Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in Patients with Advanced Thyroid Cancer

Int J Mol Sci. 2023 Mar 13;24(6):5496. doi: 10.3390/ijms24065496.

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.

Keywords: ATP-binding cassette transporters; SNPs; cytochrome P450; lenvatinib; multi-kinase inhibitors; thyroid cancer.

MeSH terms

  • Antineoplastic Agents* / adverse effects
  • Cytochrome P-450 CYP3A / genetics
  • Drug-Related Side Effects and Adverse Reactions* / drug therapy
  • Genotype
  • Humans
  • Hypertension* / drug therapy
  • Iatrogenic Disease
  • Pilot Projects
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / adverse effects
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics

Substances

  • Cytochrome P-450 CYP3A
  • lenvatinib
  • Antineoplastic Agents
  • Protein Kinase Inhibitors