HER2基因状态与晚期肺腺癌患者一线培美曲塞联合铂类化疗疗效的关系
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摘要
背景与目的人类表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)突变是非小细胞肺癌(non-small cell lung cancer, NSCLC)的分子标记物之一,研究显示培美曲塞在HER2突变NSCLC中的疗效存在争议。本研究拟探讨培美曲塞联合铂类化疗在HER2突变和HER2野生型肺腺癌患者中的疗效。方法回顾性分析在郑州大学第一附属医院经组织病理学证实的106例EGFR、ALK、ROS-1、KRAS、BRAF、RET、MET均为阴性的晚期肺腺癌患者的临床资料。分析HER2基因状态、临床特征、化疗疗效及无进展生存期(progression-free survival, PFS)之间的关系。结果 106例患者均进行了HER2基因检测,HER2突变32例(30.2%),未发生突变74例(69.8%)。HER2突变在年轻、未吸烟、女性患者中多见。所有患者均接受一线培美曲塞联合铂类的化疗,HER2突变肺腺癌患者的客观缓解率(objective response rate, ORR)和疾病控制率(disease control rate, DCR)均高于HER2野生型患者(40.6%vs 14.9%,χ~2=8.464, P=0.004; 93.8%vs 68.9%,χ~2=6.327, P=0.012),差异有统计学意义。单因素分析显示:PFS与有无脑转移、有无维持化疗和HER2基因状态相关(P<0.05),而与年龄、性别、是否有吸烟史、是否寡转移、有无肝转移及铂的种类无关(P>0.05)。Cox多因素分析显示:HER2突变是PFS的独立正性预后因素(P=0.038)。结论HER2突变相比HER2野生型肺腺癌患者一线应用培美曲塞联合铂类的化疗有更大的临床获益。
Background and objective Human epidermal growth factor receptor 2(HER2) is one of the driver genes of non-small cell lung cancer(NSCLC). Several studies have shown that the efficacy of pemetrexed in HER2-mutant NSCLC is controversial. The aim of this study is to investigate the efficacy of pemetrexed combined with platinum chemotherapy in patients with HER2-mutant and HER2 wild-type lung adenocarcinoma. Methods The clinical data of 106 cases of EGFR, ALK, ROS-1, KRAS, BRAF, RET and MET-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology in the First Affiliated Hospital of Zhengzhou University were retrospectively reviewed. The relationships between HER2 gene status, clinical characteristics and response and progression-free survival(PFS) were analyzed. Results All of the 106 patients' HER2 status were determined. HER2 mutations occurred in 32 cases(30.2%), no mutations in 74 cases(69.8%). HER2 mutations were common in young, non-smoking and female patients. All patients received first-line pemetrexed and platinum-based chemotherapy. The objective response rate(ORR) and disease control rate(DCR) of patients with HER2-mutant lung adenocarcinoma were significantly higher than those without HER2 mutations(40.6% vs 14.9%, χ~2=8.464, P=0.004; 93.8% vs 68.9%, χ~2=6.327, P=0.012), and the difference was statistically significant. According to univariate analysis, the PFS was significantly associated with the brain metastases, maintenance chemotherapy and HER2 gene status(P<0.05), but not with age, gender, smoking history, oligometastases, liver metastases and type of platinum(P>0.05). Cox multivariate analysis indicated that HER2 mutation was an independent positive prognostic factor of PFS(P=0.038). Conclusion HER2-mutant lung adenocarcinoma patients with first-line pemetrexed combined with platinum chemotherapy have greaterclinical benefit than HER2 wild-type patients.
Background and objective Human epidermal growth factor receptor 2(HER2) is one of the driver genes of non-small cell lung cancer(NSCLC). Several studies have shown that the efficacy of pemetrexed in HER2-mutant NSCLC is controversial. The aim of this study is to investigate the efficacy of pemetrexed combined with platinum chemotherapy in patients with HER2-mutant and HER2 wild-type lung adenocarcinoma. Methods The clinical data of 106 cases of EGFR, ALK, ROS-1, KRAS, BRAF, RET and MET-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology in the First Affiliated Hospital of Zhengzhou University were retrospectively reviewed. The relationships between HER2 gene status, clinical characteristics and response and progression-free survival(PFS) were analyzed. Results All of the 106 patients' HER2 status were determined. HER2 mutations occurred in 32 cases(30.2%), no mutations in 74 cases(69.8%). HER2 mutations were common in young, non-smoking and female patients. All patients received first-line pemetrexed and platinum-based chemotherapy. The objective response rate(ORR) and disease control rate(DCR) of patients with HER2-mutant lung adenocarcinoma were significantly higher than those without HER2 mutations(40.6% vs 14.9%, χ~2=8.464, P=0.004; 93.8% vs 68.9%, χ~2=6.327, P=0.012), and the difference was statistically significant. According to univariate analysis, the PFS was significantly associated with the brain metastases, maintenance chemotherapy and HER2 gene status(P<0.05), but not with age, gender, smoking history, oligometastases, liver metastases and type of platinum(P>0.05). Cox multivariate analysis indicated that HER2 mutation was an independent positive prognostic factor of PFS(P=0.038). Conclusion HER2-mutant lung adenocarcinoma patients with first-line pemetrexed combined with platinum chemotherapy have greaterclinical benefit than HER2 wild-type patients.
引文
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2 Jacques F,Isabelle S,Rajesh D,et al.Cancer incidence and mortality worldwide:Sources,methods and major patterns in GLOBOCA N2012.Int J Cancer,2015,136(5):E359-E386.doi:10.1002/ijc.29210
3 Citri A,Skaria KB,Yarden Y.The deaf and the dumb:the biology of ErbB-2 and ErbB-3.Exp Cell Res,2003,284(1):54-65.doi:10.1016/S0014-4827(02)00101-5
4 Peters S,Zimmermann S.Targeted therapy in NSCLC driven by HER2insertions.Trans Lung Cancer Res,2014,3(2):84-88.doi:10.3978/j.issn.2218-6751.2014.02.06
5 Stephens P,Hunter C,Bignell G,et al.Lung cancer:intragenic ERBB2kinase mutations in tumours.Nature,2004,431(7008):525-526.doi:10.1038/431525b
6 Wa ng Y,Zha ng S,Wu F,e t al.Outcomes of pemet re xed-ba sed chemotherapies in HER2-mutant lung cancers.BMC Cancer,2018,18(1):326.doi:10.1186/s12885-018-4277-x
7 Shigematsu H,Takahashi T,Nomura M,et al.Somatic mutations of the HER2 kinase domain in lung adenocarcinomas.Cancer Res,2005,65(5):1642-1646.doi:10.1158/0008-5472.can-04-4235
8 A rcila M E,Chaft JE,Nafa K,et al.Prevalence,clinicopathologic associations,and molecular spectrum of ER BB2(HER 2)tyrosine kinase mutations in lung adenocarcinomas.Clin Cancer Res,2012,18(18):4910-4918.doi:10.1158/1078-0432.ccr-12-0912
9 Mazieres J,Peters S,Lepage B,et al.Lung cancer that harbors an HER2mutation:Epidemiologic characteristics and therapeutic perspectives.JClin Oncol,2013,31(16):1297-1307.doi:10.1200/Jco.2012.45.6095
10 Song Z,Yu X,Shi Z,et al.HER2 mutations in Chinese patients with non-small cell lung cancer.Oncotarget,2016,7(47):78152-78158.doi:10.18632/oncotarget.11313
11 NCC N C l i n ic a l P r ac t ic e Gu idel i ne s i n Non-Sm a l l C el l L u ng Cancer(2019 Version 1)[Internet].2018 Oct 19[cited:2018 Nov 1].Available from:http://www.nccn.org/
12 Lopez-Chavez A,Thomas A,Rajan A,et al.Molecular profiling and targeted therapy for advanced thoracic malignancies:a biomarkerderived,multiarm,multihistology phase II basket trial.J Clin Oncol,2015,33(9):1000-1007.doi:10.1200/jco.2014.58.2007
13 Mazières J,Barlesi F,Filleron T,et al.Lung cancer patients with HER2mutations treated with chemotherapy and H ER 2-targeted drugs:results from the European EUHER2 cohort.Ann Oncol,2016,27(2):281-286.doi:10.1093/annonc/mdv573
14 Expanding targeted therapies for NSCLC.Cancer Discov,2014,4(12):OF1.doi:10.1158/2159-8290.cd-nb2014-161
15 Kris MG,Camidge DR,Giaccone G,et al.Targeting HER2 aberrations as actionable drivers in lung cancers:phase II trial of the pan-HERtyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.Ann Oncol,2015,26(7):1421-1427.doi:10.1093/annonc/mdv186
16 Li BT,Shen R,Buonocore D,et al.Ado-trastuzumab emtansine for patients with HER 2-mutant lung cancers:results from a phase IIbasket trial.J Clin Oncol,2018,36(24):2532-2537.doi:10.1200/jco.2018.77.9777
17 K im TM,Lee K W,Oh DY,et al.Phase 1 studies of poziotinib,an irreversible Pan-H ER t y rosine k inase inhibitor in patients w ith advanced solid tumors.Cancer Res Treat,2018,50(3):835-842.doi:10.4143/crt.2017.303
18 Tsai CM,Chang KT,Li L,et al.Interrelationships between cellular nucleotide excision repair,cisplatin cytotoxicity,HER-2/neu gene expression,and epidermal growth factor receptor level in non-small cell lung cancer cells.Jpn J Cancer Res,2000,91(2):213-222.doi:10.1111/j.1349-7006.2000.tb00934.x
19 Hou X P,Liu B,Yu Z,et al.The role of HER 2 in secondar y drugresistance in A549 lung adenocarcinoma cells induced by pemetrexed.Xian Dai Sheng Wu Yi Xue Jin Zhan,2013,13(18):3448-3451.[侯宪鹏,刘冰,于壮,等.HER2在人肺腺癌A549细胞培美曲塞继发性耐药中的作用研究.现代生物医学进展,2013,13(18):3448-3451.]doi:10.13241/j.cnki.pmb.2013.18.047
20 Eng J,Hsu M,Chaft JE,et al.Outcomes of chemotherapies and HER2directed therapies in advanced HER 2-mutant lung cancers.Lung Cancer,2016,99:53-56.doi:10.1016/j.lungcan.2016.05.030
2 Jacques F,Isabelle S,Rajesh D,et al.Cancer incidence and mortality worldwide:Sources,methods and major patterns in GLOBOCA N2012.Int J Cancer,2015,136(5):E359-E386.doi:10.1002/ijc.29210
3 Citri A,Skaria KB,Yarden Y.The deaf and the dumb:the biology of ErbB-2 and ErbB-3.Exp Cell Res,2003,284(1):54-65.doi:10.1016/S0014-4827(02)00101-5
4 Peters S,Zimmermann S.Targeted therapy in NSCLC driven by HER2insertions.Trans Lung Cancer Res,2014,3(2):84-88.doi:10.3978/j.issn.2218-6751.2014.02.06
5 Stephens P,Hunter C,Bignell G,et al.Lung cancer:intragenic ERBB2kinase mutations in tumours.Nature,2004,431(7008):525-526.doi:10.1038/431525b
6 Wa ng Y,Zha ng S,Wu F,e t al.Outcomes of pemet re xed-ba sed chemotherapies in HER2-mutant lung cancers.BMC Cancer,2018,18(1):326.doi:10.1186/s12885-018-4277-x
7 Shigematsu H,Takahashi T,Nomura M,et al.Somatic mutations of the HER2 kinase domain in lung adenocarcinomas.Cancer Res,2005,65(5):1642-1646.doi:10.1158/0008-5472.can-04-4235
8 A rcila M E,Chaft JE,Nafa K,et al.Prevalence,clinicopathologic associations,and molecular spectrum of ER BB2(HER 2)tyrosine kinase mutations in lung adenocarcinomas.Clin Cancer Res,2012,18(18):4910-4918.doi:10.1158/1078-0432.ccr-12-0912
9 Mazieres J,Peters S,Lepage B,et al.Lung cancer that harbors an HER2mutation:Epidemiologic characteristics and therapeutic perspectives.JClin Oncol,2013,31(16):1297-1307.doi:10.1200/Jco.2012.45.6095
10 Song Z,Yu X,Shi Z,et al.HER2 mutations in Chinese patients with non-small cell lung cancer.Oncotarget,2016,7(47):78152-78158.doi:10.18632/oncotarget.11313
11 NCC N C l i n ic a l P r ac t ic e Gu idel i ne s i n Non-Sm a l l C el l L u ng Cancer(2019 Version 1)[Internet].2018 Oct 19[cited:2018 Nov 1].Available from:http://www.nccn.org/
12 Lopez-Chavez A,Thomas A,Rajan A,et al.Molecular profiling and targeted therapy for advanced thoracic malignancies:a biomarkerderived,multiarm,multihistology phase II basket trial.J Clin Oncol,2015,33(9):1000-1007.doi:10.1200/jco.2014.58.2007
13 Mazières J,Barlesi F,Filleron T,et al.Lung cancer patients with HER2mutations treated with chemotherapy and H ER 2-targeted drugs:results from the European EUHER2 cohort.Ann Oncol,2016,27(2):281-286.doi:10.1093/annonc/mdv573
14 Expanding targeted therapies for NSCLC.Cancer Discov,2014,4(12):OF1.doi:10.1158/2159-8290.cd-nb2014-161
15 Kris MG,Camidge DR,Giaccone G,et al.Targeting HER2 aberrations as actionable drivers in lung cancers:phase II trial of the pan-HERtyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.Ann Oncol,2015,26(7):1421-1427.doi:10.1093/annonc/mdv186
16 Li BT,Shen R,Buonocore D,et al.Ado-trastuzumab emtansine for patients with HER 2-mutant lung cancers:results from a phase IIbasket trial.J Clin Oncol,2018,36(24):2532-2537.doi:10.1200/jco.2018.77.9777
17 K im TM,Lee K W,Oh DY,et al.Phase 1 studies of poziotinib,an irreversible Pan-H ER t y rosine k inase inhibitor in patients w ith advanced solid tumors.Cancer Res Treat,2018,50(3):835-842.doi:10.4143/crt.2017.303
18 Tsai CM,Chang KT,Li L,et al.Interrelationships between cellular nucleotide excision repair,cisplatin cytotoxicity,HER-2/neu gene expression,and epidermal growth factor receptor level in non-small cell lung cancer cells.Jpn J Cancer Res,2000,91(2):213-222.doi:10.1111/j.1349-7006.2000.tb00934.x
19 Hou X P,Liu B,Yu Z,et al.The role of HER 2 in secondar y drugresistance in A549 lung adenocarcinoma cells induced by pemetrexed.Xian Dai Sheng Wu Yi Xue Jin Zhan,2013,13(18):3448-3451.[侯宪鹏,刘冰,于壮,等.HER2在人肺腺癌A549细胞培美曲塞继发性耐药中的作用研究.现代生物医学进展,2013,13(18):3448-3451.]doi:10.13241/j.cnki.pmb.2013.18.047
20 Eng J,Hsu M,Chaft JE,et al.Outcomes of chemotherapies and HER2directed therapies in advanced HER 2-mutant lung cancers.Lung Cancer,2016,99:53-56.doi:10.1016/j.lungcan.2016.05.030