非小细胞肺癌中医寒热分型与表皮生长因子受体（EGFR）的相关性研究

The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) have been important in advanced Non-Small Cell Lung Cancer(NSCLC) treatment, and the EGFR gene test for exon 18-21 mutation has been a necessary test for guiding treatment strategy in NSCLC. In clinical practice, we found that EGFR-TKIs achieved better effect in patients with Cold type syndrome in traditional Chinese medicine theory than those with Heat type syndrome. We also found that after taking EGFR-TKIs, patients may turn to Heat type syndrome. When resisited to EGFR-TKIs, most of them were with Heat type syndrom. However, there is no evidence. In order to identify the relationship between the TCM syndrome type and the EGFR gene statement, the treatment effect of EGFR-TKIs in Stage III/IV NSCLC patients, and to observe the changing pattern of TCM syndrome in Stage III/IV NSCLC patients when taking EGFR-TKIs, a total of 300 previously untreated patients with III/IV NSCLC are going to be enrolled in our research. Patients are going to be divided into Cold group or Heat group according to the TCM syndromes, and to be divided into mutation group or wild group according to the EGFR gene test for exon 18-21 mutation. Relationship between the TCM syndrome type and the EGFR gene statement is analyzed. For those who take EGFR-TKIs, we will record the TCM syndromes every 4 weeks , and assess the effect of EGFR-TKIs every 8 weeks till progression and the relationship between the TCM syndrome type and the effect of EGFR-TKIs is analyzed. Meanwhile, the changing pattern of TCM syndrome is observed. This research may found another factor to forecast effect of EGFR-TKIs in TCM theory, and provide theoretical basis for reversing EGFR-TKIs resistanc with TCM treatment.

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TIKs）是治疗EGFR突变的晚期非小细胞肺癌（NSCLC）的一线方案。实践中发现该药在中医寒证患者中疗效优于热证患者，且治疗过程中证型逐渐向热证转化，而发生耐药时多属热证，但缺乏循证医学证据。为探讨NSCLC患者中医寒热证型与EGFR基因状态、EGFR-TKIs疗效及耐药之间的关联性，本研究应用临床流行病学方法与分子生物学技术，连续性采集300例初治的ⅢB/Ⅳ期NSCLC患者中医证候及EGFR基因状态信息，根据证候特点分为寒、热两型，统计分析寒热证型与EGFR状态的相关性。对接受EGFR-TKIs治疗的患者每4周采集中医证候信息，每8周评估疗效，直到肿瘤进展，观察证候变化规律，统计分析寒热证型与EGFR-TKIs疗效及耐药的相关性。结果可作为EGFR－TKIs应用的疗效预测因子，并为研究中药逆转EGFR-TKIs耐药提供药物选择的理论依据。

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TIKs）是治疗EGFR突变的晚期非小细胞肺癌（NSCLC）的一线方案，EGFR-TKIs联合中医药治疗在临床应用广泛。根据中医理法方药思路，明确与EGFR-TKIs联合的中医治疗原则尤其重要，而其基础是先明确非小细胞肺癌中医寒热证型与EGFR状态的相关性。.为此，本研究第一阶段采集310例NSCLC患者中医证候，299例检测了EGFR基因状态，结果寒证者EGFR突变率（45.24%）显著高于热证患者( 25.95%, p = 0.001)。在聚类分析中，132例分组为与寒证类似的A组，160例分组到与热证类似的B组。在281例检测了EGFR基因状态的患者中，A组EGFR突变率（45.67%）显著高于B组（28.57%, p = 0.003）。在多因素logistic回归中，EGFR基因状态是中医寒热证型、聚类分析分组情况的独立相关因子。中医寒证患者EGFR突变率更高。.257例患者进入第二阶段验证和随访阶段。其中，246例检测了EGFR基因状态，寒证者EGFR突变率（56.46%）显著高于热证者(29.29%, p < 0.001)，验证了第一阶段结果。88例接受了EGFR-TKIs治疗，随访至2016年12月，54例进展，寒证和热证者中位PFS分别为11.47和13月（p=0.0466）。41例患者记录到进展时中医证型，寒证25例（60.98%），22例初始寒证进展时仍为寒证，12例初始寒证进展时转化为热证，4例初始热证进展时仍为热证，3例初始热证进展时转化为寒证，进展时阳热证患者显著增多（p= 0.046）。进展时寒证和热证患者中位PFS分别为8.8月和12.93月（p=0.1509）。. 利用数字微滴PCR（ddPCR）技术检测113例患者血浆中的EGFR基因，与肿瘤组织检测相比敏感度为78.13%，特异度为97.96%。64例组织EGFR突变患者中，血浆EGFR突变浓度与可评估病灶直径总和呈正相关(p=0.0048)，肿瘤高负荷患者中血浆EGFR的浓度显著高于低负荷患者（中位数：386.9 vs. 13.4 copies/ml; p<0.0001）。57例接受了EGFR-TKIs治疗的患者中，高EGFR突变浓度组的中位PFS为8.43月，显著低于低浓度组（16.23月，p=0.0019）。