Effects Of Expression Of RRM1 And ERCC1 On Chemotherapy Response And Prognosis Of Advanced NSCLC Patients Treated By Cisplatin Combined With Gemcitabine Chemotherapy

[Background and objective]Lung cancer is the most lethal malignancy worldwide. According to statistics, more than 85% of lung cancer is non-small cell lung cancer(NSCLC). Newly diagnosed each year in the United States in NSCLC,75% of patients have lost the chance of operation. The advent of third generation chemotherapy improves the efficacy of NSCLC, but it is still not satisfactory. The overall 5-year survival rate of NSCLC patients is below 15%. For advanced NSCLC, the effective rate of first-line chemotherapy (gemcitabine/cisplatin, docetaxel/ cisplatin, paclitaxel/cisplatin, paclitaxel/carboplatin) is only from 20% to 40%, and the overall median survival time is only 7.9 months. A significant proportion of patients receive an invalid chemotherapy, and have to bear the side effects of chemotherapy. The current studies show that the clinical and pathological characteristics can not explain the different effects of chemotherapy between individuals. The main factor that affects the effect of chemotherapy is pharmacogenomics.In DNA synthesis and repair, the ribonucleotide reductase (RR) restores the 5 'ribonucleotide diphosphate to the 5'nucleotide diphosphate deoxyribose. The ribonucleotide reductase consists of two subunits, which are named M1 (RRM1) and M2 (RRM2). Basic researchs show that RRM1 is the only composition in ribonucleotide reductase that can influence the effect of gemcitabine. RRM1 is involved in tumor growth, invasion and metastasis. Overexpression of RRM1 can remove gemcitabine, so its overexpression is associated with drug resistance.The nucleotide excision repair is the most important DNA repair pathway. The excision repair cross complementation 1(ERCC1) participates in the repair of DNA damage caused by platinum, and can maintain the integrity and stability.Also, it can clear and correct replication errors. ERCC1 plays an important role in avoiding harmful mutations and carcinogenesis. Recent studies have found that the overexpression of ERCC1 protein is associated with the pathogenesis, biology, drug resistance and prognosis of many tumors.This study determined the expression of RRM1 and ERCC1 of pathological tissues in advanced(ⅢB～Ⅳ) NSCLC patients by immunohistochemistry, discussed the relationships with clinicopathological features, chemotherapy efficacy and survival time, and expected to provide a theoretical basis to clincal medicine.[Research methods]This study randomly selected 47 cases of NSCLC patients who have received gemcitabine and cisplatin (GP) regimen in Provincial Hospital Affiliated to Shandong University from December 2006 to October 2009. The study determined the expression of RRM1 and ERCC1 of paraffin-embedded tissue sections in 47 patients. Firstly, to analysis the relationships between the expression of RRM1 and ERCC1 and the clinical and pathological characteristics such as gender, age, PS, histopathological type, TNM stage and smoking. Secondly, to analysis the relationships between the expression of RRM1 and ERCC1 and efficacy of GP regimen. Thirdly, to analysis the associations between the expression of RRM1 and ERCC1 and the survival time. Fourthly, to analysis the independent risk factors that can influence the survival time.[Results]The RRM1 and ERCC1 positive staining accounted for 46.81%%(22/47) and 42.55%(20/47) in 47 patients.There was no correlation between RRM1 and ERCC1 expression and gender, age, PS, pathological type, TNM stage and smoking. The response rate was 36.17%(17/47). The response rates of patients with high and low RRM1 expression were 18.18%(4/22) and 52.00%(13/25) (P=0.016). The response rates of patients with high and low ERCC1 expression were 20.00%(4/20) and 48.15%(13/27) (P=0.047). Low expression of RRM1 or ERCC1 was correlated with the longer median overall survival (14.1months and 14.1months),and the median overall survival times of high expression of RRM1 or ERCC1 protein were 6.8months and 7.1months(P=0.008,0.017) by Kaplan-Meier survival analysis.The patients with low expression of RRM1 and ERCC1 had longer median overall survival time(14.8 months) than those with high expression of RRM1 and/or ERCC1(7.6months)(P=0.012).COX regression analysis revealed that TNM stage was an independent prognostic factor.[Conclusions]The expressions of RRM1 and ERCC1 have negative corrections with the chemotherapy response of cisplatin combined with gemcitabine (GP) and prognosis.The advanced NSCLC patients with low expression of RRM1 or ERCC1 get more probablely benefits from cisplatin combine gemcitabine chemotherapy. The levels of the expression of RRM1 and ERCC1 may be one of indicators to predict the efficacy of GP regimen and the survival time in NSCLC patients who received GP regimen.