Publications

The safety and effectiveness of Novomics' nProfiler® 1 Stomach Cancer Assay has been evaluated and validated through clinical trials. The results of the clinical utility were published in the Lancet Oncology and Journal of Gastric Cancer in 2018 and Yonsei Medical Journal in 2019.

• Validation of Prognosis Classification with CLASSIC Cohort

  
  

  
  
  Overall survival in the validation cohort by SPC, (A) Overall survival by SPC-prognosis groups. (B) Overall survival by treatment (D2 gastrectomy plus adjuvant chemotherapy or D2 gastrectomy only). (C-D) Overall survival by treatment according to SPC-prediction (C) No benefit group and (D) chemotherapy-benefit group. Abbreviation: SPC, Single Patient Classifier.

  CLASSIC (Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy) trial is a phase 3, open-label, randomized, prospective study done at 35 cancer centers, medical centers, and hospitals in China, South Korea, and Taiwan with 1,035 gastric cancer patients between 2006 and 2009 (ClinicalTrials.gov Identifier: NCT03403296).
  
  Of the 1,035 patients with gastric cancer randomized in CLASSIC trial, 629 tumor specimens were obtained and used to evaluate the prognosis classification associated with 5-year overall survival to assess the clinical validity of nProfiler® 1. Using nProfiler® 1, 5-year overall survival was 83.2% in the Low risk group, 74.8% in the Intermediate risk group, and 66.0% in the High risk group (p-value =0.012).
  In chemotherapy response prediction with nProfiler® 1, 5-year overall survival was 64.5% in patients who received surgery only versus 80.0% in those who received adjuvant chemotherapy. By contrast, among patients assigned to the no-benefit group by the single patient classifier, 5-year overall survival was similar between patients who received adjuvant chemotherapy and those who did not, as 72.9% and 72.5%, respectively.
  
  In case of patients who assigned into Low risk and no-benefit group, the hazard rates with or without chemotherapy-treated were calculated as 1.12 (p-value=0.72) and 1.65 (p-value=0.40) through the multivariate Cox analysis, in conclusion, patients in Low risk with good prognosis do not benefit from chemotherapy.

  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.

• Better Prognostic Performance with Modification of the TNM Staging System

  
  

  The prognostic performance of the modified TNM staging system based on nProfiler® 1 was validated in multiple cohorts, which were used in previous studies.
  
  · Discovery Clinical Trial approved by *MFDS (n=307)
  · Confirmatory Clinical Trial approved by MFDS (n=652)
  · NCT03403296 Clinical Trial (n=625)
  * MFDS: Ministry of Food and Drug Safety
  
  187 (11.8%) patients who were classified into Low risk out of 1,584 patients according to nProfiler® 1 underwent one-grade down-staging in the modified TNM staging system to validate prognostic performance.

  TNM Staging System
  		ⅡA	ⅡB	ⅢA	ⅢB	total
  Modified TNM Staging System	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

  Using Harrell's C-index, the prognostic performance of the modified TNM system was evaluated, and the results showed that its prognostic performance was better than that of the TNM staging system in terms of overall survival (0.635 vs. 0.620, p-value<0.001).
  With the increase in the knowledge on cancer biology, classic TNM staging, which was only based on anatomical factors, has been modified to include biologic factors that are associated with patient prognoses, and such modified staging systems have been proposed for various cancers. Along with the trend, as well as in gastric cancer, there is the need for an improved predictive test for prognosis and chemotherapy response.

  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.

• Associations among SPC, MSI and EBV statuses for a precise prognostic information

  
  

  From a total of 1,035 patients enrolled in CLASSIC trial, the medical records of 586 patients, for whom it was possible to identify SPC, MSI and EBV statuses, were reviewed to investigate and evaluate disease-free survival (DFS) in MSI-High, MSS/MSI-Low, EBV-positive and EBV-negative.
  
  MSI-High patients showed a relevantly good prognosis compared to MSS/MSI-Low patients, however, there was no significant difference in prognosis between EBV-positive and EBV-negative. In the analysis of the combinatory prognostic factors; SPC and MSI, different prognoses of Low-, Intermediate-, and high-risk groups obtained from SPC-prognosis were significantly well-preserved in MSS/MSI-Low patients. Low risk/MSS/MSI-Low patients had as good a prognosis as MSI-High patients. Additionally, a combination of SPC and EBV statuses revealed a distinct trend whereby the survival by SPC-prognosis was well-stratified regardless of EBV status.

  
  
  Kaplan-Meier survival curves for DFS in patients with stage II/III gastric cancer according to (A) status of MSI and (B) status of SPC-prognosis among MSS/MSI-L patients. Abbreviation: DFS, Disease-free survival; MSI, Microsatellite-instability; SPC, Single Patient Classifier; MSS, Microsatellite-stable; MSI-L, Microsatellite instability-Low.

  The proportion of MSI-High or EBV-positive patients was slightly higher as 18.6% (13 patients, p-value<0.001) and 31.9% (22 patients, p-value<0.001), respectively, in Low risk than other groups, indicating a positive association with MSI and EBV in Low risk.
  MSI is known as a prognostic biomarker in gastric cancer and can be used as a combined marker with the prognosis classification result of nProfiler® 1 Stomach Cancer Assay for a more precise prognostic performance. MSI-High patients in colon cancer are suggested receiving chemotherapy by treatment guidelines in the U.S. and Europe. Thus, a new treatment for MSI-High/no-benefit/Low risk patients is required in treatment guideline for gastric cancer.

  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.