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Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study

  • Translational Research
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Abstract

Background

Identification of positive biomarkers for the effects of nivolumab on patients with advanced gastric cancer (AGC) is significant. The Gustave Roussy Immune Score (GRIm-s) is associated with therapeutic resistance of immune checkpoint inhibitors (ICIs) in other cancers. This multicenter, retrospective study was designed to analyze the association of GRIm-s with therapeutic sensitivity of nivolumab in patients with AGC.

Methods

We reviewed 58 patients with AGC treated with nivolumab from October 2017 to November 2018 at five participating institutions. We performed blood tests before the start of nivolumab and after administration of two courses. We evaluated the correlation between the best overall response and GRIm-s. Additionally, we focused on the changes in GRIm-s before the start of nivolumab and after administration of two courses.

Results

Of the 58 patients, 21 (36.2%) were classified into the disease control (DC) group and 37 (63.8%) into the progressive disease (PD) group. GRIm-s before nivolumab treatment did not correlate with the best therapeutic response (p = 0.086). However, GRIm-s after two courses of nivolumab showed that significantly more PD cases were in the high-risk group (p < 0.0001). After two courses of nivolumab, overall survival was significantly worse in the high-risk group (p < 0.0001). For progression-free survival, the high-risk group had a significantly worse prognosis both before (p = 0.04) and after two courses of nivolumab treatment (p < 0.0001).

Conclusions

GRIm-s after two courses of nivolumab and its changes compared to pretreatment values proved beneficial in predicting nivolumab sensitivity.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics. CA Cancer J Clin. 2015;65:87–108. https://doi.org/10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  2. Yamashita K, Sakuramoto S, Nemoto M, et al. Trend in gastric cancer: 35 years of surgical experience in Japan. World J Gastroenterol. 2011;17:3390–7. https://doi.org/10.3748/wjg.v17.i29.3390.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71. https://doi.org/10.1016/S0140-6736(17)31827-5.

    Article  CAS  PubMed  Google Scholar 

  4. Janjigian YY, Shitara K, Moehler M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/oesophageal adenocarcinoma (CheckMate 649): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40. https://doi.org/10.1016/S0140-6736(21)00797-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ito S, Masuda T, Noda M, et al. Prognostic significance of PD-1, PD-L1 and CD8 gene expression levels in gastric cancer. Oncology. 2020;98:501–11. https://doi.org/10.1159/000506075.

    Article  CAS  PubMed  Google Scholar 

  6. Wu Y, Cao D, Qu L, et al. PD-1 and PD-L1 co-expression predicts favorable prognosis in gastric cancer. Oncotarget. 2017;8:64066–82.

    Article  Google Scholar 

  7. Shin HM, Kim G, Kim S, et al. Chromatin accessibility of circulating CD8 + T cells predicts treatment response to PD-1 blockade in patients with gastric cancer. Nat Commun. 2021;12:975. https://doi.org/10.1038/s41467-021-21299-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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. Ann Oncol. 2019;30:1479–86. https://doi.org/10.1093/annonc/mdz197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Choi E, Chang MS, Byeon SJ, et al. Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas. Diagn Pathol. 2020;15:69. https://doi.org/10.1186/s13000-020-00979-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2016;2:46–54. https://doi.org/10.1001/jamaoncol.2015.3638.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nakazawa N, Sohda M, Yamaguchi A, et al. An elevated serum lactate dehydrogenase-to-albumin ratio is a useful poor prognostic predictor of nivolumab in patients with gastric cancer. Anticancer Res. 2021;41:3925–31.

    Article  CAS  Google Scholar 

  12. Ota Y, Takahari D, Suzuki T, et al. Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival. Cancer Chemother Pharmacol. 2020;85:265–72. https://doi.org/10.1007/s00280-019-04023-w.

    Article  CAS  PubMed  Google Scholar 

  13. Bigot F, Castanon E, Baldini C, et al. Prospective validation of a prognostic score for patients in immunotherapy phase I trials: the Gustave Roussy Immune Score (GRIm-Score). Eur J Cancer. 2017;84:212–8. https://doi.org/10.1016/j.ejca.2017.07.027.

    Article  CAS  PubMed  Google Scholar 

  14. Minami S, Ihara S, Ikuta S, Komuta K. Gustave Roussy immune score and Royal Marsden Hospital prognostic score are biomarkers of immune-checkpoint inhibitor for non-small cell lung cancer. World J Oncol. 2019;10:90–100.

    Article  CAS  Google Scholar 

  15. Aldea M, Benitez JC, Mezquita L. The Lung Immune Prognostic Index (LIPI) stratifies prognostic groups in advanced non-small cell lung cancer (NSCLC) patients. Transl Lung Cancer Res. 2020;9:967–70.

    Article  Google Scholar 

  16. Lenci E, Cantini L, Pecci F, et al. The Gustave Roussy Immune (GRIm)-score variation is an early-on-treatment biomarker of outcome in advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. J Clin Med. 2021;10:1005. https://doi.org/10.3390/jcm10051005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sano A, Sohda M, Nakazawa N, et al. Clinical features as potential prognostic factors in patients treated with nivolumab for highly pretreated metastatic gastric cancer: a multicenter retrospective study. BMC Cancer. 2022;22:22. https://doi.org/10.1186/s12885-021-09118-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009. https://doi.org/10.1007/s12325-020-01229-w.

    Article  PubMed  Google Scholar 

  19. Russo A, Russano M, Franchina T, et al. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and outcomes with nivolumab in pretreated non-small cell lung cancer (NSCLC): A large retrospective multicenter study. Adv Ther. 2020;37:1145–55. https://doi.org/10.1007/s12325-020-01229-w.

    Article  CAS  PubMed  Google Scholar 

  20. Capone M, Giannarelli D, Mallardo D, et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer. 2018;6:74. https://doi.org/10.1186/s40425-018-0383-1.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tachinami H, Tomihara K, Ikeda A, et al. Neutrophil-to-lymphocyte ratio (NLR) as a predictive indicator of the response to nivolumab in patients with oral squamous cell carcinoma. Gan To Kagaku Ryoho. 2021;48:1485–90.

    PubMed  Google Scholar 

  22. Ueda T, Chikuie N, Takumida M, et al. Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcome in recurrent or metastatic head and neck cancer patients treated with nivolumab. Acta Oto-Laryngol. 2020;140:181–7. https://doi.org/10.1080/00016489.2019.1699250.

    Article  CAS  Google Scholar 

  23. Ota Y, Takahari D, Suzuki T, et al. Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival. Canc Chemother Pharmacol. 2020;85:265–72. https://doi.org/10.1007/s00280-019-04023-w.

    Article  CAS  Google Scholar 

  24. Wu CY, Wu MS, Chiang EP, et al. Elevated plasma osteopontin associated with gastric cancer development, invasion and survival. Gut. 2007;56:782–9. https://doi.org/10.1136/gut.2006.109868.

    Article  CAS  PubMed  Google Scholar 

  25. Middleton K, Jones J, Lwin Z, Coward JI. Interleukin-6: an angiogenic target in solid tumours. Crit Rev Oncol Hematol. 2014;89:129–39. https://doi.org/10.1016/j.critrevonc.2013.08.004.

    Article  PubMed  Google Scholar 

  26. Ock CY, Nam AR, Lee J, et al. Prognostic implication of antitumor immunity measured by the neutrophil–lymphocyte ratio and serum cytokines and angiogenic factors in gastric cancer. Gastric Cancer. 2017;20:254–62. https://doi.org/10.1007/s10120-016-0613-5.

    Article  CAS  PubMed  Google Scholar 

  27. Motomura T, Shirabe K, Mano Y, et al. Neutrophil–lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58:58–64. https://doi.org/10.1016/j.jhep.2012.08.017.

    Article  CAS  PubMed  Google Scholar 

  28. Aday U, Tatlı F, Akpulat FV, et al. Prognostic significance of pretreatment serum lactate dehydrogenase-to-albumin ratio in gastric cancer. Contemp Oncol (Pozn). 2020;24:145–9. https://doi.org/10.5114/wo.2020.100219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Taniguchi Y, Tamiya A, Isa SI, et al. Predictive factors for poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab. Anticancer Res. 2017;37:5857–62.

    CAS  PubMed  Google Scholar 

  30. Agulló-Ortuño MT, Gómez-Martín Ó, Ponce S, et al. Blood predictive biomarkers for patients with non-small-cell lung cancer associated with clinical response to nivolumab. Clin Lung Cancer. 2020;21:75–85. https://doi.org/10.1016/j.cllc.2019.08.006.

    Article  CAS  PubMed  Google Scholar 

  31. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Lett. 2008;582:1783–7. https://doi.org/10.1016/j.febslet.2008.04.057.

    Article  CAS  PubMed  Google Scholar 

  32. Feng JF, Wang L, Yang X, Chen S, Score GRI. Gustave Roussy Immune Score (GRIm-Score) is a prognostic marker in patients with resectable esophageal squamous cell carcinoma. J Cancer. 2020;11:1334–40. https://doi.org/10.7150/jca.37898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Ms. Harumi Kanai for her excellent assistance. The authors have no conflicts of interest to declare and disclose no grant support.

Funding

The authors disclose no grant support.

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Authors and Affiliations

  1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Nobuhiro Nakazawa MD, PhD, Makoto Sohda MD, PhD, Yasunari Ubukata MD, PhD, Kengo Kuriyama MD, PhD, Akiharu Kimura MD, PhD, Norimichi Kogure MD, PhD, Kyoichi Ogata MD, PhD, Akihiko Sano MD, PhD, Makoto Sakai MD, PhD, Hiroomi Ogawa MD, PhD, Ken Shirabe MD, PhD, FACS & Hiroshi Saeki MD, PhD, FACS

  2. Department of Gastroenterology, Gunma Prefectural Cancer Center, Ota, Gunma, Japan

    Hisashi Hosaka MD, PhD

  3. Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma, Japan

    Atsushi Naganuma MD, PhD

  4. Department of Gastroenterology, Isesaki Municipal Hospital, Isesaki, Gunma, Japan

    Masanori Sekiguchi MD, PhD

  5. Department of Surgery, Japan Community Healthcare Organization Gunma Central Hospital, Maebashi, Gunma, Japan

    Kana Saito MD, PhD

Authors
  1. Nobuhiro Nakazawa MD, PhD
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Correspondence to Makoto Sohda MD, PhD.

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Nakazawa, N., Sohda, M., Ubukata, Y. et al. Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study. Ann Surg Oncol 29, 7400–7406 (2022). https://doi.org/10.1245/s10434-022-12226-4

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