«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2022年06期

页码:

782-786

栏目:

论著

出版日期:

2022-12-20

文章信息/Info

Title:

Characteristics and mechanism of pathological transformation of lung adenocarcinoma

作者:

马蓉蓉; 明宗娟; 李维; 张德信; 杨拴盈

710061 西安,西安交通大学附属第二医院

Author(s):

Ma Rongrong;  Ming Zongjuan;  Li Wei;  Zhang Dexin;  Yang Shuanying.

The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China

关键词:

肺腺癌;  转化;  小细胞肺癌;  鳞状细胞癌

Keywords:

Lung adenocarcinoma;  Transformation;  Small cell lung cancer;  Squamous cell carcinoma

分类号:

R734.2

DOI:

10.3877/cma.j.issn.1674-6902.2022.06.003

摘要:

目的 分析肺腺癌转化为鳞状细胞癌(small cell lung cancer, SCC)和小细胞肺癌(squamous cell carcinoma, SCLC)的可能机制及治疗策略。方法 选择2017年1月至2022年2月我院收治的肺腺癌转化为SCLC及SCC 患者7例为对象,分析临床病理特征及基因检测结果,随访并记录转归及预后。结果 7例肺腺癌转化前病例1未检测到驱动基因,病例3为ROS1融合,其余为EGFR突变,病例6伴随TP53、BRCA1突变; 转化后SCC 5例,SCLC 2例,转化后病例1检测到ALK融合,病例3、5和病例6保持原有突变,其余病例转化后未完善基因检测; 7例肺腺癌转化前TKI中位治疗时间14个月(0～74个月)。初诊时,2例SCC SCC-Ag升高,1例SCLC NSE升高; 转化后1例SCC SCC-Ag升高,1例SCLC NSE水平升高约4.7倍,2例SCLC Pro-GRP升高约16倍。7例中位转化时间27个月(11～92个月),SCC 27个月,SCLC 11个月。化疗为基础的综合治疗,一线治疗ORR 100%, DCR 100%,转化后一线治疗中位PFS 7个月,OS为9个月,转化后SCLC与SCC的一线治疗中位PFS分别为7个月和8个月,OS为9个月和8个月; 性别、吸烟、初始接受TKI治疗大于12个月、接受三代EGFR-TKI治疗、EGFR突变对转化时间影响无统计学意义(P>0.05)。结论 病理类型转化是肺腺癌重要的耐药机制之一,SCC-Ag、NSE、Pro-GRP水平升高及TP53突变可能与病理类型转分化有关; 转化后一线化疗具有临床意义。

Abstract:

Objective To analyze the clinical features of LUAD transformed into SCC or SCLC and explore its possible molecular mechanism and treatment. Method The clinical characteristics and genetic tests of 7 LUAD patients transformed into SCC or SCLC were retrospectively analyzed. The 7 patients were followed up by telephone, and the outcome and prognosis of the patients were recorded. Result Before the transformation of the 7 LUAD patients, case 1 detected no driver gene, case 3 was ROS1 fusion, and the others were EGFR mutations; case 6 was accompanied by TP53 and BRCA1 mutations. After transformation, 5 cases were SCC and 2 cases were SCLC; case 1 detected ALK fusion, cases 3, 5 and 6 remained original mutations. The rest cases didn't receive the genetic test after transformation. The median time of taking TKIs was 14 months(0-74 months). At initial diagnosis, SCC-Ag was higher than the upper limit of normal in 2 of the patients transformed into SCC; NSE was higher than the upper limit of normal in 1 of the patients transformed into SCLC. After transformation, SCC-Ag was higher than the upper limit of normal in 1 of the patients transformed into SCC; NSE was about 4.7 times higher than the initial level in 1 of the patients transformed into SCLC; Pro-GRP in 2 SCLC patients was about 16 times higher than the initial level. The median transformation time of 7 LUAD patients was 27 months(11-92 months), the median transformation time of SCC was 27 months, and SCLC was 11 months. All patients received chemotherapy-based comprehensive therapy after transformation. The ORR of first-line therapy was 100%, the DCR was 100%, and the median PFS of first-line therapy was 7 months. the median OS after transformation was 9 months. The median OS of SCLC and SCC after transformation was 9 months and 8 months, respectively; and the median PFS of first-line therapy was 7 months and 8 months, respectively. Gender, smoking, initial TKI treatment for more than 12 months, third-generation TKI treatment, and EGFR mutation had no significant effect on transformation time(P>0.05). Conclusion Pathological transformation is one of the important drug resistance mechanisms of LUAD. Elevated levels of SCC-Ag, NSE, Pro-GRP and TP53 mutation may be related to pathological transformation; first-line chemotherapy can still benefit after transformation.

参考文献/References:

1 吴国明, 钱桂生. 非小细胞肺癌靶向治疗研究进展及新理念[J/CD]. 中华肺部疾病杂志(电子版), 2019, 12(4): 405-408.
2 徐 瑜, 白 莉. 广泛期小细胞肺癌免疫治疗新理念[J/CD]. 中华肺部疾病杂志(电子版), 2021, 14(4): 407-411.
3 Travis WD, Brambilla E, Nicholson A G, et al. The 2015 world health organization classification of lung tumors impact of genetic, clinical and radiologic advances since the 2004 classification-sciencedirect[J]. J Thorac Oncol, 2015, 10(9): 1243-1260.
4 陈玥清, 陈雨婷, 童欣媛, 等. 腺鳞癌转化在肺癌耐药中的功能和机制研究[J]. 生物医学转化, 2021, 2(1): 39-49.
5 Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[J]. Clin Cancer Res, 2013, 19(8): 2240-2247.
6 Sutherland KD, Proost N, Brouns I, et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1in distinct cell types of adult mouse lung[J]. Cancer Cell, 2011, 19(6): 754-764.
7 Camolotto SA, Pattabiraman S, Mosbruger TL, et al. FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer[J]. ELife, 2018, 26(7): e38579- e38607.
8 Gao Y, Zhang W, Han X, et al. Erratum: YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression[J]. Nature Communicat, 2014, 5(1): 4629-4643.
9 Han X, Li F, Fang Z, et al. Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma[J]. Nature Publish Group, 2014, 5(1): 3261-3274.
10 Li F, Han X, Li F, et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response[J]. Cancer cell, 2015, 27(5): 698-711.
11 Zhang H, Brainson CF, Koyama S, et al. Lkb1 inactivation drives lung cancer lineage switching governed by polycomb repressive complex 2[J]. Nature Communicat, 2017, 7(8): 14922-14936.
12 Quintanal-Villalonga A, Taniguchi H, Zhan YA, et al. Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation[J]. J Hematol Oncol, 2021, 14(1): 170-189.
13 Rudin CM, Brambilla E, Faivre-Finn C, et al. Small-cell lung cancer[J]. Nat Rev Dis Primers, 2021, 7(1): 3-4.
14 Hamilton G, Rath B, Ulsperger E. How to target small cell lung cancer[J]. Oncosc, 2015, 2(8): 684-692.
15 Park KS, Liang MC, Raiser DM, et al. Characterization of the cell of origin for small cell lung cancer[J]. Cell Cycle, 2011, 10(16): 2806-2815.
16 Dick FA, Goodrich DW, Sage J, et al. Non-canonical functions of the RB protein in cancer[J]. Nat Rev Cancer, 2018, 18(7): 442-451.
17 Ku SY, Rosario S, Wang Y, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance[J]. Science, 2017, 355(6320): 78-83.
18 Sutherland KD, Proost N, Brouns I, et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung cancer cell[J]. 2011, 19(6): 754-764.
19 Wang S, Xie T, Hao X, et al Comprehensive analysis of treatment modes and clinical outcomes of small cell lung cancer transformed from epidermal growth factor receptor mutant lung adenocarcinoma[J]. Thorac Cancer, 12(19): 2585-2593.
20 Lee JK, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas [J]. J Clin Oncol, 2017, 35(26): 3065-3074.
21 Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes[J]. J Thorac Oncol, 2019, 14(10): 1784-1793.
22 Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin[J]. Lancet Oncol, 2015, 16(4): e165-e172.
23 Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors[J]. Sci Translat Med, 2011, 3(75): 75ra26.
24 Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer[J]. Clin Cancer Res, 2020, 26(11): 2654-2663.
25 Nagaraj AS, Lahtela J, Hemmes A, et al. Cell of origin links histotype spectrum to immune microenvironment diversity in non-small-cell lung cancer driven by mutant kras and loss of Lkb1[J]. Cell Reports, 2017, 18(3): 673-684.
26 Ferrer L, Levra MG, Brevet M, et al. A brief report of transformation from non-small cell to small cell lung cancer: Molecular and therapeutic characteristics[J]. J Thorac Oncol, 2018, 14(1): 130-134.
27 Shi X, Duan H, Liu X, et al. Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors[J]. Oncotarget, 2016, 7(23): 34240-34249.
28 张红军, 房延凤, 谢永宏, 等. 肺癌患者异常糖链糖蛋白与传统肿瘤标志物的相关性分析[J/CD]. 中华肺部疾病杂志(电子版), 2019, 12(1): 24-27.
29 Fang L, He J, Xia J, et al. Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report[J]. Oncol Lett, 2017, 14(1): 593-598.
30 Kato Y, Tanaka Y, Hino M, et al. ProGRP as early predictive marker of non-small-cell lung cancer to small-cell lung cancer transformation after EGFR-TKI treatment[J]. Respir Med Case Rep, 2019, 27: 100837.
31 Levin PA, Mayer M, Hoskin S, et al. Histologic transformation from adenocarcinoma to squamous cell carcinoma as a mechanism of resistance to EGFR inhibition[J]. J Thorac Oncol, 2015, 10( 9): e86-e88.
32 Xie T, Li Y, Xing P. Mechanism of histologic transformation of drive gene positive lung adenocarcinoma in targeted therapy and treatment strategy[J]. Chin J Lung Cancer, 2020, 23(8): 701-709.

备注/Memo

备注/Memo:

基金项目: 陕西省重点研发计划(2021SF-039)
通信作者: 杨拴盈, Email: yangshuanying66@163.com

常用功能

更新日期/Last Update: 2022-12-20