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不同二代
ALK -TKIs 二线治疗ALK 阳性晚期非小细胞肺癌的耐药基因变异分子图谱差异Second-generation
ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment forALK fusion positive advanced NSCLC- 陆军军医大学学报 2022年44卷第24期 页码：2493-2499
- 作者机构：
1.200032 上海，复旦大学附属中山医院呼吸与危重症医学科
2.201104 上海，上海市老年医学中心呼吸与危重症医学科
- 作者简介：
[ 胡洁，E-mail: hu.jie@zs-hospital.sh.cn HU Jie, E-mail: hu.jie@zs-hospital.sh.cn
- 基金信息：上海市临床重点专科建设项目(shslczdzk02201)
DOI：10.16016/j.2097-0927.202209192
中图分类号： R734.2;R969.4;R979.19收稿：2022-09-21，
修回：2022-10-08，
纸质出版：2022-12-30
- 稿件说明：
移动端阅览
丁宁, 徐晓波, 周洁白, 等. 不同二代
ALK -TKIs 二线治疗ALK 阳性晚期非小细胞肺癌的耐药基因变异分子图谱差异[J]. 陆军军医大学学报, 2022,44(24):2493-2499.Ning DING, Xiaobo XU, Jiebai ZHOU, et al. Second-generation
ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment forALK fusion positive advanced NSCLC[J]. Journal of Army Medical University, 2022, 44(24): 2493-2499.丁宁, 徐晓波, 周洁白, 等. 不同二代
ALK -TKIs 二线治疗ALK 阳性晚期非小细胞肺癌的耐药基因变异分子图谱差异[J]. 陆军军医大学学报, 2022,44(24):2493-2499. DOI： 10.16016/j.2097-0927.202209192.Ning DING, Xiaobo XU, Jiebai ZHOU, et al. Second-generation
ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment forALK fusion positive advanced NSCLC[J]. Journal of Army Medical University, 2022, 44(24): 2493-2499. DOI： 10.16016/j.2097-0927.202209192.
摘要
目的
2
比较和探索不同二代间变性淋巴瘤激酶-酪氨酸激酶抑制剂(anaplastic lymphoma kinase-tyrosine kinase inhibitors，
ALK-TKIs
)获得性耐药基因变异图谱差异，为
ALK
阳性晚期非小细胞肺癌(non-small cell lung cancer，NSCLC)的全程管理提供依据。
方法
2
本研究为观察性研究，纳入2014年至2020年共计103例
ALK
阳性晚期NSCLC患者，在一线克唑替尼治疗和二线二代
ALK-TKIs
治疗发生耐药后，通过组织样本或液体样本行下一代测序(next generation sequencing，NGS)检测，分析不同的二代靶向药物发生获得性耐药的基因变异分子图谱的异同。
结果
2
二代TKIs获得性耐药以
ALK
激酶结构域突变为主(66.7%)，发生率
V
3型显著高于
V
1型(85.7%
vs
. 55.6%，
P
=0.003 9)；最常见
G
1202
R/K
和
L
1196
M
，前者多见于
V
3型(57.1%
vs
.4.4%，
P
<
0.000 1)，后者在
V
1型相对多见(31.1%
vs
. 14.3%，
P
=0.079 4)。阿来替尼耐药以
ALK
继发突变发生率最高，常见
G
1202
R
(31.6%)和
G
1269
A
(12.3%)；色瑞替尼
G
1202
R
、
L
1196
M
、
F
1174
X
和
C
1156
Y
发生率较高；而布加替尼
F
1174
X
>
、
D
1203
N
、
E
1210
K
发生率较高。
D
1203
N
(0
vs
. 6.7%
vs
. 20%，
P
=0.000 2)和
E
1210
K
(1.8%
vs
. 0
vs
.15%，
P
=0.003 5)主要发生在布加替尼耐药后。
ALK-TKIs
的序贯应用可引起
ALK
基因的复合突变。
结论
2
二代
ALK-TKIs
二线治疗耐药后基因变异图谱复杂多样，不同药物、不同
ALK
变体之间差异较大，且存在复合突变，增加后线治疗难度，因此
ALK
阳性晚期NSCLC的临床治疗决策需充分考虑耐药分子机制后进行全局化管理。
Abstract
Objective
2
To compare and investigate the molecular profiles in acquired resistance-associated genetic alterations of second-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (
ALK-TKIs
) in order to provide evidence for the management of
ALK
fusion positive advanced non-small cell lung cancer (NSCLC).
Methods
2
An observational study was conducted on 103 patients with
ALK
-fusion positive advanced NSCLC who received first-line treatment of crizotinib and then second-line treatment of second-generation
ALK-TKIs
in Zhongshan Hospital from 2014 to 2020. Genetic alteration profiles were analyzed by next generation sequencing (NGS) on tissue or liquid samples after relapse of second-generation ALK-TKIs.
Results
2
The acquired
ALK-TKIs
-resistant genetic alterations were dominated by
ALK
kinase domain mutations (66.7%)
which had a significant higher incidence in
V
3 variant compared with
V
1 variant (85.7%
vs
55.6%
P
=0.003 9). The most common
ALK
mutations were
G
1202
R/K
and
L
1196
M
and the former was more common in
V
3 subtype (57.1%
vs
4.4%
P
<
0.000 1) while the latter in
V
1 subtype (31.1%
vs
14.3%
P
=0.079 4). The patients who were resistant to alectinib had the highest incidence of secondary mutations
with
G
1202
R
(31.6%) and
G
1269
A
(12.3%) were the top 2 mutations.
G
1202
R
L
1196
M
F
1174
X
and
C
1156
Y
were more common in the patients resistant to ceritinib.
F
1174
X
D
1203
N
and
E
1210
K
were the top 3 mutations among the patients who progressed after brigatinib therapy.
D
1203
N
(0
vs
6.7%
vs
20%
P
=0.000 2) and
E
1210
K
(1.8%
vs
0
vs
15.0%
P
=0.003 5) mainly occurred in the brigatinib group. The sequential application of
ALK TKIs
may cause co-mutations of
ALK
gene.
Conclusion
2
The profile of genetic alteration failed from second-line second-generation
ALK-TKIs
treatment are complex and diverse. There are differences between different drugs and different
ALK
variants
as well as compound mutations
which increase the difficulty in later line therapy. Therefore
the clinical treatment decisions of advanced NSCLCs with
ALK
positive should be established on the fully consideration of the drug resistance m
echanism.
关键词
Keywords
references
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