Publications

nProfiler® 1 Stomach Cancer Assay的完整性与信赖性的根据是发布了分析性性能实验及临床性性能实验的结果与运用相应技术的临床结果论文。Novomics2018年，在Lancet Oncology 和 Journal of Gastric Cancer，2019年在 Yonsei Medical Journal上，发布了论文。

• 通过CLASSIC样本检测nProfiler® 1的临床性预后预测力

  
  

  
  
  通过nProfiler® 1预测CLASSIC样本的5年生存率 (A) 预后群分别5年生存率 (B) 根据有无抗癌剂治疗,比较5年生存率 (抗癌剂治疗群 vs 只手术群) (C-D) 抗癌生存菲获益群的5年生存率比较 (C) 抗癌剂治疗群 vs. 只手术群 (D) 抗癌剂治疗群 vs 只手术群

  CLASSIC(Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy) 临床是第三阶段临床，为了检测胃癌手术后，辅助抗癌疗法有无生存获益，在中国，台湾，韩国，35个机关里，从2006年到2010年为止，以1035名胃癌患者为对象进行的随机前瞻临床。(Clinicaltrials.gov 登录编号 NCT03403296)  
  
  nProfiler® 1观察了1035名中能确保患者样本代表性的629个样本的预后群区分及追踪每个预后群的生存率。每个预后群5年生存率分析结果用 nProfiler® 1划分，确认了5年生存率，低风险群83.2%，中风险群74.8%，高风险群66.0%。并且，通过Log-rank验证，确认了预后群之间存在有意义的差异。(p-value = 0.012)。
  通过 nProfiler® 1并根据有无抗癌生存获益，分为收益群与非收益群时，在抗癌生存受益群里，根据有无抗癌治疗，5年生存率从64.5%上升至80.0%。但另一方面，在抗癌生存非收益群里，根据有无抗癌治疗，5年生存率在72.9%和72.5%之间，确认了差异显示不大。    
  
  特别是划分成抗癌生存非收益群里的低风险患者，在多变数cox回归分析里面，观察到，接受抗癌治疗的患者和不接受抗癌的治疗患者各自风险比为1.21(p-value = 0.72)和1.65(p-value = 0.40)，所以确认了预后好的患者对抗癌治疗没有生存意义。

  Cheong JH, Yang HK, Kim H, Kim WH, Kim YW, Kook MC, Park YK, Kim HH, Lee HS, Lee KH, Gu MJ, Kim HY, Lee J, Choi SH, Hong S, Kim JW, Choi YY, Hyung WJ, Jang E, Kim H, Huh YM, Noh SH. Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis. Lancet Oncol. 2018 May;19(5):629-638.

  Cited by

  1: Xiao X, Chen W, Wei ZW, Chu WW, Lu XF, Li B, Chen H, Meng SJ, Hao TF, Wei JT, He YL, Zhang CH. The Anti-Tumor Effect of Nab-Paclitaxel Proven by Patient-Derived Organoids. Onco Targets Ther. 2020 Jun 24;13:6017-6025. doi: 10.2147/OTT.S237431. PMID: 32612367; PMCID: PMC7322144.
  2: Koushyar S, G Powell A, Vincan E, J Phesse T. Targeting Wnt Signaling for the Treatment of Gastric Cancer. Int J Mol Sci. 2020 May 30;21(11):3927. doi: 10.3390/ijms21113927. PMID: 32486243; PMCID: PMC7311964.
  3: Yoon SJ, Park J, Shin Y, Choi Y, Park SW, Kang SG, Son HY, Huh YM. Deconvolution of diffuse gastric cancer and the suppression of CD34 on the BALB/c nude mice model. BMC Cancer. 2020 Apr 15;20(1):314. doi: 10.1186/s12885-020-06814-4. PMID: 32293340; PMCID: PMC7160933.
  4: Park SY, Lee YJ, Park J, Kim TH, Hong SC, Jung EJ, Ju YT, Jeong CY, Park HJ, Ko GH, Song DH, Park M, Yoo J, Jeong SH. PRDX4 overexpression is associated with poor prognosis in gastric cancer. Oncol Lett. 2020 May;19(5):3522-3530. doi: 10.3892/ol.2020.11468. Epub 2020 Mar 19. PMID: 32269626; PMCID: PMC7114939.
  5: Li B, Jiang Y, Li G, Fisher GA Jr, Li R. Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit. JCI Insight. 2020 May 7;5(9):e136570. doi: 10.1172/jci.insight.136570. PMID: 32229725; PMCID: PMC7253031.
  6: Li R, Liu H, Cao Y, Wang J, Chen Y, Qi Y, Lv K, Liu X, Yu K, Lin C, Zhang H, He H, Li H, Chen L, Shen Z, Qin J, Zhang W, Sun Y, Xu J. Identification and validation of an immunogenic subtype of gastric cancer with abundant intratumoural CD103⁺CD8⁺ T cells conferring favourable prognosis. Version 2. Br J Cancer. 2020 May;122(10):1525-1534. doi: 10.1038/s41416-020-0813-y. Epub 2020 Mar 24. PMID: 32205862; PMCID: PMC7217759.
  7: Di Bartolomeo M, Morano F, Raimondi A, Miceli R, Corallo S, Tamborini E, Perrone F, Antista M, Niger M, Pellegrinelli A, Randon G, Pagani F, Martinetti A, Fucà G, Pietrantonio F; ITACA-S study group. Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial. Oncologist. 2020 Mar;25(3):e460-e468. doi: 10.1634/theoncologist.2019-0471. Epub 2019 Nov 25. PMID: 32162808; PMCID: PMC7066701.
  8: Chen Q, Gao P, Song Y, Huang X, Xiao Q, Chen X, Lv X, Wang Z. Predicting the effect of 5-fluorouracil-based adjuvant chemotherapy on colorectal cancer recurrence: A model using gene expression profiles. Cancer Med. 2020 May;9(9):3043-3056. doi: 10.1002/cam4.2952. Epub 2020 Mar 9. PMID: 32150672; PMCID: PMC7196071.
  9: Wu M, Ding Y, Jiang X, Chen Y, Wu N, Li L, Wang H, Huang Y, Xu N, Teng L. Overexpressed MAGP1 Is Associated With a Poor Prognosis and Promotes Cell Migration and Invasion in Gastric Cancer. Front Oncol. 2020 Jan 17;9:1544. doi: 10.3389/fonc.2019.01544. PMID: 32010630; PMCID: PMC6978879.
  10: Kim DG, An JY, Kim H, Shin SJ, Choi S, Seo WJ, Roh CK, Cho M, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Choi YY. Clinical Implications of Microsatellite Instability in Early Gastric Cancer. J Gastric Cancer. 2019 Dec;19(4):427-437. doi: 10.5230/jgc.2019.19.e38. Epub 2019 Nov 8. PMID: 31897345; PMCID: PMC6928080.
  11: Kim BK, Cheong JH, Im JY, Ban HS, Kim SK, Kang MJ, Lee J, Kim SY, Park KC, Paik S, Won M. PI3K/AKT/β-Catenin Signaling Regulates Vestigial-Like 1 Which Predicts Poor Prognosis and Enhances Malignant Phenotype in Gastric Cancer. Cancers (Basel). 2019 Dec 3;11(12):1923. doi: 10.3390/cancers11121923. PMID: 31816819; PMCID: PMC6966677.
  12: Di Bartolomeo M, Morano F, Raimondi A, Miceli R, Corallo S, Tamborini E, Perrone F, Antista M, Niger M, Pellegrinelli A, Randon G, Pagani F, Martinetti A, Fucà G, Pietrantonio F; ITACA‐S study group. Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial. Oncologist. 2019 Nov 25: theoncologist.2019-0471. doi: 10.1634/theoncologist.2019-0471. Epub ahead of print. PMID: 31767795.
  13: Liu T, Fang P, Han C, Ma Z, Xu W, Xia W, Hu J, Xu Y, Xu L, Yin R, Wang S, Zhang Q. Four transcription profile-based models identify novel prognostic signatures in oesophageal cancer. J Cell Mol Med. 2020 Jan;24(1):711-721. doi: 10.1111/jcmm.14779. Epub 2019 Nov 19. PMID: 31746108; PMCID: PMC6933393.
  14: Jeon J, Cheong JH. Clinical Implementation of Precision Medicine in Gastric Cancer. J Gastric Cancer. 2019 Sep;19(3):235-253. doi: 10.5230/jgc.2019.19.e25. Epub 2019 Aug 12. PMID: 31598369; PMCID: PMC6769368.
  15: Zubarayev M, Min EK, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol. 2019 Aug 20;4:59. doi: 10.21037/tgh.2019.08.05. PMID: 31559340; PMCID: PMC6737396.
  16: Ho SWT, Tan P. Dissection of gastric cancer heterogeneity for precision oncology. Cancer Sci. 2019 Nov;110(11):3405-3414. doi: 10.1111/cas.14191. Epub 2019 Sep 25. PMID: 31495054; PMCID: PMC6825006.
  17: Hwang JE, Kim H, Shim HJ, Bae WK, Hwang EC, Jeong O, Ryu SY, Park YK, Cho SH, Chung IJ. Lymph-node ratio is an important clinical determinant for selecting the appropriate adjuvant chemotherapy regimen for curative D2-resected gastric cancer. J Cancer Res Clin Oncol. 2019 Aug;145(8):2157-2166. doi: 10.1007/s00432-019-02963-7. Epub 2019 Jul 4. PMID: 31273512.
  18: Suenaga Y, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y. Prognostic significance of perioperative tumor marker levels in stage II/III gastric cancer. World J Gastrointest Oncol. 2019 Jan 15;11(1):17-27. doi: 10.4251/wjgo.v11.i1.17. PMID: 30984347; PMCID: PMC6451928.
  19: Harada H, Hosoda K, Moriya H, Mieno H, Ema A, Ushiku H, Washio M, Nishizawa N, Ishii S, Yokota K, Tanaka Y, Kaida T, Soeno T, Kosaka Y, Watanabe M, Yamashita K. Cancer-specific promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene as an important prognostic biomarker of gastric cancer. PLoS One. 2019 Apr 1;14(4):e0214872. doi: 10.1371/journal.pone.0214872. PMID: 30934021; PMCID: PMC6443169.
  20: Chen Y, Wang D, Song Y, Zhang X, Jiao Z, Dong J, Lü L, Zou Z, Du W, Qu F. Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer. Cancer Med. 2019 Apr;8(4):1919-1929. doi: 10.1002/cam4.2050. Epub 2019 Mar 7. PMID: 30843665; PMCID: PMC6488121.
  21: Choi YY, Cho M, Kwon IG, Son T, Kim HI, Choi SH, Cheong JH, Hyung WJ. Ten Thousand Consecutive Gastrectomies for Gastric Cancer: Perspectives of a Master Surgeon. Yonsei Med J. 2019 Mar;60(3):235-242. doi: 10.3349/ymj.2019.60.3.235. PMID: 30799586; PMCID: PMC6391520.
  22: Xu BB, Lu J, Zheng ZF, Xie JW, Wang JB, Lin JX, Chen QY, Cao LL, Lin M, Tu RH, Huang ZN, Lin JL, Zheng CH, Huang CM, Li P. The predictive value of the preoperative C-reactive protein-albumin ratio for early recurrence and chemotherapy benefit in patients with gastric cancer after radical gastrectomy: using randomized phase III trial data. Gastric Cancer. 2019 Sep;22(5):1016-1028. doi: 10.1007/s10120-019-00936-w. Epub 2019 Feb 9. PMID: 30739259.
  23: Roh CK, Choi YY, Choi S, Seo WJ, Cho M, Jang E, Son T, Kim HI, Kim H, Hyung WJ, Huh YM, Noh SH, Cheong JH. Single Patient Classifier Assay, Microsatellite Instability, and Epstein-Barr Virus Status Predict Clinical Outcomes in Stage II/III Gastric Cancer: Results from CLASSIC Trial. Yonsei Med J. 2019 Feb;60(2):132-139. doi: 10.3349/ymj.2019.60.2.132. PMID: 30666834; PMCID: PMC6342711.
  24: Jiang Y, Yuan Q, Lv W, et al. Radiomic signature of 18F fluorodeoxyglucose PET/CT for prediction of gastric cancer survival and chemotherapeutic benefits. Theranostics. 2018;8(21):5915-5928. Published 2018 Nov 12. doi:10.7150/thno.28018
  25: Jin M. Unique roles of tryptophanyl-tRNA synthetase in immune control and its therapeutic implications. Exp Mol Med. 2019 Jan 7;51(1):1-10. doi: 10.1038/s12276-018-0196-9. PMID: 30613102; PMCID: PMC6321835.
  26: Smyth EC, Nyamundanda G, Cunningham D, Fontana E, Ragulan C, Tan IB, Lin SJ, Wotherspoon A, Nankivell M, Fassan M, Lampis A, Hahne JC, Davies AR, Lagergren J, Gossage JA, Maisey N, Green M, Zylstra JL, Allum WH, Langley RE, Tan P, Valeri N, Sadanandam A. A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial. Ann Oncol. 2018 Dec 1;29(12):2356-2362. doi: 10.1093/annonc/mdy407. PMID: 30481267; PMCID: PMC6311954.
  27: Lu J, Cao LL, Li P, Xie JW, Wang JB, Lin JX, Chen QY, Lin M, Tu RH, Huang CM, Zheng CH. Significance of Preoperative Systemic Immune Score for Stage I Gastric Cancer Patients. Gastroenterol Res Pract. 2018 Jul 11;2018:3249436. doi: 10.1155/2018/3249436. PMID: 30116261; PMCID: PMC6079442.
  28: Choi YY, Jang E, Seo WJ, Son T, Kim HI, Kim H, Hyung WJ, Huh YM, Noh SH, Cheong JH. Modification of the TNM Staging System for Stage II/III Gastric Cancer Based on a Prognostic Single Patient Classifier Algorithm. J Gastric Cancer. 2018 Jun;18(2):142-151. doi: 10.5230/jgc.2018.18.e14. Epub 2018 May 31. PMID: 29984064; PMCID: PMC6026714.

• 通过完善好的TNM病理分类(modified TNM staging)检测预后预测力上升

  
  

  用 nProfiler® 1验证的3次临床结果做了事后分析，验证了 nProfiler® 1预后群与TNM病理之间的预后预测力的互补性关系。
  
  · 食药局第705号 临床使用的307个检体的临床实验结果
  · 食药局第745号 临床使用的652个检体的临床实验结果
  · NCT03403296 临床使用的625个检体的临床实验结果
  * MFDS: Ministry of Food and Drug Safety
  
  一共1584名胃癌患者中，划分成低危险群的187名患者在原有的TNM病理分类里降低一级后，并在完善好的TNM病理中被划分，并验证了各个病理的预后预测力。

  基准TNM病理分类
  		ⅡA	ⅡB	ⅢA	ⅢB	total
  完善好的TNM病例分类	ⅠB	10	0	0	0	10
  	ⅡA	126	57	0	0	183
  	ⅡB	0	369	76	0	445
  	ⅢA	0	0	531	44	575
  	ⅢB	0	0	0	371	371
  	total	136	426	607	415	1584

  和原有的TNM病理对比，确认了在完善好的TNM里面，预后预测力的C-index值从0.620上升至0.635。患者的治疗指南设计角度里，预后因子是重要的决定变数。乳腺癌的情况，解刨学性的分类模式TNM病理分类法，已经反映了肿瘤生物学性的信息，树立了预后因子分层并呈现商业化的趋势。目前在相关研究还不足的胃癌方面，反映这样的趋势，提升预后预测能力是有必要的。

  Choi YY, Jang E, Seo WJ, Son T, Kim HI, Kim H, Hyung WJ, Huh YM, Noh SH, Cheong JH. Modification of the TNM Staging
  System for Stage II/III Gastric Cancer Based on a Prognostic Single Patient Classifier Algorithm. J Gastric Cancer.

• 根据MSI及EBV状态分析预后预测力的相互完善性关系

  
  

  CLASSIC临床（NCT03403296）所使用的样本中，把可以确认MSI及EBV状态的586个样本的临床实验结果作为对象，比较了MSI-high与MSI-low/MSS， EBV(+)与EBV(-)各自预后群之间的5年生存率，分析了相互关系。
  
  MSI-high患者为对象，与MSI-low/MSS患者比较预后较好，根据EBV infection状态（+/-）患者之间的预后差别并没有得到确认。 MSI-low/MSS患者的预后群确认了具有统计学性意义。特别是MSS/MSI-LOW同时也是低风险群患者们，与MSI-high患者一起确认了预后呈现较好。与EBV状态无关，确定了预后群可以很好的区分。

  
  
  通过kaplan-meier生存分析得出的(A)MSI状态与(B)MSS/MSI-L患者预后群的无病生存率(DFS)
  简称: DFS,无病生存率；MSI，微卫星不稳定性；MSS, 微卫星稳定性；MSI-L，微卫星不稳定性(-)。

  低风险群同时也是MSI-high的情况有13例（低风险群中占18.6%；p<0.001），是低风险同时也是EBV阳性的情况有22例（低风险群中占31.9%；p0.001）可以看出比起其他预后群，低风险群中MSI及EBV在统计学中有很高的相关性。
  众所周知MSI是胃癌预测预后的生物标记物，用nProfiler® 1 Stomach Cancer Assay划分出的预后群，作为相互补充正在充分利用。美国及欧洲的治疗方针指南里，已经对MSI-high的大肠癌患者抑制了抗癌治疗。在胃癌方面也是，和MSI-high显示出较高的关联性，同时对于抗癌生存非获益群的低风险群患者来说，新的治疗方针设计也是有必要性的。

  Roh CK, Choi YY, Choi S, Seo WJ, Cho M, Jang E, Son T, Kim HI, Kim H, Hyung WJ, Huh YM, Noh SH, Cheong JH. Single Patient Classifier Assay, Microsatellite Instability, and Epstein-Barr Virus Status Predict Clinical Outcomes in Stage
  II/III Gastric Cancer: Results from CLASSIC Trial. Yonsei Med J. 2019 Feb;60(2):132-139.