新生物标志物在胃肠道肿瘤中疗效预测和预后价值的研究进展

doi:10.16150/j.1671-2870.2019.06.020

摘要/Abstract

中图分类号:

R735.2
735.3

陈海燕, 杨小宝, 许大康. 新生物标志物在胃肠道肿瘤中疗效预测和预后价值的研究进展[J]. 诊断学理论与实践, 2019, 18(06): 704-710.

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参考文献 68

[1]	Sanmamed MF, 陈列平. 肿瘤免疫治疗的策略转换: 从“肿瘤的免疫增强化疗法”到“肿瘤的免疫正常化疗法”[J]. 中国生物工程杂志, 2019, 39(2):26-37.
[2]	Banna GL, Olivier T, Rundo F, et al. The Promise of digital biopsy for the prediction of tumor molecular features and clinical outcomes associated with immunotherapy[J]. Front Med, 2019, 6:172. doi: 10.3389/fmed.2019.00172 URL
[3]	王鹏飞, 朱茜, 张丽芳, 等. CEA多表位融合蛋白在胃肠道肿瘤血清学诊断中的研究价值[J]. 医学研究杂志, 2014, 43(11):54-56.
[4]	潘利锋, 梁君林. 血清CEA、CA199、CA242在结直肠癌中的应用[J]. 延边医学, 2015:232-235.
[5]	Bel Hadj Hmida Y, Tahri N, Sellami A, et al. Sensitivity, specificity and prognostic value of CEA in colorectal cancer: results of a Tunisian series and literature review[J]. Tunis Med, 2001, 79:434-440.
[6]	张永乐, 薛英威, 蓝秀文, 等. 肿瘤标记物CA19-9、CEA对胃癌转移和预后预测价值的分析[J]. 哈尔滨医科大学学报, 2010, 44(2):181-184,188.
[7]	张红霞, 张一帆, 霍美凤. 血清COLⅣ、CEA水平在结直肠癌肝转移诊断及预后判断中的价值[J]. 山东医药, 2017, 57(28):83-85.
[8]	Liang Y, Wang W, Fang C, et al. Clinical significance and diagnostic value of serum CEA, CA19-9 and CA72-4 in patients with gastric cancer[J]. Oncotarget, 2016, 7(31):49565-49573. doi: 10.18632/oncotarget.10391 pmid: 27385101
[9]	Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer[J]. Eur J Surg Oncol, 2007, 33(3):266-270. doi: 10.1016/j.ejso.2006.10.004 URL
[10]	付生弟, 谢辉. 肿瘤标志物CEA、CA19-9、CA72-4及CA242在胃癌诊断及预后判断中的应用价值[J]. 标记免疫分析与临床, 2016, 23(4):428-430,450.
[11]	Piccart-Gebhart MJ, Marion P, Brian LJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer[J]. N Engl J Med, 2005, 353:1659. doi: 10.1056/NEJMoa052306 URL
[12]	李保奇, 岑洪, 胡晓桦. HER2过表达与胃癌预后及靶向治疗的关系[J]. 医学综述, 2010, 16(9):1321-1323.
[13]	Cutsem Y. Kang E. Van. Efficacy results from the To GA trial: A phase Ⅲ study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC)[J]. Journal of Clinical Oncology, 2009, 27(18S):LBA4509. 9.[查不到 ]
[14]	贾长河, 谢毅, 张昊, 等. 胃癌组织中CD151、c-Met、Integrinα3表达及其与临床病理特征的关系[J]. 山东医药, 2019, 59(5): 65-67.
[15]	Fioroni I, Dell'Aquila E, Pantano F, et al. Role of c-mese-nchymal-epithelial transition pathway in gastric cancer[J]. Expert Opin Pharmacother, 2015, 16(8):1195-1207. doi: 10.1517/14656566.2015.1037739 pmid: 25881479
[16]	张沛. 宫颈鳞癌中c-Met蛋白表达与细胞增殖的相关性研究[D]. 华中科技大学, 2007.
[17]	Ma PC, Jagadeeswaran R, Jagadeesh S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer[J]. Cancer Res, 2005, 65(4):1479-1488. doi: 10.1158/0008-5472.CAN-04-2650 URL
[18]	Xu XY, Chen P. Research progress on non-small-cell lung cancer drugs targeting Met[J]. Drugs Clin, 2016, 31(4):562-566.
[19]	Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients[J]. J Clin Oncol, 2009, 27(10):1667-1674. doi: 10.1200/JCO.2008.19.1635 URL
[20]	邓小英, 惠二京, 李招发. 大肠癌疗效及预后预测生物标志物的研究进展[J]. 胃肠病学和肝病学杂志, 2013, 22:393-396.
[21]	单宝珍. 大肠癌中EGFR、Ras蛋白表达及K-ras基因突变的研究[D]. 大连医科大学, 2009.
[22]	Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers[J]. Nat Commun, 2017, 8:15180. doi: 10.1038/ncomms15180 pmid: 28585546
[23]	Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types[J]. JCO Precis Oncol, 2017:2017.
[24]	Taieb J, Shi Q, Pederson L, et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage Ⅲ colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies[J]. Ann Oncol, 2019, 30(9):1466-1471. doi: S0923-7534(19)45995-4 pmid: 31987401
[25]	王怡, 孙孟红, 施达仁. 错配修复基因功能缺陷与相关肿瘤发生[J]. 临床与实验病理学杂志, 2003, 19:547-550.
[26]	Corso G, Pedrazzani C, Marrelli D. Correlation of microsatellite instability at multiple loci with long-term survival in advanced gastric carcinoma[J]. Arch Surg, 2009, 144(8):722-727. doi: 10.1001/archsurg.2009.42 URL
[27]	朱涤潮, 张涛, 张明辉, 等. MMR/MSI在结直肠癌抗PD-1/PD-L1免疫检查点治疗中的作用[J]. 肿瘤学杂志, 2017, 23(10): 904-909.
[28]	Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens[J]. Nature, 2014, 515(7528):577-581. doi: 10.1038/nature13988 URL
[29]	郑璐瑶, 王薇, 苏乌云. 免疫靶点抑制剂在晚期非小细胞肺癌治疗中的应用研究进展[J]. 山东医药, 2018, 58(31):93-95.
[30]	Yarchoan M, Albacker LA, Hopkins AC, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers[J]. JCI Insight, 2019, 4(6)pii: 126908.
[31]	郭雅静. PD-L1、PD-1表达与肺癌生物学特征关系的研究[D]. 河北医科大学, 2018.
[32]	Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage Ⅲ or Ⅳ melanoma[J]. N Engl J Med, 2017, 377(19):1824-1835. doi: 10.1056/NEJMoa1709030 URL
[33]	Brahmer JR, Drake CG, Wollner I, et al. Phase Ⅰ study of single-agent anti-programmed death-1 (MDX-1106) in re-fractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates[J]. J Clin Oncol, 2010, 28(19):3167-3175. doi: 10.1200/JCO.2009.26.7609 pmid: 20516446
[34]	Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366(26):2443-2454. doi: 10.1056/NEJMoa1200690 URL
[35]	Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med, 2010, 363(8):711-723. doi: 10.1056/NEJMoa1003466 URL
[36]	Callahan MK, Postow MA, Wolchok JD. Targeting T Cell Co-receptors for Cancer Therapy[J]. Immunity, 2016, 44(5):1069-1078. doi: 10.1016/j.immuni.2016.04.023 URL
[37]	Postow MA. Managing immune checkpoint-blocking an-tibody side effects[J]. Am Soc Clin Oncol Educ Book, 2015, 35:76-83.
[38]	Weber JS, Yang JC, Atkins MB, et al. Toxicities of Immunotherapy for the Practitioner[J]. J Clin Oncol, 2015, 33(18):2092-2099.
[39]	Naidoo J, Page DB, Li BT, et al. Toxicities of the Anti-PD-1 and Anti-PD-L1 Immune Checkpoint Antibodies[J]. Ann Oncol, 2016, 27(7):1362. doi: 10.1093/annonc/mdw141 pmid: 27072927
[40]	Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper[J]. Ann Oncol, 2016, 27(4):559-574. doi: 10.1093/annonc/mdv623 pmid: 26715621
[41]	Garber K. Pursuit of tumor-infiltrating lymphocyte immunotherapy speeds up[J]. Nat Biotechnol, 2019, 37(9):969-971. doi: 10.1038/d41587-019-00023-6 pmid: 31485043
[42]	Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy[J]. Clin Cancer Res, 2011, 17(13):4550-4557. doi: 10.1158/1078-0432.CCR-11-0116 pmid: 21498393
[43]	Besser MJ, Shapira-Frommer R, Itzhaki O, et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies[J]. Clin Cancer Res, 2013, 19(17):4792-4800. doi: 10.1158/1078-0432.CCR-13-0380 URL
[44]	Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients[J]. Clin Cancer Res, 2012, 18(24): 6758-6770. doi: 10.1158/1078-0432.CCR-12-1177 pmid: 23032743
[45]	Pilon-Thomas S, Kuhn L, Ellwanger S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma[J]. J Immunother, 2012, 35(8):615-620. pmid: 22996367
[46]	Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4⁺ T cells in a patient with epithelial cancer[J]. Science, 2014, 344(6184):641-645. doi: 10.1126/science.1251102 URL
[47]	Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells[J]. J Clin Oncol, 2015, 33(14):1543-1550. doi: 10.1200/JCO.2014.58.9093 URL
[48]	肖长春. 大肠癌肝转移预后与肿瘤浸润淋巴细胞CD3⁺、CD8⁺表达的关系[D]. 复旦大学, 2009.
[49]	卢慧敏, 王琰, 陈陆俊, 等. CD103⁺CD8⁺T细胞在结直肠癌组织中的浸润分布及其临床意义[J]. 中国肿瘤生物治疗杂志, 2019, 26(1):50-57.
[50]	朱玲燕, 周嘉, 刘彦章,等. 自然杀伤细胞在原发性肝细胞肝癌中的浸润及其与预后的关系[J]. 癌症, 2009, 28(11):1198-1202.
[51]	张燕, 郭爱萍, 张晓君, 等. 三阴性乳腺癌组织PD-L1和HIF-1α表达临床意义[J]. 中华肿瘤防治杂志, 2018, 25(18):39-43.
[52]	Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028[J]. J Clin Oncol, 2019, 37(4):318-327.
[53]	叶妮, 陈卫昌. 免疫抑制性细胞Treg和MDSCs与胃癌临床病理特征关系的研究[J]. 胃肠病学, 2015, 20(4):210-213.
[54]	Page EC, Bancroft EK, Brook MN, et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers[J]. Eur Urol, 2019, 76(6):831-842. doi: 10.1016/j.eururo.2019.08.019 URL
[55]	罗漫君, 彭昆伟, 尤长宣. 肿瘤突变负荷在免疫检查点抑制剂中的疗效预测作用及临床应用进展[J]. 肿瘤, 2018, 38(11):1077-1081.
[56]	Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ⅰb/Ⅱ clinical trial NCT02915432[J]. Ann Oncol, 2019, 30(9):1479-1486. doi: S0923-7534(19)45988-7 pmid: 31987403
[57]	Huang AC, Postow MA, Orlowski RJ, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response[J]. Nature, 2017, 545(7652):60-65. doi: 10.1038/nature22079 URL
[58]	Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ⅰb/Ⅱ clinical trial NCT02915432[J]. Ann Oncol, 2019, 30(9):1479-1486. doi: S0923-7534(19)45988-7 pmid: 31987403
[59]	杨萌. 恶性肿瘤的循环突变图谱特征研究[D]. 天津医科大学, 2018.
[60]	Creemers A, Krausz S, Strijker M, et al. Clinical value of ctDNA in upper-GI cancers: A systematic review and meta-analysis[J]. Biochim Biophys Acta Rev Cancer, 2017, 1868(2):394-403. doi: 10.1016/j.bbcan.2017.08.002 URL
[61]	周娜. 非小细胞肺癌患者血液循环DNA含量及完整性的研究[D]. 济南大学, 2016.
[62]	张音洁, 王晰程. 循环肿瘤DNA在消化系统肿瘤中的临床应用[J]. 癌症进展, 2019, 17(2):131-136.
[63]	Ueda M, Iguchi T, Masuda T, et al. Somatic mutations in plasma cell-free DNA are diagnostic markers for esophageal squamous cell carcinoma recurrence[J]. Oncotarget, 2014, 7(38):62280-62291. doi: 10.18632/oncotarget.11409 URL
[64]	Lecomte T, Berger A, Zinzindohoué F, et al. Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis[J]. Int J Cancer, 2002, 100(5):542-548. doi: 10.1002/ijc.10526 URL
[65]	Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles[J]. Annu Rev Cell Dev Biol, 2014, 30:255-289. doi: 10.1146/annurev-cellbio-101512-122326 pmid: 25288114
[66]	Bobrie A, Colombo M, Raposo G, et al. Exosome secretion: molecular mechanisms and roles in immune responses[J]. Traffic, 2011, 12(12):1659-1668. doi: 10.1111/j.1600-0854.2011.01225.x URL
[67]	Del Boccio P, Raimondo F, Pieragostino D, et al. A hyphenated microLC-Q-TOF-MS platform for exosomal lipidomics investigations: application to RCC urinary exosomes[J]. Electrophoresis, 2012, 33(4):689-696. doi: 10.1002/elps.201100375 pmid: 22451062
[68]	Zhang H, Deng T, Liu R, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis[J]. Nat Commun, 2017, 8:15016. doi: 10.1038/ncomms15016 URL

肿瘤标志物	肿瘤类型	检测手段	临床应用
CEA	结肠癌、胰腺癌、胃癌、肝癌等	放射免疫分析法、酶联免疫吸附试验检测血清、脑脊液、乳汁、胃液、胸腹水及尿液、粪便等多种体液和排泄物	连续监测CEA,可用于手术后、化疗不同时期的疗效观察,灵敏度和特异度不高
CA19-9	胰腺癌、肝胆系癌、胃癌、 CRC等	酶联免疫吸附试验检测血清样本	胰腺癌患者85%~95% CA19-9为阳性,肿瘤切除后浓度会下降,再上升则可表示复发;CRC、胆囊癌、胆管癌、肝癌和胃癌的阳性率高,同时检测 CEA和AFP可进一步提高阳性率
HER2 c-MET K-RAS	胃癌（扩增或过度表达）胃癌、结肠癌(扩增或过度表达) 结肠癌 (突变)	酶联免疫分析、酶联免疫吸附试验、化学发光免疫分析法等检测血清样本	靶向治疗预后和预测因素,HER2是胃食管腺癌的治疗靶点
MSI-H dMMR	胃癌、CRC 胃癌、CRC	免疫组织化学	dMMR对结肠癌、胃癌和胰腺癌患者的生存有积极的预后,并可预测PD-1抑制剂抗癌疗效

肿瘤标志物	肿瘤类型	检测方法	临床应用
肿瘤微环境		免疫组织化学、流式细胞仪分析
PD1/PDL1 肿瘤浸润淋巴细胞免疫抑制性骨髓细胞	广谱癌结肠癌和胃癌胰腺癌、肝癌和胃癌		选择对抗PD-1/PD-L1疗法反应佳的患者. FDA批准了PD-1单抗O药nivolumab和K药pembrolizumab用于治疗PD-L1表达阳性的胃癌,作用机制是阻断PD-1和PD-L1之间的相互作用PD-L1抗体atezolizumab T药在结直肠癌等中有效提示预后良好提示预后不良较多数量的骨髓细胞,包括骨髓来源的抑制细胞、中性粒细胞、单核细胞,是肿瘤免疫治疗预后较差的标志
肿瘤基因组学
靶基因panels TMB	广谱癌广谱癌	新一代测序 TMB计算(每1Mb蛋白编码区的平均突变个数)	适合用于分析某些功能集合的基因或基因区域,预测和判断疾病表型 DNA修复系统出现问题会导致DNA损伤突变的积累,即TMB升高,而较高的非同义突变负荷预示免疫治疗将有较好的客观缓解率,适用于TMB高、对抗PD-1/PD-L1疗法有反应的患者人群
液体活检
ctDNA CTC 外泌体	胃肠道恶性肿瘤	血浆ctDNA靶向深度测序免疫细胞化学法、流式细胞仪分析、核酸检测法超速离心法、试剂盒提取法	胃结肠癌的早期筛查和诊断、治疗疗效的判断、预后的分析,指导晚期肿瘤患者选择药物,监测微小残余病灶早期检测CTC可辅助临床诊断、预测临床疗效和预后,实现多次、实时监测肿瘤转移、复发及耐药肿瘤早期诊断标志物,提示肿瘤的残留、进行性发展或复发,预估治疗反应

新生物标志物在胃肠道肿瘤中疗效预测和预后价值的研究进展

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