Association Of Methylenetetrahy Drofolate Reductase Gene Polymorphisms With Efficacy And Toxicity In Advanced Non-small Lung Cancer Patients Treated With Platinum-based Chemotherapy

Non-small cell lung cancer (NSCLC), a majority present with Ⅲ or Ⅳ stage, accounts for 80% approximately of lung cancer which is the leading cause of cancer death worldwide and the most dangerous malignant tumor in our Country. Platinum-based chemotherapeutic agents are first-line regimens widely used in stage Ⅲ-Ⅳ NSCLC patients based on a favorable efficacy and longer survival. However, platinum-based treatment for NSCLC is associated with variable side effects as well as potential for efficacy between individuals, which may cause distressing symptoms and prevent further therapies.Gene polymorphism may affect the enzyme activity, which plays critical roles in drug metabolism, and thus may be associated with individual difference of drug metabolism. Methylenetetrahydrofolate reductase (MTHFR) enzyme involves in Folate-associated one-carbon metabolism (FOCM), which comprises a complex cycle of biological reactions providing one-carbon groups needed for numerous intracellular processes including DNA methylation and synthesis. Many studies showed that MTHFR gene polymorphisms might influence the enzyme activity, and thus might relate to individual variability of chemotherapy outcomes.In this study, we assume that MTHFR genetic variants may affect individual efficacy and severe toxicity to chemotherapy of NSCLC patients. We selected 10 single nucleotide polymorphisms (SNPs) from MTHFR gene, and investigated the association of genetic variants with treatment outcomes (containing response, clinical benefit, survival, and severe toxicity) in 1004 stage Ⅲ-Ⅳ NSCLC patients receiving first-line, platinum-based Chemotherapy regimens.Polymorphism of rs1537514 showed the most significant effect:heterozygote associated with better clinical benefit (OR=2.30, P=0.002) and decreased risk of grade 3 or 4 gastrointestinal toxicity (OR=0.40, P=0.027), while the mutant homozygote associated with increased risk of severe gastrointestinal toxicity (OR=5.09, P=0.031) and thrombocytopenia (OR=9.34, P=0.009), when compared to wide homozygote. The heterozygotes of common reported exon polymorphisms (rs1801131, rs1801133) also performed better clinical benefit (OR=1.52, P=0.030 for rs1801131), decreased risk of severe gastrointestinal toxicity (OR=0.40, P=0.004 for rs 1801131), or thrombocytopenia (OR=0.40, P=0.016 for 1801133). However, no significant association was observed between MTHFR polymorphisms and overall survival (OS) as well as progression-free survival (PFS), except for heterozygote of rsl537514 showing marginal effects with longer PFS time (OR=0.77, P=0.025). Clinical factors were important for the OS (age, gender, and smoking status) and PFS (performance status and chemotherapy regimens).Our results indicated that a heterozygous advantage may exist in certain MTHFR variants, and the polymorphisms (especially rs1537514) may play a predictive role of treatment efficacy and adverse effects in NSCLC patients treated with platinum-based chemotherapy. It can help patients select the most optimal regimen, thus being of significant benefit for NSCLC individualized treatment in the future.