高通量药物敏感性筛选系统在非小细胞肺癌伴恶性胸腔积液治疗中的应用

doi:10.3969/j.issn.1674-8115.2022.01.012

上海交通大学学报(医学版) ›› 2022, Vol. 42 ›› Issue (1): 82-89.doi: 10.3969/j.issn.1674-8115.2022.01.012

高通量药物敏感性筛选系统在非小细胞肺癌伴恶性胸腔积液治疗中的应用

张宇¹(), 吴晓渊²(), 管丽华³, 刘译远⁴, 彭星月⁴, 谢海燕¹, 胡玮¹, 郝可可¹, 夏宁¹, 陆国军¹, 侯志波¹

^1.南京市胸科医院 / 南京医科大学附属脑科医院呼吸一科，南京 210029
^2.南京市胸科医院 / 南京医科大学附属脑科医院中心实验室，南京 210029
^3.南京市胸科医院 / 南京医科大学附属脑科医院信息科，南京 210029
^4.南京融康博临床医学研究院，南京 210018

收稿日期:2021-08-04 出版日期:2022-01-28 发布日期:2022-02-18
通讯作者: 张宇 E-mail:zhangyu2113_nj@163.com
作者简介:张宇（1973—），女，主任医师，硕士；电子信箱：zhangyu2113_nj@163.com
张宇（1973—），女，主任医师，硕士；电子信箱：zhangyu2113_nj@163.com
基金资助:
江苏省卫生计生委医学科研课题面上项目(H2018030)

Application of high-throughput drug sensitivity screening system in the treatment of non-small cell lung cancer with malignant pleural effusion

Yu ZHANG¹(), Xiaoyuan WU²(), Lihua GUAN³, Yiyuan LIU⁴, Xingyue PENG⁴, Haiyan XIE¹, Wei HU¹, Keke HAO¹, Ning XIA¹, Guojun LU¹, Zhibo HOU¹

^1.Department of Respiratory Medicine, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
^2.Central laboratory, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
^3.Information Department, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
^4.Nanjing TechBoon Clinical Medicine Institute, Nanjing 210018, China

Received:2021-08-04 Online:2022-01-28 Published:2022-02-18
Contact: Yu ZHANG E-mail:zhangyu2113_nj@163.com
Supported by:
General Program of Medical Scientific Research Project of Jiangsu Health and Family Planning Commission(H2018030)

摘要/Abstract

摘要：

目的·探讨体外高通量药物敏感性筛选系统指导非小细胞肺癌（non-small cell lung cancer，NSCLC）伴恶性胸腔积液（malignant pleural effusion，MPE）患者个体化治疗的可行性。方法·纳入2019年1月—2020年5月就诊于南京市胸科医院的30例NSCLC伴MPE患者，收集并分离胸水中的肿瘤细胞，培养原代细胞，使用自动数字荧光扫描仪的高通量药物敏感性筛选系统，检测30种化学治疗（化疗）药物和分子靶向药物的体外直接敏感性，评估药物敏感检测结果与患者临床治疗效果的一致性。结果·胸腔积液原代肿瘤细胞的体外药物敏感性检测结果显示药物反应存在很大的异质性。大部分原代细胞对表柔比星、洛铂、吉西他滨和伊立替康敏感。23例患者可评价其临床疗效，对于表皮生长因子受体（epidermal growth factor receptor，EGFR）基因突变阳性的初治NSCLC晚期患者，靶向治疗的效果与高通量药敏试验结果的一致性为44.4%（4/9）；对于EGFR突变阴性的患者和EGFR突变阳性接受靶向治疗耐药的晚期NSCLC患者，采用化疗的效果与体外高通量药物敏感试验结果一致率为85.7%（12/14）。结论·基于NSCLC患者MPE原代细胞培养的高通量药物敏感性试验与化疗的临床疗效一致性较高，有助于临床制定个体化化疗方案。

关键词: 非小细胞肺癌, 胸腔积液, 体外药物敏感试验, 个体化治疗

Abstract:

Objective·To explore the feasibility of individualized treatment of malignant pleural effusion (MPE) patients with non-small cell lung cancer (NSCLC) guided by in vitro high-throughput drug sensitivity screening system.

Methods·Thirty NSCLC patients with MPE treated in Nanjing Chest Hospital from January 2019 to May 2020 were included. The tumor cells in MPE were collected and isolated, and primary cells were cultured. The ex vivo drug sensitivity of primary cells was assessed for 30 chemotherapeutical and molecular targeted drugs by using the high-throughput drug sensitivity screening system of automated digital fluorescence imager. The consistency between the drug sensitivity assay results and the clinical efficacy of patients was evaluated.

Results·The ex vivo drug sensitivity results of primary tumor cells cultured from MPE revealed considerable heterogeneity in drug response. Most of the primary cells were sensitive to Epirubicin, Lobaplatin, Gemcitabine and Irinotecan. Clinical efficacy of 23 patients can be evaluated. For patients with previously untreated, epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC, the consistency between the efficacy of targeted therapy and the high-throughput drug sensitivity assay results was 44.4% (4/9). For the EGFR negative untreated patients and EGFR mutation-positive advanced NSCLC patients with acquired resistance to targeted treatment, the consistency between the therapeutic effect of chemotherapy and the high-throughput drug sensitivity assay results was 85.7% (12/14).

Conclusion·The high-throughput drug sensitivity assay based on MPE primary cell culture in NSCLC patients has a high consistency with the clinical efficacy of chemotherapy, which is helpful for decision-making of personalized chemotherapy.

Key words: non-small cell lung cancer, pleural effusion, in vitro chemosensitivity assay, individualized treatment

中图分类号:

R734.2

张宇, 吴晓渊, 管丽华, 刘译远, 彭星月, 谢海燕, 胡玮, 郝可可, 夏宁, 陆国军, 侯志波. 高通量药物敏感性筛选系统在非小细胞肺癌伴恶性胸腔积液治疗中的应用[J]. 上海交通大学学报(医学版), 2022, 42(1): 82-89.

Yu ZHANG, Xiaoyuan WU, Lihua GUAN, Yiyuan LIU, Xingyue PENG, Haiyan XIE, Wei HU, Keke HAO, Ning XIA, Guojun LU, Zhibo HOU. Application of high-throughput drug sensitivity screening system in the treatment of non-small cell lung cancer with malignant pleural effusion[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(1): 82-89.

图/表 5

参考文献 30

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Sample	Gender	Age /year	Therapy line	Histology	EGFR/ALK/ ROS1 testing	Treatment	Clinical efficacy	High-throughput drug sensitivity test in vitro	Consistency analysis
S1	Male	72	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S3	Female	48	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S4	Female	78	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Low sensitive to Pemetrexed and Carboplatin	Consistent
S5	Female	48	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Low sensitive to Gefitinib	Consistent
S7	Female	48	1	Adenocarcinoma	Negative	Pemetrexed + Cisplatin + Bevacizumab	PR	Low sensitive to Pemetrexed and Cisplatin	Consistent
S10	Female	60	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Low sensitive to Pemetrexed and Carboplatin	Consistent
S15	Female	67	1	Adenocarcinoma	Negative	Pemetrexed + Cisplatin	PR	Resistant to Pemetrexed and Cisplatin	Inconsistent
S16	Male	63	1	Adenocarcinoma	EGFR21L858R	Gefitinib	SD	Low sensitive to Gefitinib	Consistent
S19	Male	74	1	Adenosquamous	Negative	Docetaxel + Nedaplatin	SD	Low sensitive to Docetaxel and Nedaplatin	Consistent
S20	Female	57	1	Adenocarcinoma	EGFR19DEL	Afatinib	PR	Afatinib resistance	Inconsistent
S23	Male	65	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S24	Male	77	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Resistant to Pemetrexed and Carboplatin	Inconsistent
S25	Male	74	1	Adenocarcinoma	EGFR21L858R	Gefitinib	PR	Moderate sensitive to Gefitinib	Consistent
S26	Female	66	1	Adenocarcinoma	EGFR21L861Q	Afatinib	PR	Low sensitive to Afatinib	Consistent
S27	Male	92	1	Adenocarcinoma	EGFR19DEL	Gefitinib	SD	Gefitinib resistance	Inconsistent
S8	Male	45	3	Adenocarcinoma	Negative	Vinorelbine + Lobaplatin	SD	Low sensitive to Vinorelbine， moderate sensitive to Lobaplatin	Consistent
S11	Female	48	3	Adenocarcinoma	EGFR19DEL	Pemetrexed + Carboplatin + Bevacizumab	PR	Moderate sensitive to Pemetrexed and Carboplatin	Consistent
S13	Male	55	2	Squamous	Negative	Gemcitabine + Nedaplatin	SD	Moderate sensitive to Gemcitabine， low sensitive to Nedaplatin	Consistent
S14	Female	82	3	Adenocarcinoma	EGFR21L858R/T790M/C797S（trans）	S1+Anlotinib	SD	Low sensitive to Tegafur and Nintedanib	Consistent
S18	Male	72	3	Squamous	Negative	S1	SD	Low sensitive to Tegafur	Consistent
S21	Male	45	5	Adenocarcinoma	EGFR19DEL/ T790M/C797S（trans）	Gemcitabine + Lobaplatin	PR	High sensitive to Gemcitabine， moderate sensitive to Lobaplatin	Consistent
S22	Female	71	3	Adenocarcinoma	EGFR21L858R/T790M/C797S（trans）	Pemetrexed + Carboplatin +Bevacizumab	PR	Moderate sensitive to Pemetrexed and Carboplatin	Consistent
S29	Female	60	3	Adenocarcinoma	EGFR21L858R+BRAF V600E	Pemetrexed + Carboplatin	PD	Resistant to Pemetrexed and Carboplatin	Consistent

Sample	Gender	Age /year	Therapy line	Histology	EGFR/ALK/ ROS1 testing	Treatment	Clinical efficacy	High-throughput drug sensitivity test in vitro	Consistency analysis
S1	Male	72	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S3	Female	48	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S4	Female	78	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Low sensitive to Pemetrexed and Carboplatin	Consistent
S5	Female	48	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Low sensitive to Gefitinib	Consistent
S7	Female	48	1	Adenocarcinoma	Negative	Pemetrexed + Cisplatin + Bevacizumab	PR	Low sensitive to Pemetrexed and Cisplatin	Consistent
S10	Female	60	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Low sensitive to Pemetrexed and Carboplatin	Consistent
S15	Female	67	1	Adenocarcinoma	Negative	Pemetrexed + Cisplatin	PR	Resistant to Pemetrexed and Cisplatin	Inconsistent
S16	Male	63	1	Adenocarcinoma	EGFR21L858R	Gefitinib	SD	Low sensitive to Gefitinib	Consistent
S19	Male	74	1	Adenosquamous	Negative	Docetaxel + Nedaplatin	SD	Low sensitive to Docetaxel and Nedaplatin	Consistent
S20	Female	57	1	Adenocarcinoma	EGFR19DEL	Afatinib	PR	Afatinib resistance	Inconsistent
S23	Male	65	1	Adenocarcinoma	EGFR19DEL	Gefitinib	PR	Gefitinib resistance	Inconsistent
S24	Male	77	1	Adenocarcinoma	Negative	Pemetrexed + Carboplatin	SD	Resistant to Pemetrexed and Carboplatin	Inconsistent
S25	Male	74	1	Adenocarcinoma	EGFR21L858R	Gefitinib	PR	Moderate sensitive to Gefitinib	Consistent
S26	Female	66	1	Adenocarcinoma	EGFR21L861Q	Afatinib	PR	Low sensitive to Afatinib	Consistent
S27	Male	92	1	Adenocarcinoma	EGFR19DEL	Gefitinib	SD	Gefitinib resistance	Inconsistent
S8	Male	45	3	Adenocarcinoma	Negative	Vinorelbine + Lobaplatin	SD	Low sensitive to Vinorelbine， moderate sensitive to Lobaplatin	Consistent
S11	Female	48	3	Adenocarcinoma	EGFR19DEL	Pemetrexed + Carboplatin + Bevacizumab	PR	Moderate sensitive to Pemetrexed and Carboplatin	Consistent
S13	Male	55	2	Squamous	Negative	Gemcitabine + Nedaplatin	SD	Moderate sensitive to Gemcitabine， low sensitive to Nedaplatin	Consistent
S14	Female	82	3	Adenocarcinoma	EGFR21L858R/T790M/C797S（trans）	S1+Anlotinib	SD	Low sensitive to Tegafur and Nintedanib	Consistent
S18	Male	72	3	Squamous	Negative	S1	SD	Low sensitive to Tegafur	Consistent
S21	Male	45	5	Adenocarcinoma	EGFR19DEL/ T790M/C797S（trans）	Gemcitabine + Lobaplatin	PR	High sensitive to Gemcitabine， moderate sensitive to Lobaplatin	Consistent
S22	Female	71	3	Adenocarcinoma	EGFR21L858R/T790M/C797S（trans）	Pemetrexed + Carboplatin +Bevacizumab	PR	Moderate sensitive to Pemetrexed and Carboplatin	Consistent
S29	Female	60	3	Adenocarcinoma	EGFR21L858R+BRAF V600E	Pemetrexed + Carboplatin	PD	Resistant to Pemetrexed and Carboplatin	Consistent

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高通量药物敏感性筛选系统在非小细胞肺癌伴恶性胸腔积液治疗中的应用

Application of high-throughput drug sensitivity screening system in the treatment of non-small cell lung cancer with malignant pleural effusion

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