Relationship Between Cytochrome P450Gene Polymorphisms And Sensitivity To DP Regimen Chemotherapy In â…£-stage Non Small Cell Lung Cancer

BackgroundLung cancer is the most frequent reason which caused cancer related death.Depending on biological behavior, lung cancer is divided into small cell lung cancer(SCLC) and non small cell lung caner (NSCLC).80%of total lung cancer patients areNSCLC patients. And most patients are in advanced stage usually when diagnosedwithout any chance for radical operation. Up to now, chemotherapy is stll maintherapeutic way for Ⅲ B/Ⅳ stage NSCLC cases. However, the chemotherapeuticsensitivities are obviously different among advanced NSCLC patients. CytochromeP450is a heme-containing superfamily. It is a terminal oxidative enzyme of mixedfunctional oxidative enzyme system on endoplasmic reticulum and is widely distributedamong human tissues and organs. It involves in biotransformation of internal materials,and activation and degradation of external materials. Research in pharmacologicalgenetics shows that polymorphisms can lead to diverse capacities in drug metabolismand influence chemotherapeutic sensitivities. In this study, we detected genepolymorphism of CYP450to observe differences between such differences in gene andthe curative effect of antitumor drug for guiding the clinical treatment which is of greatsignificance, providing methods for the future study of individual chemotherapyprogram. ObjectiveOur study conducted a study to investigate the relationship between polymorphismof CYP1B1*3、CYP3A4*18B and CYP3A5*3and chemotherapeutic sensitivity tofirst-line chemotherapy in IV-stage NSCLC patients.MethodsIn the study, we included109patients with IV-stage NSCLC who conformed bythe pathlogy or cytology of Shandong Provincial Tumor Hospital from Augest2011toJuly2012.All patients were selected DP regimen chemotherapy (docetaxel70mg/m2,ivdrip, d1、8; cisplatin25mg/m2, ivdrip, d1-3；repeated every21days) as the first-linechemotherapy. After2cycles of chemotherapy, response was evaluated in accordancewith the WHO criteria. Patients were classified into two groups based on treatmentresponse as responder (complete response+partial response) or non-responder (stabledisease+progressive disease).We conducted a study to detected the genotype of thesepolymorphisms by pyrosequencing in109patients with IV-stage NSCLC.And thenanalyzed the relationship between genotype and response chemotherapy. All statisticaltesting was conducted at the0.05level and SPSS software (version17.0) was used forstatistical analysis.2tests was used to analyse whether objective response rate tofirst-line chemotherapy in IV-stage NSCLC patients with various genotypes ofCYP1B1、CYP3A4and CYP3A5was statistically different.Results1.Among109IV-stage NSCLC patients, frequency distribution of the CYP1B1*3gene C/C, C/G and G/G genotypes were70.6%(77/109),23.9%(26/109) and5.5%(6/109); frequency distribution of CYP3A4*18B gene T/T, C/T and C/C genotypeswere8.3%(9/109),27.5%(30/109) and63.3%(69/109); frequency distribution ofCYP3A5*3gene A/A, A/G and G/G genotypes were6.4%(7/109),26.6%(29/109) and60.0%(73/109). They were all consistent with Hardy-Weinberg law which had good representation.2Among109cases of advanced NSCLC with DP regimen, CR9(8.3%), PR36(33%), SD59(54.1%), PD5(4.6%), RR(response rate)was41.3%(45/109).3. Objective effective rate of male(36.7%,22/60) and female(46.9%,23/49),patients with DP chemotherapy was different, but the difference wasn’t statisticallysignificant (χ2=1.174, P=0.279).Age and objective effective rate of chemotherapy hadno significant correlation (t=-1.474, P=0.144).Effective rate of patients with PS0~1(41.4%,36/87) and PS2(40.9%,9/22) was different, but the difference wasn’tstatistically significant (χ2=0.002, P=0.968).Patients’ objective response rate inadenocarcinoma, squamous cell carcinoma and other pathological was68.9%(31/82),20%(9/21) and11.1%(5/6), but there was no significant difference (χ2=4.807,P=0.094.4、 Response rates in C/C, C/G and G/G genotype of CYP1B1*3were49.4%(38/77)、23.1%(6/26) and16.7%（1/6）.There was statistical difference inresponse rate between the three genotypes （P=0.028，95%CI：0.022~0.028）. C/Cgenotype of CYP1B1had higher response rate.5. Response rates in T/T、T/C和C/C genotype of CY3A4*18B were12.5%（1/8）、48.4%(15/31) and42.0%(29/69).There was no statistical difference in responserate between the three genotypes （P=0.133，95%CI：0.135~0.149）esponse rates inA/A、A/G and G/Ggenotype of CY3A5*3were16.7%（1/6）、44.8%(13/16)和42.5%(31/73). There was no statistical difference in response rate between the threegenotypes（P=0.317，95%CI：0.345~0.363）.Conclusions1. DP chemotherapy for IV-stage patients of NSCLC, there is no statisticaldifference between clinical characteristics including gender, age, PS, pathologicaltypes and response rate DP chemotherapy； 2. C/C, C/G and G/G genotype of CYP1B1gene had different efficiency, responserate of patients carrying C/C genotype was higher than those with C/G and G/Ggenotype；3. T/T, T/C and C/C genotypes of CYP3A4*18B had no statistical difference inresponse rate；A/A, A/G and G/G genotypes of CY3A5*3gene had no statisticaldifference，too；4. From this study, we concluded that CYP450gene polymorphism has associationto DP regimen chemotherapy for advanced non small cell lung cancer patients.But asthe sample size is small, we need research of larger samples to reveal individualdifferences in CYP450gene polymorphism and chemosensitivity in a certain extent.