AUTHOR=Majam Teerapat , Sukasem Chonlaphat , Reungwetwattana Thanyanan , Chansriwong Phichai , Atasilp Chalirmporn , Trachu Narumol , Thamrongjirapat Thanaporn , Sukprasong Rattanaporn , Meanwatthana Jennis 

TITLE=CYP450 and drug efflux transporters polymorphism influence clinical outcomes of Thai osimertinib-treated non-small cell lung cancer patients

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1222435

DOI=10.3389/fphar.2023.1222435

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring <italic>epidermal growth factor receptor</italic> (<italic>EGFR</italic>) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient’s ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (<italic>CYP450</italic>) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients.</p><p><bold>Methods:</bold> This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher’s exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test.</p><p><bold>Results:</bold> We identified six SNPs (rs2231142 and rs2622604 in <italic>ABCG2</italic>, rs762551 in <italic>CYP1A2</italic>, rs1057910 in <italic>CYP2C9</italic>, rs28371759 in <italic>CYP3A4</italic>, and <italic>CYP2A6</italic> deletion polymorphism (<italic>CYP2A6</italic>*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in <italic>CYP1A2</italic> and rs1057910 in <italic>CYP2C9</italic>) that significantly decreased the median TTF, and two SNPs (rs28399433 in <italic>CYP2A6</italic> and rs1057910 in <italic>CYP2C9</italic>) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in <italic>CYP2C9</italic>) influenced ADRs, TTF, and PFS. Additionally, SNPs in the <italic>CYP2A6</italic> heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%).</p><p><bold>Conclusion:</bold> Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The <italic>CYP2C9</italic> (*3) and <italic>CYP2A6</italic> (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.</p>