Abstract
BackgroundErlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. An increasing number of evidences show that the treatment efficacy and toxicities are considerably heterogeneous among individuals. Hence, it is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients.MethodsOur present study enrolled 87 cases of NSCLC patients who had been administrated erlotinib with a fixed dose (150 mg/d). Eleven polymorphisms in seven genes of drug-metabolizing enzymes and transporters were genotyped and the steady state trough concentrations were also determined.ResultsThere were significant variances in the steady-state erlotinib trough plasma concentrations, ranging from 315.6 ng/ml to 4479.83 ng/ml. Erlotinib steady state trough concentration was remarkably lower in current smoking patients. The steady state trough concentration of GG in rs1048943 of CYP1A1 was significantly higher than that of AA allele carriers. The polymorphism of CYP1A2 was significantly associated with the severity of skin rash, and the development of diarrhea was associated with SNPs in ABCB1 and CYP3A5. We also observed that GG allele in CYP1A1 was accompanied with a longer PFS in our study.ConclusionA large variability of erlotinib steady state trough concentration was found among Chinese Han population. SNPs in CYP1A1 appeared to influence the steady state trough concentration of erlotinib. Correlation between CYP1A2 polymorphisms and severity of skin rash was observed, together with the correlation between the development of diarrhea and SNPs in ABCB1 and CYP3A5.
Highlights
Non-small cell lung cancer (NSCLC) is a very common carcinoma, accounting for 80%–85% of lung cancer cases, and the leading cause of cancer-related deaths worldwide. (Maemondo et al, 2010; Novello et al, 2016)
We found that the steady state trough level of erlotinib was significantly increased with this SNP mutation, and previous studies have reported that progression free survival (PFS) are positively related with trough concentration in NSCLC patients
Our results demonstrated that a large variability of erlotinib steady state trough concentration exists in NSCLC patients
Summary
Non-small cell lung cancer (NSCLC) is a very common carcinoma, accounting for 80%–85% of lung cancer cases, and the leading cause of cancer-related deaths worldwide. (Maemondo et al, 2010; Novello et al, 2016). Numerous studies have showed that aberrant epidermal growth factor receptor (EGFR) pathway is a driving gene of NSCLC cancerogenesis, playing a considerable role in the process of malignancies, such as cell proliferation, differentiation and migration (Doerks et al, 2002; Bardelli et al, 2003). Erlotinib is an orally administered, reversible TKI indicated as first-line treatment for advanced NSCLC in patients with activating EGFR mutations and as second- and third-line treatment in patients with EGFR wild-type NSCLC (Timmers et al, 2015). Compared with standard platinum doublet therapy, erlotinib showed dramatically improved the long-term survival rate and clinical response of EGFR sensitive mutation NSCLC. Erlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. It is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients
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