血浆ctDNA T790M突变和总代谢肿瘤体积对晚期EGFR突变NSCLC患者TKIs治疗及预后意义

doi:10.3877/cma.j.issn.1674-6902.2024.03.007

目的

分析血浆循环肿瘤DNA(circulating tumor DNA, ctDNA)T790M突变和总代谢肿瘤体积(total metabolic tumor volume, TMTV)在经酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)治疗的晚期表皮生长因子受体(epidermal growth factor receptor, EGFR)突变非小细胞肺癌(non-small cell lung cancer, NSCLC)患者预后中的意义。

方法

选取2018年1月至2021年2月我院收治的96例晚期EGFR突变型NSCLC患者，随访至2023年9月30日，利用¹⁸F-FDG正电子发射断层扫描/X射线计算机断层成像(FDG-PET/CT)测定TMTV，微滴式数字聚合酶链式反应测定血浆ctDNA T790M突变，分析TMTV和ctDNA T790M在预后中的意义。

结果

整个随访期间，48例(50.0%)NSCLC进展和29例(30.21%)预后不佳，中位无进展生存时间(PFS)为11个月，中位总生存期(OS)为17个月。经过EGFR TKIs治疗后52例(54.17%)患者出现ctDNA T790M突变，ctDNA T790M突变组患者TMTV、预后差、NSCLC进展比例低于ctDNA T790M野生型组(P<0.05)。NSCLC进展或预后不佳患者TMTV显著(P<0.001)。受试者工作特征曲线显示TMTV预测疾病进展、最佳截断值为26.10 cm³、59.20 cm³(P<0.001)。ctDNA T790M突变患者PFS[Log-Rank(Mantel-Cox)＝22.732]和OS[Log-Rank(Mantel-Cox)＝26.663]高于ctDNA T790M野生型患者；TMTV≥26.10 cm³患者PFS[Log-Rank(Mantel-Cox)＝23.199]低于TMTV<26.10 cm³患者；TMTV≥59.20 cm³患者OS[Log-Rank(Mantel-Cox)＝34.201]低于TMTV<59.20 cm³患者；在ctDNA T790M野生型且TMTV≥26.10 cm³患者中PFS[Log-Rank(Mantel-Cox)＝33.604]最短；在ctDNA T790M野生型且TMTV≥59.20 cm³患者中OS[Log-Rank(Mantel-Cox)＝57.078]最短(P<0.001)。COX多因素模型显示，TMTV和ctDNA T790M突变状态与PFS或OS相关(P<0.05)。

结论

接受EGFR TKI治疗的患者中检测血浆ctDNA T790M和基线TMTV用于预测NSCLC患者的预后是可行的。治疗后ctDNA T790M和基线TMTV是NSCLC患者PFS、OS的预后因素。

关键词: 非小细胞肺癌, 表皮生长因子受体, T790M, 总代谢肿瘤体积, 预后

Objective

To investigate the significance of plasma circulating tumor DNA (ctDNA) T790M mutation and total metabolic tumor volume (TMTV) in the prognosis of patients with advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs).

Methods

96 patients with advanced EGFR mutant NSCLC were included consecutively from January 2018 to February 2021. The significance of TMTV and ctDNA T790M mutations was analyzed by ¹⁸F-FDG positron emission tomography/X-ray computed tomography (FDG-PET/CT) and plasma ctDNA T790M mutations by droplet digital polymerase chain reaction (TBT) to analyze the prognostic significance of TMTV and ctDNA T790M.

Results

Throughout the follow-up period, there were 48 (50.0%) patients with disease progression and 29 (30.21%) deaths, with a median progression-free survival (PFS) of 11 months and a median overall survival (OS) of 17 months. After treatment with EGFR TKIs, 52 patients (54.17%) developed ctDNA T790M mutations, and the proportions of TMTV, death and disease progression in the ctDNA T790M mutation group were significantly lower than those in the ctDNA T790M wild-type group(P<0.05). TMTV was significantly higher in the disease progression group or death group (P<0.001). The receiver operating characteristic curve showed that the best cut-off values of TMTV for predicting disease progression and mortality were 26.10 cm³ and 59.20 cm³(P<0.001). The PFS[Log-Rank (Mantel-Cox)=22.732] and OS[Log-Rank (Mantel-Cox)=26.663] in patients with ctDNA T790M mutation were significantly higher than those in patients with ctDNA T790M mutation; the PFS[Log-Rank (Mantel-Cox)=23.199] was significantly lower in patients with TMTV≥26.10 cm³ than in patients with TMTV<26.10 cm^3; the OS[Log-Rank (Mantel-Cox)=34.201] in patients with TMTV≥59.20 cm³ was significantly lower than that in patients with TMTV<59.20 cm^3; the PFS[Log-Rank (Mantel-Cox)=33.604] in patients with ctDNA T790M negative and TMTV≥26.10 cm³ was the shortest; the OS[Log-Rank (Mantel-Cox)=57.078] in ctDNA T790M negative and TMTV≥59.20 cm³ was the shortest; all P<0.001. The COX multivariate model showed that TMTV and ctDNA T790M mutation status were independently associated with PFS or OS (P<0.05).

Conclusion

It is feasible to detect plasma ctDNA T790M and baseline TMTV in patients treated with EGFR TKI for predicting the prognosis of NSCLC patients. After treatment, ctDNA T790M and baseline TMTV were independent prognostic factors for PFS and OS in NSCLC patients.

Key words: Non-small cell lung cancer, Epidermal growth factor receptor, T790M, Total metabolic tumor volume, Prognosis

表1 治疗后ctDNA T790M突变和野生型患者临床特征及代谢参数比较[(

±s)(%)，M₅₀(P₂₅，P₇₅)]

临床资料	T790M野生型(n＝44)	T790M突变型(n＝52)	t/Z/χ²	P值
BMI(kg/m²)	23.92±3.23	23.97±4.13	－0.488	0.627
病理亚型			2.485	0.289
腺癌	20(45.45)	24(46.15)
SCC	13(29.55)	21(40.38)
其它	11(25.00)	7(13.46)
肿瘤位置			1.161	0.281
左肺	18(40.91)	27(51.92)
右肺	26(59.09)	25(48.08)
¹⁸F-FDG PET/CT
TMTV(cm³)	64.24(21.10，122.17)	31.80(13.57，61.18)	－2.177	0.030
TLGWB(g)	361.04(131.84，912.12)	181.91(80.80，461.53)	－2.221	0.026
TNM分期			0.110	0.740
3	13(29.55)	17(32.69)
4	31(70.45)	35(67.31)
TKI相关不良反应	25(56.82)	22(42.31)	2.008	0.157
预后不良	25(56.82)	4(7.69)	27.280	0.000
肿瘤进展	35(79.55)	13(25.0)	28.360	0.000

表1 治疗后ctDNA T790M突变和野生型患者临床特征及代谢参数比较[(

±s)(%)，M₅₀(P₂₅，P₇₅)]

临床资料	T790M野生型(n＝44)	T790M突变型(n＝52)	t/Z/χ²	P值
BMI(kg/m²)	23.92±3.23	23.97±4.13	－0.488	0.627
病理亚型			2.485	0.289
腺癌	20(45.45)	24(46.15)
SCC	13(29.55)	21(40.38)
其它	11(25.00)	7(13.46)
肿瘤位置			1.161	0.281
左肺	18(40.91)	27(51.92)
右肺	26(59.09)	25(48.08)
¹⁸F-FDG PET/CT
TMTV(cm³)	64.24(21.10，122.17)	31.80(13.57，61.18)	－2.177	0.030
TLGWB(g)	361.04(131.84，912.12)	181.91(80.80，461.53)	－2.221	0.026
TNM分期			0.110	0.740
3	13(29.55)	17(32.69)
4	31(70.45)	35(67.31)
TKI相关不良反应	25(56.82)	22(42.31)	2.008	0.157
预后不良	25(56.82)	4(7.69)	27.280	0.000
肿瘤进展	35(79.55)	13(25.0)	28.360	0.000

图1 患者的PFS和OS Kaplan-Meier曲线

图2 不同组别TMTV比较

表2 COX回归分析影响PFS或OS的临床因素

变　量	无进展生存期					总生存期
变　量	β	S.E	Wald	HR(95%CI)	P值	β	S.E	Wald	HR(95%CI)	P值
单因素分析
饮酒史(是vs.否)	1.367	0.598	5.225	3.922(1.215～12.662)	0.022	1.945	1.019	3.645	6.991(0.950～51.469)	0.056
ctDNA T790M(突变型vs.野生型)	－1.421	0.328	18.827	0.241(0.127～0.459)	0.000	－2.253	0.539	17.457	0.105(0.037～0.302)	0.000
T分期(1～2期vs. 3～4期)	－0.421	0.301	1.952	0.656(0.364～1.185)	0.162	－0.959	0.372	6.657	0.383(0.185～0.794)	0.010
TMTV(≥26.10 cm³ vs. <26.10 cm³)	1.644	0.439	13.996	5.176(2.187～12.249)	0.000	－	－	－	－	－
TMTV(≥59.20 cm³ vs. <59.20 cm³)	－	－	－	－	－	2.211	0.461	22.968	9.127(3.695～22.547)	0.000
多因素分析
ctDNA T790M(突变型vs.野生型)	－1.334	0.329	16.414	0.263(0.138～0.502)	0.000	－1.801	0.554	10.579	0.165(0.056～0.489)	0.001
TMTV(≥26.10 cm³ vs.<26.10 cm³)	1.476	0.444	11.031	4.377(1.831～10.459)	0.001	－	－	－	－	－
TMTV(≥59.20 cm³ vs.<59.20 cm³)	－	－	－	－	－	1.779	0.489	13.223	5.922(2.270～15.447)	0.000

表2 COX回归分析影响PFS或OS的临床因素

变　量	无进展生存期					总生存期
变　量	β	S.E	Wald	HR(95%CI)	P值	β	S.E	Wald	HR(95%CI)	P值
单因素分析
饮酒史(是vs.否)	1.367	0.598	5.225	3.922(1.215～12.662)	0.022	1.945	1.019	3.645	6.991(0.950～51.469)	0.056
ctDNA T790M(突变型vs.野生型)	－1.421	0.328	18.827	0.241(0.127～0.459)	0.000	－2.253	0.539	17.457	0.105(0.037～0.302)	0.000
T分期(1～2期vs. 3～4期)	－0.421	0.301	1.952	0.656(0.364～1.185)	0.162	－0.959	0.372	6.657	0.383(0.185～0.794)	0.010
TMTV(≥26.10 cm³ vs. <26.10 cm³)	1.644	0.439	13.996	5.176(2.187～12.249)	0.000	－	－	－	－	－
TMTV(≥59.20 cm³ vs. <59.20 cm³)	－	－	－	－	－	2.211	0.461	22.968	9.127(3.695～22.547)	0.000
多因素分析
ctDNA T790M(突变型vs.野生型)	－1.334	0.329	16.414	0.263(0.138～0.502)	0.000	－1.801	0.554	10.579	0.165(0.056～0.489)	0.001
TMTV(≥26.10 cm³ vs.<26.10 cm³)	1.476	0.444	11.031	4.377(1.831～10.459)	0.001	－	－	－	－	－
TMTV(≥59.20 cm³ vs.<59.20 cm³)	－	－	－	－	－	1.779	0.489	13.223	5.922(2.270～15.447)	0.000

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Significance of plasma ctDNA T790M mutation and total metabolic tumor volume in the prognostic significance of TKIs treatment in patients with advanced EGFR mutant NSCLC

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Significance of plasma ctDNA T790M mutation and total metabolic tumor volume in the prognostic significance of TKIs treatment in patients with advanced EGFR mutant NSCLC