利用藥物作用與病因途徑中之基因多型性預測肺癌病人接受鉑類藥物治療之療效與血液毒性

Genetic Polymorphisms in Drug Action and Disease Etiology Pathways to Predict Therapeutic Response and Hematologic Toxicity of Platinum-based Chemotherapy in Lung Cancer Patients

劉世清(Shih-Ching Liu)

指導教授 ： 陳香吟

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

肺癌目前為台灣癌症死因之首，而肺癌之第一線化學治療藥物為cisplatin與carboplatin，但其使用常因病人的癌細胞產生抗藥性或是藥物對正常細胞產生嚴重毒性而受限制，目前研究顯示藥作作用途逕及病因途徑中之基因多型性，可能與鉑類藥物產生抗藥性與毒性具有關聯性，但這些關聯性仍不明確。
在此回溯性研究中，將研究115位使用cisplatin或carboplatin治療之肺癌病人21項與藥物作用或病因途徑相關之基因多型性，包含與運輸蛋白有關之SLC47A1 （MATE1）-66T>C、SLC47A1G>A、SLC22A2（OCT2） G808T、ABCB1 C3435T、ABCC2 -24C>T；DNA修復之XPG His1104Asp、XPA A23G、XPD Arg156Arg、OGG1 Ser326Cys、APEX Asp148Glu、ERCC1 C118T、ERCC1 C8092A、ERCC4 T2505C；藥物代謝解毒相關之GSTP1 A313G、UGT1A7 T387G、UGT1A7 T622C、NAT2 T481C、NAT2 G590A、NAT2 G857A,、NQO1 C609T；細胞凋亡之p53 Arg72Prp，並收集病人相關臨床檢驗數據，使用Response evaluation criteria in solid tumors （RECIST）之療效定義及National cancer institute common terminology criteria for adverse events之血液毒性定義進行分析。分析方法使用邏輯回歸、分類與迴歸樹及多因子降維法分析基因多型性與療效及血液毒性之關聯性，並建立預測模型。
在療效分析中，XPD Arg156Arg 為變異型之病人療效較差（OR=0.20，95% CI= 0.04-1.00，p=0.05）；XPG His1104Asp中則是帶有His之病人療效較差（OR=0.26，95% CI = 0.09-0.75，p=0.01）。在多因子交互作用及預測模型建立中，則發現由XPG 156、XPG 1104、ERCC4、UGT1A7、GSTP1可建立較佳之預測模型，ROC（receiver operating characteristic curve）之曲線下面積為0.802。
在血液毒性分析中，XPD Arg156Arg變異之病人發生血液毒性機率較低（OR=0.21，95% CI = 0.05-0.86，p=0.03）；OGG1 Ser326Cys中則是發現Cys/Cys之病人發生血液毒性機率較低（OR=0.19，95% CI = 0.04-0.81，p=0.03）；在藥物運輸之ABCB1 C3435T中則發現病人為變異型時發生血液毒性機率較高（OR=5.23， 95% CI = 1.79-15.27，p<0.01）。在多因子交互作用及預測模型建立中，則發現由XPG 156、ERCC1 C8092A、OGG1 Ser326Cys、ABCB1C3435T可建立較佳之預測模型，ROC之曲線下面積為0.742。
本研究結果顯示XPD Arg156Arg、XPG His1104Asp、ERCC4 T2505C及UG1A7、GSTP1 A313G基因多型性可用來預測肺癌病人鉑類藥物治療之療效；XPD Arg156Arg、OGG1 Ser326Cys、ABCB1 C3435T及ERCC1 C8092A基因多型性可用來預測肺癌病人使用鉑類藥物治療產生之三級以上血液毒性，但未來仍需更多研究驗證本研究之結果。

關鍵字

基因多型性 ； 鉑類藥物 ； 療效 ； 血液毒性

並列摘要

Lung cancer is the leading cause of cancer-related death in Taiwan. The use of platinum-based drug, the most widely used cytotoxic agents for lung cancer, is limited by the acquired resistance and severe toxicity. It has been shown that genetic polymorphisms in drug action and disease etiology pathways are closely related to the development of resistance and toxicity; however, the detail relationship is still inclusive.
In this retrospective study, we investigated several SNPs which are responsible for drug influx and efflux (SLC47A1 -66T>C, SLC47A1G>A, SLC22A2 G808T, ABCB1 C3435T, ABCC2 -24C>T), DNA damage repair (XPG His1104Asp, XPA A23G, XPD Arg156Arg, ERCC1 C118T, ERCC1 C8092A, ERCC4 T2505C, OGG1 Ser326Cys, APEX Asp148Glu), cell apoptosis (p53 Arg72Pro), metabolism and detoxification(GSTP1 A313G, UGT1A7 T387G, UGT1A7 T622C, NAT2 T481C, NAT2 G590A, NAT2 G857A, NQO1 C609T) in 115 lung cancer patient treated with platinum-based chemotherapy. Two clinical outcomes, response and grade 3 or 4 hematologic toxicity, were collected to evaluate the association with genetic polymorphisms. Classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were used to analyze the interaction between genetic factors and nongenetic factors among these polymorphisms.We evaluated the association and interaction between these SNPs and drug response/toxicity of platinum-based chemotherapy and to establish a prediction model.
In response analysis, XPD 156 TT type showed a worse response compared to wild type GG [odds ratios (OR) = 0.20, 95% confidence interval, (CI) =0.04-1.00; p=0.05]. XPG 1104 Asp/Asp and Asp/His showed worse response compared to His/His type (OR=0.26, 95% CI = 0.09-0.75; p=0.01). Based on the results of multivariate logistic regression, CART and MDR analysis, the best mode was established with the following factors: XPD, XPG, ERCC and, UGT1A7. In this model, the AUC of the ROC was 0.802.
In hematologic toxicity analysis, XPD GT and TT showed a lower risk in grade 3 or 4 hematologic toxicity compared to GG (OR = 0.21, 95% CI = 0.05-0.86; p=0.03). OGG1 Cys/Cys showed a lower risk compared to Ser/Ser (OR = 0.19, 95% CI = 0.04-0.81; p=0.03). ABCB1 TT and TC significantly increased the risk of hematologic toxicity compared to wild type (OR = 5.23, 95% CI = 1.79-15.27; p<0.01). Based on the results of multivariate logistic regression, CART and MDR analysis, the best model was established with the following factors: XPD, OGG1, ABCB1, ERCC18092. The AUC of ROC in this model was 0.742.
Our findings suggested that XPD Arg156Arg, XPG His1104Asp, ERCC4 T2505C and UGT1A7, GSTP1 A313G polymorphisms can be used to predict treatment response of cisplatin- or carboplatin- based chemotherapy. XPD Arg156Arg, OGG Ser326Cys, ABCB1 C3435T and, ERCC1 C8092A polymorphisms can be used to predict platinum-induced grade 3 or 4 hematologic toxicity in lung cancer patients in Taiwan. More studies are required to comfirm this conclusion.

並列關鍵字

genetic polymorphism ； platinum drug ； response ； hematologic toxicity

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