Journal of Gastric Cancer

  • 제25권2호
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  • Pages.266-275
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  • 2025
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  • 2093-582X(pISSN)
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  • 2093-5641(eISSN)
대한위암학회 (The Korean Gastric Cancer Association)
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Baseline Inflammatory Burden Index Predicts Primary Resistance to Combinations of ICIs With Chemotherapy in Patients With HER-2-Negative Advanced Gastric Cancer

  • Tingting Wang (Department of Oncology, the First Affiliated Hospital of Bengbu Medical University) ;
  • Huihui Zeng (Department of Oncology, the First Affiliated Hospital of Bengbu Medical University) ;
  • Ting Hu (Department of Oncology, the First Affiliated Hospital of Bengbu Medical University) ;
  • Junhao Zhang (Department of Oncology, the First Affiliated Hospital of Bengbu Medical University) ;
  • Zishu Wang (Department of Oncology, the First Affiliated Hospital of Bengbu Medical University)
  • 투고 : 2024.06.14
  • 심사 : 2024.10.02
  • 발행 : 2025.04.01
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초록

Purpose: Combinations of immune checkpoint inhibitors (ICIs) and chemotherapy have become the standard first-line treatment for human epidermal growth factor receptor 2 (HER-2)-negative advanced gastric cancer. However, primary resistance remains a challenge, with no effective biomarkers available for its prediction. This retrospective study explores the relationship between the baseline inflammatory burden index (IBI) and primary resistance in such context. Materials and Methods: We analyzed 62 patients with HER-2-negative advanced gastric cancer who received ICIs and chemotherapy as their first-line treatment. The IBI was calculated as follows: C-reactive protein (mg/L) × neutrophil count (103/mm3)/lymphocyte count (103/mm3). Based on disease progression within 6 months, patients were categorized into the primary resistant or the control group. We compared baseline characteristics and IBI scores between the groups and assessed the predictive value of the IBI using the receiver operating characteristic curve. Both univariate and multivariate binary logistic regression analyses were conducted to identify factors influencing primary resistance. Results: Nineteen patients were included in the primary resistance group, and forty-three patients were included in the control group. The IBI was significantly higher in the resistant group compared to the control group (P<0.01). The area under the curve for the IBI was 0.82, indicating a strong predictive value. Multivariate analysis identified the IBI as an independent predictor of primary resistance (P=0.014). Conclusions: The baseline IBI holds promise as a predictor of primary resistance to combined ICIs and chemotherapy in patients with HER-2-negative advanced gastric cancer.

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과제정보

This study was supported by the Research Foundation of Education Department of Anhui Province of China (No.2023AH052001) and the Natural Science Foundation of Bengbu College (No.2022byzd035).

참고문헌

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249. https://doi.org/10.3322/caac.21660
  2. Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017;8:CD004064. https://doi.org/10.1002/14651858.CD004064.pub4
  3. Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181-1195. https://doi.org/10.1016/S1470-2045(23)00515-6
  4. Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 trial. J Clin Oncol 2024;42:2012-2020. https://doi.org/10.1200/JCO.23.01601
  5. Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. JAMA 2023;330:2064-2074. https://doi.org/10.1001/jama.2023.19918
  6. Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ 2024;385:e078876. https://doi.org/10.1136/bmj-2023-078876
  7. Rizvi N, Ademuyiwa FO, Cao ZA, Chen HX, Ferris RL, Goldberg SB, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. J Immunother Cancer 2023;11:e005920. https://doi.org/10.1136/jitc-2022-005920
  8. Dubois M, Liscia N, Brunetti O, Ziranu P, Lai E, Argentiero A, et al. The role of immune checkpoint inhibitors in the treatment sequence of advanced gastric or gastro-esophageal junction cancer: a systematic review and meta-analysis of randomized trials. Crit Rev Oncol Hematol 2022;173:103674. https://doi.org/10.1016/j.critrevonc.2022.103674
  9. Xie T, Zhang Z, Zhang X, Qi C, Shen L, Peng Z. Appropriate PD-L1 cutoff value for gastric cancer immunotherapy: a systematic review and meta-analysis. Front Oncol 2021;11:646355. https://doi.org/10.3389/fonc.2021.646355
  10. Lee KW, Van Cutsem E, Bang YJ, Fuchs CS, Kudaba I, Garrido M, et al. Association of tumor mutational burden with efficacy of pembrolizumab±chemotherapy as first-line therapy for gastric cancer in the phase III KEYNOTE-062 study. Clin Cancer Res 2022;28:3489-3498. https://doi.org/10.1158/1078-0432.CCR-22-0121
  11. Alborelli I, Leonards K, Rothschild SI, Leuenberger LP, Savic Prince S, Mertz KD, et al. Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer. J Pathol 2020;250:19-29. https://doi.org/10.1002/path.5344
  12. Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol 2021;7:895-902. https://doi.org/10.1001/jamaoncol.2021.0275
  13. Pietrantonio F, Randon G, Di Bartolomeo M, Luciani A, Chao J, Smyth EC, et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO Open 2021;6:100036. https://doi.org/10.1016/j.esmoop.2020.100036
  14. Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in gastric cancer: between lights and shadows. Cancer Treat Rev 2021;95:102175. https://doi.org/10.1016/j.ctrv.2021.102175
  15. Yang Y, Shi Z, Bai R, Hu W. Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival. J Med Genet 2021;58:12-19. https://doi.org/10.1136/jmedgenet-2019-106609
  16. Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, et al. Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov 2021;11:2168-2185. https://doi.org/10.1158/2159-8290.CD-21-0219
  17. Xie T, Liu Y, Zhang Z, Zhang X, Gong J, Qi C, et al. Positive status of Epstein-Barr virus as a biomarker for gastric cancer immunotherapy: a prospective observational study. J Immunother 2020;43:139-144. https://doi.org/10.1097/CJI.0000000000000316
  18. Sun YT, Guan WL, Zhao Q, Wang DS, Lu SX, He CY, et al. PD-1 antibody camrelizumab for Epstein-Barr virus-positive metastatic gastric cancer: a single-arm, open-label, phase 2 trial. Am J Cancer Res 2021;11:5006-5015.
  19. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and con sequences. Immunity 2019;51:27-41. https://doi.org/10.1016/j.immuni.2019.06.025
  20. Jin Y, Sun Y, Shi X, Zhao J, Shi L, Yu X. Prognostic value of circulating C-reactive protein levels in patients with non-small cell lung cancer: a systematic review with meta-analysis. J Cancer Res Ther 2014;10 Suppl:C160-C166. https://doi.org/10.4103/0973-1482.145854
  21. Nie D, Gong H, Mao X, Li Z. Systemic immune-inflammation index predicts prognosis in patients with epithelial ovarian cancer: a retrospective study. Gynecol Oncol 2019;152:259-264. https://doi.org/10.1016/j.ygyno.2018.11.034
  22. Shoji F, Kozuma Y, Toyokawa G, Yamazaki K, Takeo S. Complete blood cell count-derived inflammatory biomarkers in early-stage non-small-cell lung cancer. Ann Thorac Cardiovasc Surg 2020;26:248-255. https://doi.org/10.5761/atcs.oa.19-00315
  23. Ouyang H, Xiao B, Huang Y, Wang Z. Baseline and early changes in the neutrophil-lymphocyte ratio (NLR) predict survival outcomes in advanced colorectal cancer patients treated with immunotherapy. Int Immunopharmacol 2023;123:110703. https://doi.org/10.1016/j.intimp.2023.110703
  24. Liu J, Li S, Zhang S, Liu Y, Ma L, Zhu J, et al. Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab. J Clin Lab Anal 2019;33:e22964. https://doi.org/10.1002/jcla.22964
  25. Fucà G, Beninato T, Bini M, Mazzeo L, Di Guardo L, Cimminiello C, et al. The pan-immune-inflammation value in patients with metastatic melanoma receiving first-line therapy. Target Oncol 2021;16:529-536. https://doi.org/10.1007/s11523-021-00819-0
  26. Xie H, Ruan G, Ge Y, Zhang Q, Zhang H, Lin S, et al. Inflammatory burden as a prognostic biomarker for cancer. Clin Nutr 2022;41:1236-1243. https://doi.org/10.1016/j.clnu.2022.04.019
  27. Liu K, Yuan S, Wang C, Zhu H. Resistance to immune checkpoint inhibitors in gastric cancer. Front Pharmacol 2023;14:1285343. https://doi.org/10.3389/fphar.2023.1285343
  28. de Bree E, Michelakis D, Stamatiou D, Romanos J, Zoras O. Pharmacological principles of intraperitoneal and bidirectional chemotherapy. Pleura Peritoneum 2017;2:47-62. https://doi.org/10.1515/pp-2017-0010
  29. Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 2016;30:668-681. https://doi.org/10.1016/j.ccell.2016.09.011
  30. Fucà G, Cohen R, Lonardi S, Shitara K, Elez ME, Fakih M, et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J Immunother Cancer 2022;10:e004001. https://doi.org/10.1136/jitc-2021-004001
  31. Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med 2021;27:152-164. https://doi.org/10.1038/s41591-020-1131-x
  32. Flecchia C, Auclin E, Alouani E, Mercier M, Hollebecque A, Turpin A, et al. Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study. Br J Cancer 2024;130:442-449. https://doi.org/10.1038/s41416-023-02524-3
  33. Kugel CH 3rd, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res 2018;24:5347-5356. https://doi.org/10.1158/1078-0432.CCR-18-1116
  34. Cona MS, Lecchi M, Cresta S, Damian S, Del Vecchio M, Necchi A, et al. Combination of baseline LDH, performance status and age as integrated algorithm to identify solid tumor patients with higher probability of response to anti PD-1 and PD-L1 monoclonal antibodies. Cancers (Basel) 2019;11:223. https://doi.org/10.3390/cancers11020223
  35. Wu Q, Wang Q, Tang X, Xu R, Zhang L, Chen X, et al. Correlation between patients' age and cancer immunotherapy efficacy. OncoImmunology 2019;8:e1568810.
  36. Denk D, Greten FR. Inflammation: the incubator of the tumor microenvironment. Trends Cancer 2022;8:901-914. https://doi.org/10.1016/j.trecan.2022.07.002
  37. Sui Q, Zhang X, Chen C, Tang J, Yu J, Li W, et al. Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer. Nat Commun 2022;13:7316. https://doi.org/10.1038/s41467-022-35096-6
  38. Ogata T, Satake H, Ogata M, Hatachi Y, Inoue K, Hamada M, et al. Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: a multicenter retrospective study. Oncotarget 2018;9:34520-34527. https://doi.org/10.18632/oncotarget.26145
  39. Zhu M, Ma Z, Zhang X, Hang D, Yin R, Feng J, et al. C-reactive protein and cancer risk: a pan-cancer study of prospective cohort and Mendelian randomization analysis. BMC Med 2022;20:301. https://doi.org/10.1186/s12916-022-02506-x
  40. Que H, Fu Q, Lan T, Tian X, Wei X. Tumor-associated neutrophils and neutrophil-targeted cancer therapies. Biochim Biophys Acta Rev Cancer 2022;1877:188762. https://doi.org/10.1016/j.bbcan.2022.188762
  41. Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell 2023;41:450-465. https://doi.org/10.1016/j.ccell.2023.02.014