rs2231142 statistically correlated with a higher extent of mucositis and xerostomia (CC genotype). Heterozygous and rare homozygous genotypes for rs2242480 in CYP3A4 and for rs776746 for CYP3A5 were found to be statistically linked to a worse outcome. Evaluating the genetic profile before starting lenvatinib treatment may help to predict the occurrence and grade of some side effects, and may contribute to improving patient management.
Insights
Pharmacogenetics can predict lenvatinib side effects in advanced thyroid cancer. Specific gene variants in CYP3A4, CYP3A5, ABCB1, and ABCG2 correlate with hypertension, weight loss, and mucositis, aiding patient management.
Area of Science:
- Pharmacogenomics
- Oncology
- Drug Metabolism
Background:
- Multi-kinase inhibitors (MKIs) are a primary treatment for advanced thyroid cancer.
- Treatment efficacy and toxicity vary significantly among patients and are hard to predict.
- Severe adverse events often necessitate treatment interruption.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in drug-metabolizing enzymes and transporters and lenvatinib-induced adverse events in advanced thyroid cancer patients.
- To explore the potential of a pharmacogenetic approach for predicting lenvatinib toxicity.
Main Methods:
- A pharmacogenetic study involving 18 advanced thyroid cancer patients treated with lenvatinib.
- Analysis of single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes.
- Correlation of genetic variants with specific adverse events including gastrointestinal issues, mucositis, hypertension, asthenia, and hand-foot syndrome.
Main Results:
- Specific genotypes (CYP3A4 rs2242480 GG, CYP3A5 rs776746 CC) were linked to hypertension.
- ABCB1 gene heterozygosity (rs1045642, rs2235048) correlated with increased weight loss.
- ABCG2 rs2231142 CC genotype was associated with higher incidence of mucositis and xerostomia.
- Certain genotypes in CYP3A4 and CYP3A5 were linked to worse treatment outcomes.
Conclusions:
- Genetic profiling prior to lenvatinib treatment may help predict the occurrence and severity of certain side effects.
- Pharmacogenetic evaluation could improve patient management strategies for advanced thyroid cancer.
- Personalized medicine approaches using genetic markers show promise in optimizing MKI therapy.
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