晚期非小細胞肺癌患者抗藥基因多型性與病患存活之關聯性研究

Abstract

肺癌是我國最常見的癌症，也是國內癌症死因的第一位。雖然化學治療已成了晚期非小細胞肺癌的治療標準，然而其治療也面臨到瓶頸。為了提升治療成效，除了開發新的藥物與配方之外，篩選臨床上存活較久或反應較好的患者並找出其特性亦是一種作法。 本研究收納84位來自臺大醫院及台北榮總的晚期非小細胞肺癌患者。這些患者在確認無法治癒後至少存活兩年以上，並且在上述兩院留下完整的病歷記錄。本研究以限制酶片段長度多型性分析或直接定序測定基因多型性，並利用趨向分數降低第一次化療選擇所帶來的誤差。所有變數利用考克斯正比模型計算風險比例。研究結果發現晚期非小細胞肺癌患者存活的保護因子為帶有ERCC1 8092 G/G（HR=0.024；p=0.0013）和XRCC1 399 A/A（HR=0.007；p=0.0133）的點突變，以及帶有RRM1 2455 A/A的點突變並於第一次化療使用含有gemcitabine的藥物（HR=0.022；p=0.0056）；危險因子為診斷初期即為無法治癒（HR=17.948；p=0.0005）以及帶有ERCC1 8092 T/T的高度抽菸患者（HR=102.398；p=0.0002）。 研究結果發現ERCC1 8092、XRCC1 399及RRM1 2455的點突變可影響本研究晚期非小細胞肺癌患者的存活能力。該結果雖無法拓展到整體晚期非小細胞肺患者，但可為未來研究基因點突變與晚期非小細胞肺癌患者存活之關聯性提供一個方向。

In Taiwan, lung cancer is one of the most common cancer and the leading cause of cancer-related death. Although chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC), its effect has reached a plateau. Analyzing prognostic factors and predictive factors for patients who are clinical long-survivors or better responders to systemic treatments may provide hints for future research. In this study, we included 84 advanced NSCLC patients from National Taiwan University Hospital and Taipei Veterans General Hospital. These patients survived at least 2 years after diagnosis of incurable metastatic disease. Medical treatments are reviewed from both of above hospitals. Polymorphisms of some chemotherapy resistant associated genes were detected by either RFLP or direct sequence. We used propensity score method to reduce the bias of first-line chemotherapy, and Cox’s proportional model to estimate the hazard ratio for all variables. The protective factors identified were ERCC1 8092 G/G (HR=0.024; p=0.0013) and XRCC1 399 A/A (HR=0.007; p=0.0133) genotype, and RRM1 2455 A/A with regimens containing gemcitabine as first-line therapy (HR=0.022; p=0.0056). The risk factors are incurable disease in first-time diagnosis (HR=17.948; p=0.0005) and heavy smokers with ERCC1 8092 T/T genotype (HR=102.398; p=0.0002). This study shows that SNPs of ERCC1 8092, XRCC1 399 and RRM1 2455 can influence survival of selected advanced NSCLC patients. Although the results may not be applicable to the whole advanced NSCLC population, further confirmation in large NSCLC population is needed.