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BMC Cancer

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Open Access 01-12-2024 | Gastric Cancer | Research

Alpha-fetoprotein predicts the treatment efficacy of immune checkpoint inhibitors for gastric cancer patients

Authors: Jingjing Zhang, Lei Wang, Shasha Zhang, Ruijie Cao, Yufei Zhao, Yue Zhao, Yanrong Song, Zhanjun Guo

Published in: BMC Cancer | Issue 1/2024

Abstract

Background

Immune checkpoint inhibitors (ICIs) are commonly used in conjunction with chemotherapy to improve treatment outcomes for patients with gastric cancer. Since AFP could influence immunity by both inhibiting natural killer (NK) cells and regulating negatively the function of dendritic cells, we evaluated the influence of baseline serum alpha-fetoprotein (AFP) levels on the curative effect of ICIs in advanced gastric cancer (AGC) patients.

Methods

A retrospective analysis was conducted on 158 AGC patients who underwent ICI treatment. The patients were divided into high and low groups based on the AFP threshold of 20 ng/ml. The efficacy of ICI treatment was assessed using objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Results

The higher levels of baseline AFP were found to be associated with a decrease in the effectiveness of ICIs, as evidenced by a DCR of 50.0% in the group with high AFP levels compared to 87.7% in the group with low AFP levels (P < 0.001). Further analysis using Kaplan-Meier survival techniques indicated that a high AFP level was linked to shorter progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) in AGC individuals receiving ICIs. After propensity score matching, a log rank test revealed that the high AFP group had a decrease in median PFS (P = 0.011) and median OS (P = 0.036) compared to the low AFP group. The high AFP levels also showed its association with shorter PFS and OS in the subgroup analysis of ICI plus chemotherapy patients.

Conclusions

Baseline AFP levels may predict immune checkpoint inhibitor treatment efficacy in AGC patients.

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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. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.

Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:1005–20. Epub 2022 Jul 29. PMID: 35914639.CrossRefPubMed

Patel TH, Cecchini M. Targeted Therapies in Advanced Gastric Cancer. Curr Treat Options Oncol. 2020;21:70. https://doi.org/10.1007/s11864-020-00774-4. PMID: 32725377.

Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26:141–8. https://doi.org/10.1093/annonc/mdu472. Epub 2014 Oct 14. PMID: 25316259.CrossRefPubMed

Ziogas DC, Theocharopoulos C, Koutouratsas T, Haanen J, Gogas H. Mechanisms of resistance to immune checkpoint inhibitors in melanoma: what we have to overcome? Cancer Treat Rev. 2023;113:102499. https://doi.org/10.1016/j.ctrv.2022.102499. Epub 2022 Dec 13. PMID: 36542945.CrossRefPubMed

Liu T, Bai Y, Lin X, Li W, Wang J, Zhang X, et al. First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis. Int J Cancer. 2023;152:749–60. https://doi.org/10.1002/ijc.34296. Epub 2022 Oct 31. PMID: 36121651; PMCID: PMC10092493.CrossRefPubMed

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-small-cell Lung Cancer. N Engl J Med. 2015;373:1627–39. https://doi.org/10.1056/NEJMoa1507643. Epub 2015 Sep 27. PMID: 26412456; PMCID: PMC5705936.CrossRefPubMedPubMedCentral

Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020;6:e204564. https://doi.org/10.1001/jamaoncol.2020.4564. Epub 2020 Nov 12. Erratum in: JAMA Oncol. 2021;7(1):140. PMID: 33001135; PMCID: PMC7530824.

Yamada Y. First-line treatment with nivolumab and chemotherapy for metastatic gastric cancer in East Asia is not supported by results of the ATTRACTION-4 trial. Chin Clin Oncol. 2022;11:36. https://doi.org/10.21037/cco-22-81. Epub 2022 Oct 13. PMID: 36267022.CrossRefPubMed

10.

Kawazoe A, Fukuoka S, Nakamura Y, Kuboki Y, Wakabayashi M, Nomura S, et al. Lenvatinib plus Pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020;21:1057–65. Epub 2020 Jun 23. PMID: 32589866.CrossRefPubMed

11.

Chung HC, Bang YJ, Fuchs S, Qin C, Satoh SK, Shitara T. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021;17:491–501. https://doi.org/10.2217/fon-2020-0737. Epub 2020 Nov 10. PMID: 33167735; PMCID: PMC8411394.CrossRefPubMed

12.

Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. https://doi.org/10.1126/science.aan6733. Epub 2017 Jun 8. PMID: 28596308; PMCID: PMC5576142.ADSCrossRefPubMedPubMedCentral

13.

Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022;25:197–206. https://doi.org/10.1007/s10120-021-01227-z. Epub 2021 Sep 1. PMID: 34468869; PMCID: PMC8732941.CrossRefPubMed

14.

Santoni M, Piva F, Conti A, Santoni A, Cimadamore A, Scarpelli M, et al. Re: gut Microbiome influences Efficacy of PD-1-based Immunotherapy against epithelial tumors. Eur Urol. 2018;74:521–2. https://doi.org/10.1016/j.eururo.2018.05.033. Epub 2018 Jun 8. PMID: 29891391.CrossRefPubMed

15.

BERGSTRAND CG. CZAR B. Demonstration of a new protein fraction in serum from the human fetus. Scand J Clin Lab Invest. 1956;8:174. https://doi.org/10.3109/00365515609049266. PMID: 13351554.

16.

Li N, Bai C, Zhang R, Ma L, Ren X, Zhang J, et al. Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer. Transl Oncol. 2021;14:101004. https://doi.org/10.1016/j.tranon.2020.101004. Epub 2020 Dec 28. PMID: 33383486; PMCID: PMC7777135.CrossRefPubMed

17.

Matsueda K, Yamamoto H, Yoshida Y, Notohara K. Hepatoid carcinoma of the pancreas producing protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP). J Gastroenterol. 2006;41:1011–9. https://doi.org/10.1007/s00535-006-1889-8. Epub 2006 Nov 9. PMID: 17096071.CrossRefPubMed

18.

Cappetta A, Bergamo F, Mescoli C, Lonardi S, Rugge M, Zagonel V. Hepatoid adenocarcinoma of the colon: what should we target? Pathol Oncol Res. 2012;18:93– 6. doi: 10.1007/s12253-011-9424-5. Epub 2011 Jun 12. PMID: 21667305.

19.

Yamagata T, Yamagata Y, Nakanishi M, Matsunaga K, Minakata Y, Ichinose M. A case of primary lung cancer producing alpha-fetoprotein. Can Respir J. 2004;11:504-6. https://doi.org/10.1155/2004/510350. PMID: 15505704.

20.

Cao W, Chen Y, Han W, Yuan J, Xie W, Liu K, et al. Potentiality of α-fetoprotein (AFP) and soluble intercellular adhesion molecule-1 (sICAM-1) in prognosis prediction and immunotherapy response for patients with hepatocellular carcinoma. Bioengineered. 2021;12:9435–51. PMID: 34696675; PMCID: PMC8809995.CrossRefPubMedPubMedCentral

21.

Munson PV, Adamik J, Butterfield LH. Immunomodulatory impact of α-fetoprotein. Trends Immunol. 2022;43:438–48. https://doi.org/10.1016/j.it.2022.04.001. Epub 2022 May 9. PMID: 35550875.CrossRefPubMed

22.

Kim HI, Lim J, Shim JH. Role of the alpha-fetoprotein response in immune checkpoint inhibitor-based treatment of patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2022;148:2069–77. https://doi.org/10.1007/s00432-021-03727-y. Epub 2021 Aug 30. PMID: 34459972.CrossRefPubMed

23.

Shao YY, Liu TH, Hsu C, Lu LC, Shen YC, Lin ZZ, et al. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int. 2019;39:2184–9. https://doi.org/10.1111/liv.14210. Epub 2019 Aug 31. PMID: 31400295.CrossRefPubMed

24.

Kong XX, Li XL, Tian Y, Ye QC, Xu XM, Liu Y, et al. The clinicopathological characteristics of alpha-fetoprotein-producing adenocarcinoma of the gastrointestinal Tract-A single-Center Retrospective Study. Front Oncol. 2021;11:635537. https://doi.org/10.3389/fonc.2021.635537. PMID: 33996549; PMCID: PMC8118715.CrossRefPubMedPubMedCentral

25.

Li N, Bai C, Zhang R, Ma L, Ren X, Zhang J, et al. Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer. Transl Oncol. 2021;14(2):101004. https://doi.org/10.1016/j.tranon.2020.101004. Epub 2020 Dec 28. PMID: 33383486; PMCID: PMC7777135.CrossRefPubMed

26.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228– 47. https://doi.org/10.1016/j.ejca.2008.10.026. PMID: 19097774.

27.

Chen D, Lin X, Zhang C, An G, Li Z, Dong B, et al. Activated wnt signaling promotes growth and progression of AFP-producing gastric cancer in preclinical models. Cancer Manag Res. 2019;11:1349–62. PMID: 30809100; PMCID: PMC6376882.CrossRefPubMedPubMedCentral

28.

Mizejewski GJ. Does alpha-fetoprotein contribute to the mortality and morbidity of human hepatocellular carcinoma? A commentary. J Hepatocell Carcinoma. 2016;3:37–40. https://doi.org/10.2147/JHC.S114198. PMID: 27703963; PMCID: PMC5036612.CrossRefPubMedPubMedCentral

29.

Głowska-Ciemny J, Szymański M, Kuszerska A, Malewski Z, von Kaisenberg C, Kocyłowski R. The role of alpha-fetoprotein (AFP) in contemporary oncology: the path from a diagnostic biomarker to an Anticancer Drug. Int J Mol Sci. 2023;24:2539. https://doi.org/10.3390/ijms24032539. PMID: 36768863; PMCID: PMC9917199.CrossRefPubMedPubMedCentral

30.

Yang X, Chen L, Liang Y, Si R, Jiang Z, Ma B et al. Knockdown of alpha-fetoprotein expression inhibits HepG2 cell growth and induces apoptosis. J Cancer Res Ther. 2018;14:S634-S643. https://doi.org/10.4103/0973-1482.180681. PMID: 30249880.

31.

Terentiev AA, Moldogazieva NT. Alpha-fetoprotein: a renaissance. Tumour Biol. 2013;34: 2075-91. https://doi.org/10.1007/s13277-013-0904-y. Epub 2013 Jun 14. PMID: 23765762.

32.

Li C, Song B, Santos PM, Butterfield LH. Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells. Cell Immunol. 2019;335:59–67. https://doi.org/10.1016/j.cellimm.2018.10.011. Epub 2018 Nov 1. PMID: 30392891; PMCID: PMC6368446.CrossRefPubMed

33.

Suryatenggara J, Wibowo H, Atmodjo WL, Mathew G. Characterization of alpha-fetoprotein effects on dendritic cell and its function as effector immune response activator. J Hepatocell Carcinoma. 2017;4:139–51. https://doi.org/10.2147/JHC.S139070. PMID: 29238703; PMCID: PMC5713682.CrossRefPubMedPubMedCentral

34.

Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol. 2014;193:5723–32. https://doi.org/10.4049/jimmunol.1400725. Epub 2014 Oct 29. PMID: 25355916; PMCID: PMC4239186.CrossRefPubMed

35.

Vujanovic L, Stahl EC, Pardee AD, Geller DA, Tsung A, Watkins SC et al. Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer-Cell Activation and Subsequent Cell Death. Cancer Immunol Res. 2017;5:493–502. https://doi.org/10.1158/2326-6066.CIR-16-0216. Epub 2017 May 3. PMID: 28468916.

36.

Wang Y, Zhao Y, Li M, Hou H, Jian Z, Li W, et al. Conversion of primary liver cancer after targeted therapy for liver cancer combined with AFP-targeted CAR T-cell therapy: a case report. Front Immunol. 2023;14:1180001. https://doi.org/10.3389/fimmu.2023.1180001. PMID: 37256142; PMCID: PMC10225497.CrossRefPubMedPubMedCentral

37.

Liu H, Xu Y, Xiang J, Long L, Green S, Yang Z, et al. Targeting alpha-fetoprotein (AFP)-MHC complex with CAR T-Cell therapy for Liver Cancer. Clin Cancer Res. 2017;23:478–88. https://doi.org/10.1158/1078-0432.CCR-16-1203. Epub 2016 Aug 17. PMID: 27535982.CrossRefPubMed

38.

Wang B, Xie Y, Zheng L, Zheng X, Gao J, Liu X et al. Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial for predicting the prognosis of gastric adenocarcinoma. BMC Gastroenterol. 2021;21(1):408. https://doi.org/10.1186/s12876-021-01986-0. PMID: 34706681; PMCID: PMC8555135. 2021;21(1):408.

39.

Lima LDP, Machado CJ, Rodrigues JBSR, Vasconcellos LS, Junior EP, Vidigal PVT, et al. Immunohistochemical coexpression of epithelial cell adhesion molecule and alpha-fetoprotein in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2018;2018:5970852. https://doi.org/10.1155/2018/5970852. PMID: 30112355; PMCID: PMC6077358.CrossRefPubMedPubMedCentral

Title: Alpha-fetoprotein predicts the treatment efficacy of immune checkpoint inhibitors for gastric cancer patients
Authors: Jingjing Zhang
Lei Wang
Shasha Zhang
Ruijie Cao
Yufei Zhao
Yue Zhao
Yanrong Song
Zhanjun Guo
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Gastric Cancer
Gastric Cancer
Checkpoint Inhibitors
Epstein-Barr Virus
Cytostatic Therapy
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11999-z

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Abstract

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