-
摘要: 抗人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）的靶向治疗显著延长了HER2阳性晚期胃癌患者的生存期，抑制HER2通路已成为HER2阳性晚期胃癌一线治疗的基础策略。ToGA研究中的曲妥珠单抗联合5-Fu/卡培他滨及顺铂的化疗方案是HER2阳性晚期胃癌一线化疗的标准方案。后ToGA时代，曲妥珠单抗联合其它的多个化疗方案不仅在晚期胃癌的二线治疗和转化性治疗中有突出的疗效，而且在局部进展期胃癌的新辅助治疗中有望发挥更大的作用。目前胃癌抗HER2治疗的研究方向是开发新的抗HER2药物，以及与其它信号通路的靶向药物联合。动态的基因检测有助于明确抗HER2治疗耐药的分子生物学机制，目前的临床研究在克服耐药性方面已取得进展。本文就HER2阳性晚期胃癌治疗方面的最新进展及今后的研究方向进行综述，以期指导临床实践。Abstract: The addition of HER2-targeted therapy has markedly improved the survival and prognosis of patients with advanced gastric cancer. Inhibiting the HER2 signaling pathway has become the backbone treatment for advanced HER2-positive gastric cancer in the first-line setting. TOGA trial established trastuzumab in combination with cisplatin and 5-flurouracil as the standard first-line treatment. In the post-TOGA era, combinations of trastuzumab with other chemotherapy agents were proven to be effective as both the second-line treatment and the conversion treatment. Such combinations are promising in the neoadjuvant treatment for locally advanced gastric cancer. Research focuses on the development of novel anti-HER2 agents in combination with agents targeting against other signal pathways. Real-time monitoring of the gene expression profile is the key to discovering the mechanism of trastuzumab resistance. The preliminary results of existing clinical trials have shown potential to overcome resistance to trastuzumab. In this review, we summarized the treatment advancement for HER2 positive gastric cancer and the direction for future development, thereby providing guidance on clinical practice.
-
Key words:
- HER2 /
- advanced gastric cancer /
- trastuzumab /
- targeted therapy
-
表 1 曲妥珠单抗一线治疗HER2阳性晚期胃癌患者的主要临床研究
Table 1. Pivotal clinical trials for HER2-positive advanced gastric cancer, including trastuzumab as first-line treatment
-
[1] Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma[J]. Nature, 2014, 513(7517): 202-209. doi: 10.1038/nature13480 [2] Akiyama T, Sudo C, Ogawara H, et al. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity[J]. Science, 1986, 232(4758):1644-1646. doi: 10.1126/science.3012781 [3] Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer[J]. Gastric cancer, 2015, 18(3):476-484. doi: 10.1007/s10120-014-0402-y [4] Hsieh AC, Moasser MM. Targeting HER proteins in cancer therapy and the role of the non-target HER3[J]. Br J Cancer, 2007, 97(4):453-457. doi: 10.1038/sj.bjc.6603910 [5] Okines A, Cunningham D, Chau I. Targeting the human EGFR family in esophagogastric cancer[J]. Nat Rev Clin Oncol, 2011, 8(8):492-503. doi: 10.1038/nrclinonc.2011.45 [6] Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial[J]. Lancet, 2010, 376(9742):687-697. doi: 10.1016/S0140-6736(10)61121-X [7] Al-Batran SE, Kroening H, Hannig CV, et al. Trastuzumab in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastro-oesophageal junction cancer: Updated findings from the German non-interventional study HerMES[J]. Eur J Cancer, 2015, 51: S444. https://www.researchgate.net/publication/293641651_2333_Trastuzumab_in_combination_with_different_first-line_chemotherapies_for_treatment_of_HER2-positive_metastatic_gastric_or_gastro-_oesophageal_junction_cancer_Updated_findings_from_the_German_non-i [8] Kurokawa Y, Sugimoto N, Miwa H, et al. Phase Ⅱ study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1)[J]. Br J Cancer, 2014, 110(5):1163-1168. doi: 10.1038/bjc.2014.18 [9] Chua C, Tan IB, Yamada Y, et al. Phase Ⅱ study of trastuzumab in combination with S-1 and cisplatin in the first-line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer[J]. Cancer Chemother Pharmacol, 2015, 76(2):397-408. doi: 10.1007/s00280-015-2811-y [10] Gong J, Liu T, Fan Q, et al. Optimal regimen of trastuzumab in combination with oxaliplatin/capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phase Ⅱ trial[J]. BMC cancer, 2016, 16:68. doi: 10.1186/s12885-016-2092-9 [11] Ryu MH, Yoo C, Kim JG, et al. Multicenter phase Ⅱ study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer[J]. Eur J Cancer, 2015, 51(4):482-488. doi: 10.1016/j.ejca.2014.12.015 [12] Nishikawa K, Takahashi T, Takaishi H, et al. Phase Ⅱ study of the effectiveness and safety of trastuzumab and paclitaxel for taxane‐and trastuzumab‐naïve patients with HER2‐positive, previously treated, advanced, or recurrent gastric cancer (JFMC45‐1102)[J]. Int J Cancer, 2017, 140(1):188-196. doi: 10.1002/ijc.30383 [13] Dai GH, Shi Y, Chen L, et al. Trastuzumab combined with docetaxelbased regimens in previously treated metastatic gastric cancer patients with HER2 over-expression[J]. Hepatogastroenterology, 2012, 59(120):2439-2444. https://www.ncbi.nlm.nih.gov/pubmed/22534547 [14] Li Q, Jiang H, Li H, et al. Efficacy of trastuzumab beyond progression in HER2 positive advanced gastric cancer: a multicenter prospective observational cohort study[J]. Oncotarget, 2016, 7(31):50656-50665. http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=10456&path%5B%5D=33038 [15] Mitsui Y, Sato Y, Miyamoto H, et al. Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy[J]. Cancer Chemother Pharmacol, 2015, 76(2):375-382. doi: 10.1007/s00280-015-2807-7 [16] Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer[J]. N Engl J Med, 2012, 366(2): 109-119. doi: 10.1056/NEJMoa1113216 [17] Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer[J]. N Engl J Med, 2015, 372(8):724-734. doi: 10.1056/NEJMoa1413513 [18] Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer[J]. N Engl J Med, 2012, 367(19):1783-1791. doi: 10.1056/NEJMoa1209124 [19] Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex[J]. Cancer cell, 2004, 5(4):317-328. doi: 10.1016/S1535-6108(04)00083-2 [20] Kang YK, Rha SY, Tassone P, et al. A phase Ⅱa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer[J]. Br J Cancer, 2014, 111(4):660-666. doi: 10.1038/bjc.2014.356 [21] Oh DY, Bang YJ. Pertuzumab in gastrointestinal cancer[J]. Expert Opin Biol Ther, 2016, 16(2):243-253. doi: 10.1517/14712598.2016.1126578 [22] LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer[J]. Clin Cancer Res, 2011, 17 (20):6437-6447. doi: 10.1158/1078-0432.CCR-11-0762 [23] Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1[J]. Clin Cancer Res, 2016, 22(20):5097-5108. doi: 10.1158/1078-0432.CCR-15-2822 [24] Grigore D, Simionescu CE, Stepan A, et al. Assessment of CD105, alphaSMA and VEGF expression in gastric carcinomas[J]. Rom J Morphol Embryol, 2013, 54(3 Suppl):701-707. http://www.rjme.ro/RJME/resources/files/541313701707.pdf [25] Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase Ⅲ trial[J]. J Clin Oncol, 2012, 30(17):2119-2127. doi: 10.1200/JCO.2011.39.9824 [26] Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial[J]. Lancet, 2014, 383(9911): 31-39. doi: 10.1016/S0140-6736(13)61719-5 [27] Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial[J]. Lancet Oncol, 2014, 15(11):1224-1235. doi: 10.1016/S1470-2045(14)70420-6 [28] Singh R, Kim WJ, Kim PH, et al. Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing gastric cancer xenografts than individual blockade[J]. Exp Mol Med, 2013, 45(11):e52. doi: 10.1038/emm.2013.111 [29] Le XF, Mao W, Lu C, et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2[J]. Cell Cycle, 2008, 7(23):3747-3758. doi: 10.4161/cc.7.23.7212 [30] Sun Y, Dey N, Brammer M, et al. Bevacizumab confers additional advantage to the combination of trastuzumab plus pertuzumab in trastuzumabrefractory breast cancer model[J].Cancer Chemother Pharmacol, 2013, 72(4):733-745. doi: 10.1007/s00280-013-2233-7 [31] Meulendijks D, Beerepoot LV, Boot H, et al. Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as firstline treatment of advanced HER2-positive gastric cancer: a multicenter phase Ⅱ study[J]. Invest New Drugs, 2016, 34(1):119-128. doi: 10.1007/s10637-015-0309-4 [32] Shimoyama S. Unraveling trastuzumab and lapatinib inefficiency in gastric cancer: Future steps (Review)[J]. Mol Clin Oncol, 2014, 2(2):175-181. https://www.researchgate.net/profile/Shouji_Shimoyama/publication/260951923_Unraveling_trastuzumab_and_lapatinib_inefficiency_in_gastric_cancer_Future_steps_Review/links/53d3c5f50cf228d363e98d5d.pdf [33] Martin HL, Smith L, Tomlinson DC. Multidrug-resistant breast cancer: current perspectives[J]. Breast Cancer (Dove Med Press), 2014, 6:1-13. http://eprints.whiterose.ac.uk/86873/1/Multidrug-resistant%20breast%20cancer%3A%20current%20perspectives..pdf [34] Lai AZ, Abella JV, Park M. Crosstalk in Met receptor oncogenesis[J]. Trends Cell Biol, 2009, 19(10):542-551. doi: 10.1016/j.tcb.2009.07.002 [35] Matsuoka T, Yashiro M. The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma[J]. Cancers, 2014, 6(3):1441-1463. doi: 10.3390/cancers6031441 -
点击查看大图
表(1)
计量
- 文章访问数: 65
- HTML全文浏览量: 4
- PDF下载量: 6
- 被引次数: 0
下载:
