Association Of DNA Base-excision Repair Genes Polymorphisms With Outcome To Platinum-based Chemotherapy In Advanced Non-small Cell Lung Cancer Patients

BackgroundCurrently, platinum-based therapy is a standard treatment option for these outcomewhich chemotherapy response rate is about30%to40%, and5-year survival rate remainless than15%. Different individuals have different chemosensitivity of the tumor. Clinicalfactors, such as patient features (age, gender and performance status) and disease extension,roughly characterized by the stage, have been associated with therapeutic response, butgenetic factors are estimated to account with up tp95%of variability in drug efficacy andtoxicity. The anti-tumor activity of many chemotherapeutic agents is directly related totheir induce to DNA damage in cancer cells. The DNA base excision repair (BER) isessential for the repair of DNA damage induced by alklating agents and ionising rediation,all of which induce base damage. There is increasing evidence that genetic polymorphismin the base excison repair pathway may be related to therapeutic response, treatment relatedtoxicity, or prognostic. In part one we investigate the effects of different chemotherapyregimens and clinical factors on efficacy, prognosis and toxicity. Then in part two wediscuss whether the BER genes SNPs have potential roles as biomarkers in NSCLC, eitheras predictive factors or prognostic factors.Objective1. To compare the efficacy from5kinds of platinum-based chemotherapy regimens inthe first-line treatment of advanced non-small cell lung cancer (NSCLC)，and furtherexplore the possible ways to improve the patients prognosis.2. Analyze four putative functional SNPs (OGG1Ser326Cys, APE1Asp148Glu,APE1-141T/G, and XRCC1Arg399Gln) in235advanced inoperable NSCLC patients, afterthey were treated with platinum-based chemotherapy, for their association with clinicaloutcome. Materials and Methods1. Clinical data of352patients with stage III and IV NSCLC were identified whoreceived at least two cyle platinum-based chemotherapy were collected.2. PCR-CTTP (PCR with confronting two-pair primers) method was used to genotypethese four SNPs（OGG1Ser326Cys、APE1-141T/G、APE1Asp148Glu and XRCC1Arg399Gln）in235cases of patients with informed consent.3. SPSS19.0statistical software was used to statistical analysis.Results1. The median age of352advanced NSCLC patients is59years, and57.39%wereadenocarcinoma. The overall objective response rate was36.36%, disease control rate was69.03%. The median PFS was7months and median OS was13months.2. There was not difference in ORR and DCR between5kind different chemotherapyregimens (P＞0.05). However, in patients≥60years，the median progression freesurvival of TP regimen and PP regimen were5months and12months (P=0.007); while theoverall survival of TP regimen were shorter than DP regimen and LP regimen. In patientswith Squamous cell carcinoma, the median overall survival of TP regimen and LP regimenwere12months and27months (P=0.026). And in patients with adenocarcinoma, themedian progression free survival of TP regimen and PP regimen were5months and11months (P=0.029).3. The incidence of grade3~4hematologic and gastrointestinal toxicity were43.18%and14.49%. The incidence of severe hematological toxicity in TP regimen washigher than DP regimen and LP regimen (56.52%vs.35.57%，P=0.002；56.52%vs.31.25%，P=0.001; respectively).4. COX model regression analysis showed that ECOG PS, tumor stage, chemotherapycycles, objective response rate, disease control rate and second-line chemotherapy candisplay their independent prognostic significance (P<0.05).5. There was no statistically significant association between any of the four SNPs(OGG1Ser326Cys、APE1-141T/G、APE1Asp148Glu and XRCC1Arg399Gln） withresponses to chemotherapy.6. The multivariate analysis showed that OGG1326GC was associated with poorPFS (HR1.730, P=0.005), while XRCC1399GA, or GA+AA, was associated with poor OS in short-term period (HR1.718, P=0.003; HR1.691, P=0.003, respectively). Patients withOGG1326/XRCC1399variant alleles had a higher risk to die early in short-term period(HR1.929, P<0.001).7. Patients with XRCC1399variant allele (GA+AA) had higher risk of hematologictoxicity (P=0.009), whereas patients carrying the OGG1326variant (GG), or the APE1-141GG variant, had reduced risk of gastrointestinal toxicity (p=0.015and p=0.023,respectively).Conclusion1. There was no statistically significant in ORR, DCR, PFS, and OS between the fivechemotherapy regimens. Compared with docetaxel and paclitaxel liposome, the incidenceof grade3~4hematologic toxicity was significantly higher in patients received Platinum-Taxol regimens.2. The multivariate analysis indicated that ECOG PS, tumor stage, chemotherapycycles, objective response rate, disease control rate and second-line chemotherapy wereindependent prognostic factors.3. Patients with age≥60years were suggested to use the region of low toxicityincidence such as DP regimen, LP regimen and PP regimen. Patients with squamous cellcarcinoma were suggested to use LP regimen. And patients with adenocarcinoma weresuggested to use PP regimen.4. There was no significance between BER genes SNPs and objective response rate ofplatinum-based chemotherapy, but OGG1326GC was associated with poor PFS, whileXRCC1399GA, or GA+AA, was associated with poor OS in short-term period. Patientswith OGG1326/XRCC1399variant alleles had a higher risk to die early in short-termperiod.5. XRCC1399variant allele (A) increase the risk of hematologic toxicity. OGG1326and APE1-141homozygous variants decrease the risk of astrointestinal toxicity.