於接受Cisplatin或Carboplatin治療之肺癌病人 運用基因及非基因因子進行療效及血液毒性之多元分析

Multiple Analytical Approaches Demonstrate a Complex Relationship of Genetic and Non-Genetic Factors with Response and Hematological Toxicity to Cisplatin- or Carboplatin-Based Chemotherapy in Lung Cancer Patients

劉世傑(Shih-Chieh Liu)

指導教授 ： 劉興璟

共同指導教授 ： 陳香吟

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

摘要

根據行政院衛生署至民國九十七年之統計，肺癌已成為台灣癌症十大死因之首1。而於肺癌病人之治療藥物中，cisplatin與carboplatin為非小細胞肺癌之第一線治療藥物，但其治療反應率(response rate)僅約40%，而年存活率(one-year survival約為30%-40%2,3。同時，cisplatin與carboplatin會引起相關副作用之產生，如骨髓抑制毒性、噁心嘔吐、或神經毒性等。因此，如何增進病人療效與避免相關副作用之產生已為重要之課題。
本研究為回溯性研究，收錄116位使用cisplatin與carboplatin治療之肺癌病人。同時檢測其7種基因中的11項基因多型性，包含GSTP1 A313G、P53 G215C、UGT1A7 T387G、UGT1A7 T622C、NAT2 T481C、NAT2 G590A、NAT2 G857A、ERCC1 C118T、ERCC1 C8092A、ERCC4 T2247C與NQO1 C609T，並收集病人相關臨床數據，利用邏輯回歸與多因子降維法分析基因多型性與cisplatin及carboplatin治療之療效及血液毒性之關聯性。同時建立預測模型，藉以預測病人之療效與血液毒性之發生。
於療效分析中，UGT1A7低活性之基因型顯示具有較好之療效反應[OR=0.160 (0.027-0.952)，P=0.044]。而於多因子降維法之分析中，UGT1A7, NAT2, NQO1 C609T與ERCC1 C118T為預測療效之最佳組合，評分量表ROC curve (Receiver Operating Characteristic curve) 之AUC (Area Under the Curve) 值為0.764。於血液毒性之分析中，NQO1 C609T CT之基因型產生較少血液毒性[OR=0.213 (0.053-0.848)，P=0.028]。藉由多因子降維法推測NQO1 C609T, UGT1A7 與 ERCC1 C8092A為預測血液毒性之最佳組合。評分量表ROC curve之AUC值為0.656。
由結果推測UGT1A7與NQO1 C609T分別對於cisplatin 或carboplatin治療之療效及血液毒性具有影響。而於療效及血液毒性之預測模型中均顯示，僅考量單一因子預測力不高，須同時考量基因因子與非基因因子才會使預測率更加準確。

關鍵字

鉑類藥物 ； 基因多型性 ； 療效 ； 血液毒性

並列摘要

Introduction
Lung cancer is the leading cause of cancer-related death in Taiwan1. Patients with lung cancer are mostly treated with cisplatin- or carboplatin-based chemotherapy. However, the development of chemoresistance and the adverse toxicities, which might be affected by genetic polymorphisms or other non-genetic factors, has become the limitations in the treatments4,5. Therefore, the purpose of this study is to evaluate and to build a predictive model of the genetic polymorphisms that may impact treatment outcome of cisplatin- or carboplatin-based chemotherapy in lung cancer patients.
Patients and Methods
In this retrospective study, 116 lung cancer patients who received cisplatin or carboplatin chemotherapy in Wanfang hospital from 2005 to March, 2011 were genotyped for 11 polymorphisms in 7 genes (GSTP1 A313G, P53 G215C, UGT1A7 T387G, UGT1A7 T622C, NAT2 T481C, NAT2 G590A, NAT2 G857A, ERCC1 C118T, ERCC1 C8092A, ERCC4 T2247C and NQO1 C609T). The clinical response and the hematological adverse events were collected to evaluate the association between genetic polymorphisms and the clinical outcomes. Meanwhile, the scoring system and MDR (Multifactor Dimensionality Reduction) were used to evaluate the complex interaction between genetic and nongenetic factors.
Results
In the response analysis, the low activity homozygous UGT1A7 polymorphisms showed a better response rate (35%) compared to the wild type [13%; OR=0.160 (0.027-0.952),P=0.044]. Combining UGT1A7, NAT2, NQO1 C609T and ERCC1 C118T was the best to predict the response. The AUC (Area Under the Curve) of ROC curve (Receiver Operating Characteristic curve) was 0.764 in the risk score model. In the hematological toxicity analysis, the heterozygote of NQO1 C609T with less toxicity compared to the wild type [64% and 84%, respectively, OR=0.213 (0.053-0.848), P=0.028]. NQO1 C609T, UGT1A7 and ERCC1 C8092A showed as the best combination to predict the hematological toxicity. The AUC of ROC curve was 0.656 in the risk score model.
Conclusion
The results show that the UGT1A7 and NQO1 C609T polymorphisms might affect the response and the hematological toxicity of cisplatin or carboplatin-based chemotherapy. Considering both genetic and non-genetic factors can provide the better predictive ability in the risk score model.

並列關鍵字

platinum drugs ； polymorphism ； response ； hematological toxicity

參考文獻

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