肺腺癌患者表皮生长因子受体突变与临床病理特征的相关性

http://dx.doi.org/10.12007/j.issn.0258-4646.2020.09.008

文章信息

黄静山, 孙媛媛, 鲁继斌

HUANG Jingshan, SUN Yuanyuan, LU Jibin

Association between clinicopathological features of lung adenocarcinoma and incidence of EGFR mutation

中国医科大学学报, 2020, 49(9): 807-811

Journal of China Medical University, 2020, 49(9): 807-811

文章历史

收稿日期：2019-09-26

网络出版时间：2020-09-11 10:07

Abstract

PDF

Figures

Tables

引用本文

黄静山, 孙媛媛, 鲁继斌. 肺腺癌患者表皮生长因子受体突变与临床病理特征的相关性[J]. 中国医科大学学报, 2020, 49(9): 807-811.

HUANG Jingshan, SUN Yuanyuan, LU Jibin. Association between clinicopathological features of lung adenocarcinoma and incidence of EGFR mutation[J]. Journal of China Medical University, 2020, 49(9): 807-811.

肺腺癌患者表皮生长因子受体突变与临床病理特征的相关性

黄静山¹ , 孙媛媛² , 鲁继斌¹

1. 中国医科大学附属盛京医院胸外科, 沈阳 110004;
2. 中国医科大学生命科学学院医学遗传学教研室, 沈阳 110122

收稿日期：2019-09-26；网络出版时间：2020-09-11 10:07

基金项目：辽宁省自然科学基金(LQNK201726)

作者简介：黄静山(1988-), 男, 医师, 博士研究生.

通信作者：鲁继斌，E-mail：lujb@sj-hospital.org.

摘要：目的分析肺腺癌患者的表皮生长因子受体(EGFR)突变情况与临床病理特征的相关性，筛选基因筛查优势人群，为EGFR突变筛查及络氨酸激酶抑制剂(TKIs)的临床应用提供理论导向。方法回顾性分析139例行EGFR突变基因筛查的肺腺癌患者相关临床病理参数及EGFR外显子突变情况，应用Pearson χ²检验进行单因素分析，采用logistic回归模型进行多因素分析，筛选靶向治疗最佳优势人群。结果肺腺癌EGFR突变多见于女性、非大量吸烟、存在肺内转移以及进展期患者。19外显子突变与肺内转移密切相关，21外显子突变与性别、吸烟史及转移器官数量密切相关。女性肺腺癌患者EGFR突变率比男性患者增加3.4倍，发生肺内转移的肺腺癌患者阳性突变率提高3.3倍。女性肺腺癌患者21外显子阳性突变率比男性患者提高7.8倍。结论肺腺癌EGFR突变状态与临床病理特征相关，女性、非大量吸烟、存在肺内转移以及进展期患者阳性突变率高，建议筛查。

关键词：肺腺癌表皮生长因子受体靶向治疗 21外显子突变

Association between clinicopathological features of lung adenocarcinoma and incidence of EGFR mutation

HUANG Jingshan¹ , SUN Yuanyuan² , LU Jibin¹

1. Department of Thoracic Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China;
2. Department of Genetics, College of Life Sciences, China Medical University, Shenyang 110122, China

Abstract: Objective To analyze the relationship between clinicopathological features of lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutation status. Methods A total of 139 patients with lung adenocarcinoma who underwent EGFR gene mutation test were selected. Their clinicopathological features and EGFR mutation status were collected retrospectively. Univariate analyses with Pearson χ² test and multivariate analyses using logistic regression model were performed to select suitable candidates for targeted therapy. Results Among the patients with lung adenocarcinoma, EGFR mutations were more prevalent in women, non-heavy smokers, patients with intrapulmonary metastasis, and patients in the advanced stages of cancer. Mutation in exon 19 was closely related to intrapulmonary metastasis, while that in exon 21 was closely related to gender, smoking history, and the number of organs with metastases. The EGFR mutation rate in the female patients with lung adenocarcinoma was 3.4 times higher than that in the male patients and mutation rate among patients with intrapulmonary metastasis was 3.3 times higher than those without. For exon 21 mutations, the mutation rate in the female patients was 7.8 times higher than that in the male patients. Conclusion The EGFR mutation in lung adenocarcinoma is associated with clinicopathological features, exhibiting high positive mutation rates in women, non-heavy smokers, patients with intrapulmonary metastasis, and patients in advanced stages of cancer, for whom the screening is recommended.

Keywords: lung adenocarcinoma EGFR targeted therapy exon 21 mutation

肺癌居我国癌症发病率和死亡率的首位^[1-3], 其中约85%为非小细胞肺癌, 而腺癌作为非小细胞肺癌的一种病理分型, 发病率最高^[4-5]。靶向治疗是治疗晚期非小细胞肺癌的重要方式^[6-7]。表皮生长因子受体络氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs)疗效确切, 不良反应轻, 临床上广泛应用于非小细胞肺癌的治疗^[8-9]。亚裔、女性、非吸烟、腺癌患者多见EGFR外显子的突变, 因此是EGFR-TKIs治疗肺癌的优势人群^[10-12]。EGFR突变中, 最常见19外显子部分缺失突变和21外显子L858R点突变, 二者约占总突变的90%, 同时也是EGFR-TKIs临床疗效评估的优势位点, 且19、21外显子突变者EGFR-TKIs治疗预后存在差异^[13]。本研究回顾分析了中国医科大学附属盛京医院收治的139例行EGFR突变检测的肺腺癌患者的EGFR突变情况及临床特点, 详尽地筛选优势人群, 为EGFR突变检测及EGFR-TKIs的临床应用提供理论依据。

1 材料与方法 1.1 临床资料

选取2018年2月至2019年2月中国医科大学附属盛京医院收治的临床资料完整的肺腺癌患者共139例。其中, 男62例, 女77例；年龄 > 50岁116例, ≤50岁23例；行肺癌根治手术49例；EGFR突变型67例, 其中, 18外显子2例, 19外显子26例, 20外显子5例, 21外显子34例；大量吸烟(吸烟≥10支/d, 且持续≥10年)患者67例, 非大量吸烟72例；无器官转移63例, 单器官转移36例, 多器官转移40例；肺内转移33例, 其他部位转移78例；左肺原发102例, 右肺原发37例；TNM分期Ⅰ期40例, Ⅱ期7例, Ⅲ期25例, Ⅳ期67例；高分化18例, 中分化10例, 低分化29例, 余82例未明确分化程度。所有患者均通过手术、穿刺活检或纤维支气管镜取病理确诊, 并检测EGFR外显子突变情况^[14]。

1.2 统计学分析

采用SPSS 24.0软件对临床信息进行统计学分析。应用Pearson χ²检验对临床资料进行单因素检验, 对显著性差异的因素进一步采用logistic回归分析, P < 0.05为差异有统计学意意义。

2 结果 2.1 不同临床病理特征EGFR总突变分析

EGFR阳性突变患者共67例(48.2%), 以女性(68.7%)、年龄 > 50岁(82.1%)、非大量吸烟(82.1%)、器官转移(56.7%, 骨转移28.4%, 肺内转移32.8%)、多器官转移(43.3%)、左肺原发(77.6%)、高分化(41.8%)、进展期(59.7%)患者多见。其中, 18外显子突变患者2例(3%), 19外显子突变患者26例(39%), 20外显子突变患者5例(7%), 21外显子突变患者34例(51%)。

EGFR突变与否在性别、大量吸烟史、肺内转移以及TNM分期方面有统计学差异(P < 0.05), 其余临床病理特征方面EGFR突变率差异无统计学意义。见表 1。

表 1 不同临床特征EGFR突变分析 Tab.1 Association of EGFR mutation with different clinical features

Characteristic	EGFR mutation status		χ²	P
Characteristic	Yes (n = 67)	No (n = 72)	χ²	P
Gender			9.21	0.002
Male	21	41
Female	46	31
Smoking history			7.45	0.006
Yes	12	28
No	55	44
Intrapulmonary metastasis			5.91	0.015
Yes	22	11
No	45	61
TNM staging			4.47	0.035
Early (Ⅰ-Ⅱ)	27	17
Advanced (Ⅲ-Ⅳ)	40	55

表选项

2.2 临床病理特征与EGFR突变的关系

进一步对各突变亚型进行单因素分析发现, 19外显子突变仅在肺内转移(阴性36.4%, 阳性63.6%, P = 0.003)方面存在统计学差异；21外显子突变在性别(女性76.5%, 男性23.5%, P = 0.004)、大量吸烟史(是29.3%, 否70.7%, P = 0.037)、转移(多发转移20.0%, 无转移80.0%, P = 0.026)方面有统计学差异。

2.3 不同临床病理特征EGFR19、21外显子突变对比分析

19、21外显子突变患者在转移器官数量及肺内转移方面存在统计学差异(P < 0.05), 在性别、年龄、吸烟史、其他转移部位、原发部位、分化程度方面均无统计学差异(P > 0.05)。进一步分析得出, 19、21外显子阳性突变在单器官转移与无转移、多器官转移与无转移方面均存在统计学差异(P < 0.05), 而单器官与多器官转移的分布无统计学差异(P > 0.05)。见表 2。

表 2 不同临床病理特征EGFR19、21外显子突变对比 Tab.2 Association of mutations in exon 19 and exon 21 of EGFR with different clinical features

Characteristic	EGFR mutation		χ²	P
Characteristic	Exon 19	Exon 21	χ²	P
Gender			2.40	0.121
Male	11	8
Female	15	26
Age (year)			0.22	0.641
≤50	5	5
＞50	21	29
Smoking history			0.24	0.621
Yes	6	5
No	20	29
Metastasis number			6.20	0.045
Single	11	9
Multiple	8	5
Negative	7	20
Intrapulmonary metastasis	12	6	5.70	0.017

表选项

2.4 肺腺癌患者EGFR突变多因素logistic回归分析

2.4.1 EGFR总突变logistic回归分析

以EGFR突变与否为因变量, 对有统计学差异的临床特征进行logistic回归分析, 吸烟情况及TNM分期无统计学意义(P > 0.05), 移除吸烟史和TNM分期参数, 得出肺腺癌患者EGFR突变与性别(P = 0.001, 0R=3.4, 95%CI:1.6~7.0)及肺内转移(P = 0.007, 0R=3.3, 95%CI:1.4~8.0)存在显著相关性。

2.4.2 21外显子突变多因素logistic回归分析

进一步对21外显子阳性突变进行logistic回归分析发现, 仅性别方面存在显著相关性(P = 0.002, OR = 7.8, 95%CI:2.1~28.0)。

3 讨论

本研究对139例肺腺癌患者的EGFR突变情况及临床病理特征进行回顾性分析, 并进行分层及组内对照分析。结果发现, EGFR外显子突变率为48.2% (67/139), EGFR突变在女性(68.7%)、不吸烟患者(82.1%)中多见, 与既往研究结果一致^[10-12]。HUANG等^[15]对101例肺癌患者进行回顾性分析发现, 除1例鳞癌外, 所有的EGFR突变均发生于腺癌, 突变率为55%。PAO等^[16]发现EGFR突变多见于非吸烟肺腺癌患者(75%)。JÄNNE等^[17]指出EGFR突变多见于亚裔(49%)、腺癌(42%)、非吸烟(54%)、女性(46%), 并指出吸烟状态是EGFR突变检测的最佳指征。ROSELL等^[14]对2 105例肺癌患者进行回顾性分析发现, EGFR突变350例(16.6%), 且多见于女性(69.7%)、非吸烟(66.6%)、腺癌(80.9%) (P < 0.001)。本研究发现, 肺腺癌患者的性别与EGFR阳性突变存在显著相关性(OR=3.4, 95%CI:1.6~7.0)。

吸烟史曾被称为EGFR突变检测的最佳指标^[17]。但本研究中单因素分析结果虽然显示吸烟史有统计学差异(P = 0.006), 但多因素分析显示其相关性并不显著(P = 0.205)。可能与样本量较小和非吸烟史的界定有关(国外研究界定“非吸烟”常为 < 100支/年^[18]), 相比性别和肺内转移, 其相关性较差。尚需大样本临床研究进一步明确。

既往研究^[19-23]多关注淋巴结转移及胸膜转移与EGFR突变状态的关系, 而对于远处器官转移及多发转移的相关性研究较少。1项针对Ⅰ期腺癌的回顾性分析发现, 对比野生型, 19、21外显子突变多见于女性(P < 0.01)及非吸烟患者(P < 0.001), 而在肿瘤大小、分期、淋巴结或胸膜转移方面差异不明显^[13]。1项针对肝转移对EGFR-TKIs预后影响的回顾性研究^[24]显示, 148例Ⅳ期腺癌患者中, 女性占96%, 非吸烟患者占76%, 初次诊断时肝转移19例(13%), 脑转移15例(10%), 对侧肺内转移66例(45%), 骨转移81例(55%), 胸膜转移92例(62%), 肾上腺转移14例(9%), 发现肝转移是预后较差的显著危险因素(HR=4.043, 95%CI:2.194~7.449, P < 0.000 1)。本研究中, 肝转移率为11%, 但本研究缺乏预后相关性研究, 无法为其佐证。与之不同的是, 本研究还发现了较多的肺内转移(66.7%), 且与EGFR突变状态存在显著相关性(OR=3.3, 95%CI:1.4~8.0)。因本研究界定的肺内转移无法排除多原发肺癌, 故可能夸大了其临床相关性。

本研究针对突变率较高且具有EGFR-TKIs易感性的19、21外显子进行了分层及对比分析。与总体突变不同的是, 19外显子仅存在肺内转移差异性(P = 0.003), 而性别及吸烟史均无差异性。21外显子则在性别(P = 0.004)和吸烟史(P = 0.037)方面均存在统计学差异, 而肺内转移方面无统计学差异(P > 0.05)。对转移器官数量进行分层分析发现, 多发转移与无转移存在明显差异, 进一步行多因素分析发现, 仅性别与EGFR 21外显子阳性突变存在显著相关性(OR = 7.8, 95%CI:2.1~28.6), 而吸烟史和转移器官数均无统计学相关(P > 0.05)。

据文献^[13]报道, 19、21外显子突变状态对于EGFR-TKIs一线治疗预后存在差异性。本研究同样对其进行了组内比较, 以预测预后。但发现此2种突变仅在是否有器官转移(P = 0.045)和肺内转移方面存在统计学差异(P = 0.013), 而2种突变预后的差异尚不明确, 缺乏前瞻性大样本研究佐证。

综上所述, 本研究显示, 肺腺癌EGFR突变多见于女性、非大量吸烟、存在肺内转移以及进展期患者。19外显子突变存在肺内转移差异性, 21外显子突变存在性别、吸烟史及转移器官数差异性。二者的突变率在已发生转移或仅肺内转移的患者中存在显著差异。女性肺腺癌患者EGFR突变率比男性患者增加3.4倍, 21外显子阳性突变率比男性患者提高7.8倍, 发生肺内转移的肺腺癌患者阳性突变率提高3.3倍。

参考文献

[1]	FENG RM, ZONG YN, CAO SM, et al. Current cancer situation in China:good or bad news from the 2018 Global Cancer Statistics?[J]. Cancer Commun (Lond), 2019, 39(1): 22. DOI:10.1186/s40880-019-0368-6
[2]	ZENG HM, CHEN WQ, ZHENG RS, et al. Changing cancer survival in China during 2003-15:a pooled analysis of 17 population-based cancer registries[J]. Lancet Glob Health, 2018, 6(5): e555-e567. DOI:10.1016/S2214-109X(18)30127-X
[3]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI:10.3322/caac.21492
[4]	UTADA M, YONEHARA S, OZASA K. Historical changes in histological diagnosis of lung cancer[J]. J Epidemiol, 2019, 29(6): 238-240. DOI:10.2188/jea.JE20180037
[5]	LIANG F, WU CX, GU HY, et al. Lung cancer incidence in female rises significantly in urban sprawl of Shanghai after introduction of LDCT screening[J]. Lung Cancer, 2019, 132: 114-118. DOI:10.1016/j.lungcan.2019.04.020
[6]	DUMA N, SANTANA-DAVILA R, MOLINA JR. Non-small cell lung cancer:epidemiology, screening, diagnosis, and treatment[J]. Mayo Clin Proc, 2019, 94(8): 1623-1640. DOI:10.1016/j.mayocp.2019.01.013
[7]	HIRSCH FR, SCAGLIOTTI GV, MULSHINE JL, et al. Lung cancer:current therapies and new targeted treatments[J]. Lancet, 2017, 389(10066): 299-311. DOI:10.1016/S0140-6736(16)30958-8
[8]	ISOMOTO K, HARATANI K, HAYASHI H, et al. Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer[J]. Clin Cancer Res, 2020, 26(8): 2037-2046. DOI:10.1158/1078-0432.CCR-19-2027
[9]	LIN G, LI C, LI PS, et al. Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma[J]. Ann Oncol, 2020, 31(4): 517-524. DOI:10.1016/j.annonc.2020.01.014
[10]	ROBICHAUX JP, ELAMIN YY, TAN Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer[J]. Nat Med, 2018, 24(5): 638-646. DOI:10.1038/s41591-018-0007-9
[11]	LIU JX, MU ZM, LIU L, et al. Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients[J]. Drug Des Devel Ther, 2019, 13: 1809-1817. DOI:10.2147/DDDT.S196189
[12]	ZHUANG XB, ZHAO C, LI JY, et al. Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF[J]. Cancer Med, 2019, cam4.2183. DOI:10.1002/cam4.2183
[13]	ISAKA T, YOKOSE T, ITO H, et al. Correlations between the EGFR mutation status and clinicopathological features of clinical stage I lung adenocarcinoma[J]. Medicine (Baltimore), 2015, 94(42): e1784. DOI:10.1097/MD.0000000000001784
[14]	ROSELL R, MORAN T, QUERALT C, et al. Screening for epidermal growth factor receptor mutations in lung cancer[J]. N Engl J Med, 2009, 361(10): 958-967. DOI:10.1056/nejmoa0904554
[15]	HUANG SF, LIU HP, LI LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan[J]. Clin Cancer Res, 2004, 10(24): 8195-8203. DOI:10.1158/1078-0432.CCR-04-1245
[16]	PAO W, MILLER VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer:current knowledge and future directions[J]. J Clin Oncol, 2005, 23(11): 2556-2568. DOI:10.1200/JCO.2005.07.799
[17]	JÄNNE PA, JOHNSON BE. Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors[J]. Clin Cancer Res, 2006, 12(14 Pt 2): 4416s-4420s. DOI:10.1158/1078-0432.CCR-06-0555
[18]	FUKUOKA M, WU YL, THONGPRASERT S, et al. Biomarker analyses and final overall survival results from a phase Ⅲ, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS)[J]. J Clin Oncol, 2011, 29(21): 2866-2874. DOI:10.1200/JCO.2010.33.4235
[19]	SCHMID K, OEHL N, WRBA F, et al. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases[J]. Clin Cancer Res, 2009, 15(14): 4554-4560. DOI:10.1158/1078-0432.ccr-09-0089
[20]	GUERRERA F, RENAUD S, TABBÓ F, et al. Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas[J]. Eur J Cardio - Thorac Surg, 2017, 51(4): 680-688. DOI:10.1093/ejcts/ezw362
[21]	NIE YQ, GAO W, LI N, et al. Relationship between EGFR gene mutation and local metastasis of resectable lung adenocarcinoma[J]. World J Surg Oncol, 2017, 15(1): 55. DOI:10.1186/s12957-017-1103-x
[22]	ITO M, MIYATA Y, HIRANO S, et al. Synchronicity of genetic variants between primary sites and metastatic lymph nodes, and prognostic impact in nodal metastatic lung adenocarcinoma[J]. J Cancer Res Clin Oncol, 2019, 145(9): 2325-2333. DOI:10.1007/s00432-019-02978-0
[23]	LIU ZC, LIANG HR, LIN J, et al. The incidence of lymph node metastasis in patients with different oncogenic driver mutations among T1 non-small-cell lung cancer[J]. Lung Cancer, 2019, 134: 218-224. DOI:10.1016/j.lungcan.2019.06.026
[24]	WU KL, TSAI MJ, YANG CJ, et al. Liver metastasis predicts poorer prognosis in stage Ⅳ lung adenocarcinoma patients receiving first-line gefitinib[J]. Lung cancer, 2015, 88(2): 187-194. DOI:10.1016/j.lungcan.2015.02.012