EGFR共突变状态对晚期肺腺癌患者预后的价值研究

摘要/Abstract

摘要：

目的探讨表皮生长因子受体（EGFR）共突变状态对晚期肺腺癌患者预后的价值。方法前瞻性收集2019年1月至2022年12月就诊于河北北方学院附属第一医院呼吸与危重症医学科首次确诊的ⅢB~Ⅳ期肺腺癌患者的临床资料。根据EGFR是否合并其他基因突变，将患者分为EGFR突变组（n=82）和EGFR共突变组（n=74）。采用实时荧光定量PCR法测定外周血循环肿瘤DNA（ctDNA）水平。比较两组客观缓解率（ORR）、疾病控制率（DCR）、患者治疗前及治疗1个月后外周血ctDNA水平、无进展生存期（PFS）。采用Cox比例风险回归模型行单因素和多因素分析。结果EGFR突变组中EGFR19缺失突变45例，EGFR21点突变37例；EGFR共突变组中EGFR19缺失突变41例，EGFR21点突变33例，合并TP53突变46例、RB1突变16例、PTEN突变6例、MET扩增2例，ERBB2突变、KRAS突变、RET重排、ALK重排各1例。EGFR突变组和EGFR共突变组肿瘤最大径（χ²=5.04，P=0.025）、分期（χ²=3.92，P=0.048）差异均有统计学意义。两组ORR分别为64.63%（53/82）、37.84%（28/74），差异有统计学意义（χ²=11.19，P<0.001）；DCR分别为96.34%（79/82）、86.49%（64/74），差异有统计学意义（χ²=4.95，P=0.026）。EGFR突变组和EGFR共突变组治疗1个月后ctDNA水平均较治疗前有所降低[2.63（1.83，3.30）ng/μl比4.73（3.92，5.49）ng/μl，Z=-7.06，P<0.001；4.26（2.26，6.07）ng/μl比5.28（4.37，6.09）ng/μl，Z=-5.15，P<0.001 ]，治疗前及治疗1个月后EGFR共突变组ctDNA水平均较EGFR突变组升高（Z=-2.47，P=0.013；Z=-4.29，P<0.001）。EGFR共突变组中，靶向治疗有效患者治疗1个月后外周血ctDNA水平较治疗前有所降低[（2.03±0.63）ng/μl比（3.92±0.82）ng/μl，t=42.94，P<0.001]，治疗前及治疗1个月后无效患者外周血ctDNA水平均高于有效患者[（5.84±0.57）ng/μl比（3.92±0.82）ng/μl，t=-11.91，P<0.001；（5.87±1.64）ng/μl比（2.03±0.63）ng/μl，t=-14.43，P<0.001]。EGFR突变组、EGFR共突变组患者中位PFS分别为10.4、8.3个月，差异有统计学意义（χ²=22.28，P<0.001）。单因素分析显示，肿瘤最大径（HR=0.10，95%CI为0.06~0.16，P<0.001）、功能状态（PS）评分（HR=0.09，95%CI为0.06~0.15，P<0.001）、分期（HR=0.09，95%CI为0.05~0.14，P<0.001）、治疗前ctDNA水平（HR=12.04，95%CI为8.21~17.65，P<0.001）、治疗1个月后ctDNA水平（HR=3.75，95%CI为3.10~4.54，P<0.001）、EGFR基因共突变（HR=2.21，95%CI为1.57~3.12，P<0.001）均是ⅢB~Ⅳ期靶向治疗后肺腺癌患者PFS的影响因素；多因素分析显示，PS评分（HR=0.25，95%CI为0.14~0.47，P<0.001）、分期（HR=0.49，95%CI为0.24~0.98，P=0.044）、治疗前ctDNA水平（HR=4.73，95%CI为3.08~7.28，P<0.001）、治疗1个月后ctDNA水平（HR=2.15，95%CI为1.65~2.80，P<0.001）、EGFR基因共突变（HR=2.26，95%CI为1.40~3.64，P<0.001）均是ⅢB~Ⅳ期靶向治疗后肺腺癌患者PFS的独立影响因素。结论EGFR突变组和EGFR共突变组治疗1个月后ctDNA水平均较治疗前有所降低，EGFR共突变患者的中位PFS较单一EGFR突变患者短，PS评分、分期、治疗前及治疗后1个月后ctDNA水平、EGFR基因共突变均是ⅢB~Ⅳ期靶向治疗后肺腺癌患者PFS的独立影响因素。

关键词:肺腺癌,基因，erbB-1,循环肿瘤DNA,预后

Abstract:

ObjectiveTo explore the prognostic value of epidermal growth factor receptor （EGFR） co-mutation status in patients with advanced lung adenocarcinoma.MethodsClinical data of patients with stage ⅢB-Ⅳ lung adenocarcinoma who were first diagnosed in the Department of Respiratory and Critical Care Medicine， First Affiliated Hospital of Hebei North University from January 2019 to December 2022 were collected prospectively. Patients were divided into EGFR mutation group （n=82） and EGFR co-mutation group （n=74） according to whether EGFR was combined with other gene mutations. The level of circulating tumor DNA （ctDNA） in peripheral blood was measured by real time fluorescence quantitative PCR. Objective response rate （ORR）， disease control rate （DCR）， the levels of ctDNA in peripheral blood， and progression-free survival （PFS） were compared between two groups of patients before and after 1 month of treatment. The univariate and multivariate analyses were conducted by Cox proportional hazards regression model.ResultsIn the EGFR mutation group， there were 45 cases of EGFR19 deletion mutation and 37 cases of EGFR21 mutation. In the EGFR co-mutation group， there were 41 cases of EGFR19 deletion mutation， 33 cases of EGFR21 mutation， 46 cases of TP53 mutation， 16 cases of RB1 mutation， 6 cases of PTEN mutation， 2 cases of MET amplification， 1 case of ERBB2 mutation， 1 case of KRAS mutation， 1 case of RET rearrangement， and 1 case of ALK rearrangement. There were statistically significant differences between the EGFR mutation group and the EGFR co-mutation group in the maximum tumor diameter （χ²=5.04，P=0.025） and stage （χ²=3.92，P=0.048）. The ORRs of the two groups were 64.63% （53/82） and 37.84% （28/74）， respectively， with a statistically significant difference （χ²=11.19，P<0.001）. The DCRs were 96.34% （79/82） and 86.49% （64/74）， respectively， with a statistically significant difference （χ²=4.95，P=0.026）. The ctDNA levels in the EGFR mutation group and EGFR co-mutation group after one month of treatment decreased compared to before treatment [2.63 （1.83， 3.30） ng/μlvs.4.73 （3.92， 5.49） ng/μl，Z=-7.06，P<0.001； 4.26 （2.26， 6.07） ng/μlvs.5.28 （4.37， 6.09） ng/μl，Z=-5.15，P<0.001]， the ctDNA levels in the EGFR co-mutation group were higher than those in the EGFR mutation group before treatment and after 1 month of treatment （Z=-2.47，P=0.013；Z=-4.29，P<0.001）. In the EGFR co-mutation group， the ctDNA levels in peripheral blood of patients who were effectively treated with targeted therapy decreased after 1 month of treatment compared to before treatment [（2.03±0.63） ng/μlvs.（3.92±0.82） ng/μl，t=42.94，P<0.001]， the levels of ctDNA in peripheral blood of ineffectively treated patients before and after 1 month of treatment were higher than those of effectively treated patients [（5.84±0.57） ng/μlvs.（3.92±0.82） ng/μl，t=-11.91，P<0.001；（5.87±1.64） ng/μlvs.（2.03±0.63） ng/μl，t=-14.43，P<0.001]. The median PFS of the EGFR mutation group and the EGFR co-mutation group of patients were 10.4 and 8.3 months， respectively， with a statistically significant difference （χ²=22.28，P<0.001）. Univariate analysis suggested that the maximum tumor diameter （HR=0.10， 95%CI： 0.06-0.16，P<0.001）， performance status （PS） score （HR=0.09， 95%CI： 0.06-0.15，P<0.001）， stage （HR=0.09， 95%CI： 0.05-0.14，P<0.001）， pre-treatment ctDNA level （HR=12.04， 95%CI： 8.21-17.65，P<0.001）， ctDNA level after 1 month of treatment （HR=3.75， 95%CI： 3.10-4.54，P<0.001） and EGFR co-mutations （HR=2.21， 95%CI： 1.57-3.12，P<0.001） were found to be significant factors affecting the PFS of stage ⅢB -Ⅳ lung adenocarcinoma patients receiving targeted therapy； Multivariate analysis demonstrated that PS score （HR=0.25， 95%CI： 0.14-0.47，P<0.001）， stage （HR=0.49， 95%CI： 0.24-0.98，P=0.044）， pre-treatment ctDNA level （HR=4.73， 95%CI： 3.08-7.28，P<0.001）， ctDNA level after 1 month of treatment （HR=2.15， 95%CI： 1.65-2.80，P<0.001）， and EGFR gene co-mutation （HR=2.26， 95%CI： 1.40-3.64，P<0.001） were independent risk factors for PFS in stage ⅢB -Ⅳ lung adenocarcinoma patients receiving targeted therapy.ConclusionBoth the EGFR mutation group and EGFR co-mutation group show a decrease in ctDNA levels after targeted therapy for one month compared to before treatment. The median PFS of EGFR co-mutation patients is shorter than that of patients with a single EGFR mutation. PS score， stage， ctDNA levels before and after treatment， and EGFR gene co-mutation are all independent factors affecting PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients after targeted therapy.

Key words:Adenocarcinoma of lung,Genes， erbB-1,Circulating tumor DNA,Prognosis

袁胜芳, 任婕, 林卫佳, 姬泽萱, 张长洪, 王布. EGFR共突变状态对晚期肺腺癌患者预后的价值研究[J]. 国际肿瘤学杂志, 2024, 51(9): 556-562.

Yuan Shengfang, Ren Jie, Lin Weijia, Ji Zexuan, Zhang Changhong, Wang Bu. Prognostic value of EGFR co-mutation status in patients with advanced lung adenocarcinoma[J]. Journal of International Oncology, 2024, 51(9): 556-562.

图/表6

表1

两组ⅢB~Ⅳ期靶向治疗肺腺癌患者一般临床资料比较[例（%）]"

一般临床资料	EGFR突变组（n=82）	EGFR共突变组（n=74）	χ²值	P值
性别
男	26（31.71）	21（28.38）	0.21	0.651
女	56（68.29）	53（71.62）	0.21	0.651
年龄（岁）
≥65	35（42.68）	31（41.89）	0.01	0.920
<65	47（57.32）	43（58.11）	0.01	0.920
吸烟史
是	24（29.27）	18（24.32）	0.48	0.487
否	58（70.73）	56（75.68）	0.48	0.487
肿瘤最大径（cm）
<5	48（58.54）	30（40.54）	5.04	0.025
≥5	34（41.46）	44（59.46）	5.04	0.025
分期
ⅢB期	37（45.12）	22（29.73）	3.92	0.048
Ⅳ期	45（54.88）	52（70.27）	3.92	0.048
PS评分（分）
0~1	60（73.17）	58（78.38）	0.57	0.449
2~3	22（26.83）	16（21.62）	0.57	0.449
靶向治疗药物
奥西替尼	32（39.02）	28（37.84）	1.03	0.906
埃克替尼	10（12.20）	9（12.16）
埃克替尼加量	15（18.29）	10（13.51）
阿美替尼	5（6.10）	6（8.11）
吉非替尼	20（24.39）	21（28.38）

表1

组别	外周血ctDNA水平	Z值	P值
EGFR组（n=82）	4.73（3.92，5.49）	2.63（1.83，3.30）	-7.06	<0.001
EGFR共突变组（n=74）	5.28（4.37，6.09）	4.26（2.26，6.07）	-5.15	<0.001
Z值	-2.47	-4.29
P值	0.013	<0.001

表2

组别	外周血ctDNA水平	t值	P值
有效患者（n=28）	3.92±0.82	2.03±0.63	42.94	<0.001
无效患者（n=46）	5.84±0.57	5.87±1.64	-0.14	0.889
t值	-11.91	-14.43
P值	<0.001	<0.001

表3

图1

因素	HR值	95%CI	P值
性别	0.94	0.66~1.34	0.723
年龄	1.02	0.99~1.05	0.192
吸烟史	0.10	0.69~1.44	0.997
肿瘤最大径	0.10	0.06~0.16	<0.001
PS评分	0.09	0.06~0.15	<0.001
分期	0.09	0.05~0.14	<0.001
治疗前ctDNA水平	12.04	8.21~17.65	<0.001
治疗1个月后ctDNA水平	3.75	3.10~4.54	<0.001
EGFR基因共突变	2.21	1.57~3.12	<0.001

表4

因素	HR值	95%CI	P值
肿瘤最大径	0.63	0.36~1.12	0.113
PS评分	0.25	0.14~0.47	<0.001
分期	0.49	0.24~0.98	0.044
治疗前ctDNA水平	4.73	3.08~7.28	<0.001
治疗1个月后ctDNA水平	2.15	1.65~2.80	<0.001
EGFR基因共突变	2.26	1.40~3.64	<0.001

表5

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