ctDNA对晚期SCLC预后评估相关性分析

Correlation Analysis of ctDNA in the Prognosis Evaluation of Advanced SCLC

摘要: 目的：对比循环肿瘤DNA (Circulating Tumor DNA, ctDNA)与传统肿瘤指标神经元特异性烯醇化酶(Neuron-specific-enolase, NSE)、癌胚抗原(Carcino-embryonic antigen, CEA)、乳酸脱氢酶(Lactic dehydrogenase, LDH)对SCLC患者近期疗效的预测，分析ctDNA与SCLC临床病理特征及预后的关系。方法：收集2017年7月~2019年8月于我院肿瘤内科经病理确诊的62例初治的SCLC患者的血液样本。ECOG评分：0~1分。行4周期化疗。分别在化疗前、2周期化疗前1天、4周期化疗前1天抽取空腹静脉血检测ctDNA、CEA、NSE、LDH。参照RECIST1.1实体瘤疗效评价标准将患者分为进展组(PD)与非进展组(CR + PR + SD)，比较治疗前后ctDNA与NSE、CEA、LDH变化，进而对比上述指标对SCLC患者近期疗效的评估价值。采用受试工作者曲线(ROC)确定化疗前ctDNA高低表达临界值，分为ctDNA高表达组和低表达组，对SCLC患者进行随访，分析ctDNA与SCLC临床病理特征及预后的关系。结果：纳入62名患者中，49名SCLC患者检测到ctDNA，该49名患者被纳入此研究。1) 化疗2周期后，ctDNA在进展组表达高于非进展组(p < 0.01)，NSE、CEA、LDH表达在进展组及非进展组中相比无统计学差异(p均>0.05)。2) 化疗4周期后，ctDNA在进展组表达高于非进展组(p < 0.01)。NSE (p < 0.01)在进展组表达高于非进展组，CEA、LDH表达在进展组及非进展组相比无统计学差异(p均>0.05)。3) ctDNA高表达与广泛期(p < 0.01)，多部位转移(p = 0.019)以及低钠血症(p = 0.013)有关。4) 发现ctDNA高表达组PFS较低表达组短(8.051 ± 0.536 Vs 9.910 ± 0.560; χ² = 4.356, p = 0.037)，OS在ctDNA高表达组和低表达组中无明显差异(10.874 ± 0.408 Vs 11.166 ± 0.428; χ² = 0.059, p = 0.807)。结论：1) ctDNA较NSE可以更早地预测小细胞肺癌治疗的近期疗效。2) 化疗前ctDNA高表达与广泛期，多部位转移以及低钠血症有关，提示ctDNA高表达患者预后较ctDNA低表达患者更差。

Abstract: Purpose: Compare Circulating Tumor DNA (ctDNA) with traditional tumor indicators Neuron-specific-enolase (NSE), Carcino-embryonic antigen (CEA), and lactate dehydrogenase (LDH) to predict the short-term efficacy of SCLC patients, analyze the relationship between ctDNA and the clinicopathological characteristics and prognosis of SCLC. Methods: Collect blood samples of 62 newly-treated SCLC patients who were pathologically diagnosed in the Oncology Department of our hospital from July 2017 to August 2019; ECOG score: 0 - 1 points; perform 4 cycles of chemotherapy. Fasting venous blood was drawn to detect ctDNA, CEA, NSE, and LDH before chemotherapy, 1 day before 2 cycles of chemotherapy, and 1 day before 4 cycles of chemotherapy. According to the RECIST1.1 solid tumor efficacy evaluation standard, the patients were divided into progressive group (PD) and non-progressive group (CR + PR + SD), and the changes of ctDNA and NSE, CEA, LDH before and after treatment were compared, and the above indicators were compared to SCLC patients in the near future. The evaluation value of efficacy was also compared. The test worker curve (ROC) was used to determine the cutoff value of ctDNA expression before chemotherapy, and divided into ctDNA high expression group and low expression group. SCLC patients were followed up to analyze the relationship between ctDNA and SCLC clinicopathological characteristics and prognosis. Results: 62 patients were included, ctDNA was detected in 49 SCLC patients, and these 49 patients were included in this study. 1) After 2 cycles of chemotherapy, the expression of ctDNA in the progressive group was higher than that in the non-progressive group (p < 0.01), and the expressions of NSE, CEA, LDH were not statistically different between the progressive group and the non-progressive group (p < 0.05). 2) After 4 cycles of chemotherapy, the expression of ctDNA in the progressive group was higher than that in the non-progressive group (p < 0.01). The expression of NSE (p < 0.01) in the progressive group was higher than that in the non-progressive group, and the expression of CEA and LDH was not statistically different between the progressive group and the non-progressive group (p > 0.05). 3) High expression of ctDNA is related to extensive phase (p < 0.01), multi-site metastasis (p = 0.019) and hyponatremia (p = 0.013). 4) It was found that the low PFS expression group of the ctDNA high expression group was short (8.051 ± 0.536 Vs 9.910 ± 0.560; χ² = 4.356, p = 0.037), and the OS was higher in ctDNA. There was no significant difference between the expression group and the low expression group (10.874 ± 0.408 Vs 11.166 ± 0.428; χ² = 0.059, p = 0.807). Conclusion: 1) ctDNA can predict the short-term efficacy of small cell lung cancer treatment earlier than NSE. 2) Before chemotherapy, the high expression of ctDNA is associated with extensive stage, multi-site metastasis and hyponatremia, suggesting that the prognosis of patients with high ctDNA expression is worse than that of patients with low ctDNA expression.