Advertisement

Gastric Cancer

, Volume 22, Issue 1, pp 147–154 | Cite as

Discordancy and changes in the pattern of programmed death ligand 1 expression before and after platinum-based chemotherapy in metastatic gastric cancer

  • Ji Hyun Yang
  • Hyunho Kim
  • Sang Young Roh
  • Myung Ah Lee
  • Jae Myung Park
  • Han Hee Lee
  • Cho Hyun Park
  • Han Hong Lee
  • Eun Sun Jung
  • Sung Hak Lee
  • Young Joon Lee
  • Moon Hyung Choi
  • Okran Kim
  • In-Ho Kim
Original Article
  • 216 Downloads

Abstract

Background

Our goal was to evaluate changes in PD-L1 expression in primary tumours of metastatic gastric cancer before and after chemotherapy.

Methods

We evaluated the PD-L1 expression of 72 patients with primary gastric cancer, before and after palliative first-line platinum-based chemotherapy, between January 2015 and March 2017. The PD-L1 ratio was defined as pre-chemotherapy PD-L1 expression divided by the post-chemotherapy PD-L1 expression.

Results

In 30 patients with PD-L1 negative pre-chemotherapy, 12 (40%) were positive post-chemotherapy; among the 42 patients with PD-L1 positive pre-chemotherapy, 24 (57.1%) were negative post-chemotherapy. The degree of PD-L1 expression decreased from 58.3% before chemotherapy to 41.7% after chemotherapy (P = 0.046). Among patients with complete response/partial response (CR/PR), the degree of PD-L1 expression decreased (P = 0.002), as well as PD-L1 positivity with statistical significance (P = 0.013) after chemotherapy, but not among patients with stable disease/progressive disease (SD/PD). Higher disease control rates (CR/PR/SD) were observed in patients with an elevated PD-L1 ratio (P = 0.043). Patients with a high PD-L1 ratio (> 1) were found to be associated with a better progression-free survival (HR 0.34, 95% CI 0.17–0.67, P = 0.002).

Conclusions

PD-L1 expression can change during chemotherapy. Moreover, changes in patterns of PD-L1 expression might be associated with patient prognosis and response to chemotherapy.

Keywords

Gastric cancer Programmed cell death ligand 1 Chemotherapy Prognosis Survival 

Notes

Acknowledgements

The authors wish to acknowledge the financial support from the Catholic Medical Center Research Foundation made in the program year of 2018.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Informed consent

Informed consents were obtained from all patients for their inclusion in the study.

Supplementary material

10120_2018_842_MOESM1_ESM.docx (39 kb)
Supplementary material 1 (DOCX 39 KB)
10120_2018_842_MOESM2_ESM.tif (4.1 mb)
Supplementary material 2 (TIF 4205 KB)
10120_2018_842_MOESM3_ESM.tif (4.5 mb)
Supplementary material 3 (TIF 4570 KB)
10120_2018_842_MOESM4_ESM.tif (3.4 mb)
Supplementary material 4 (TIF 3516 KB)
10120_2018_842_MOESM5_ESM.tif (3.2 mb)
Supplementary material 5 (TIF 3243 KB)
10120_2018_842_MOESM6_ESM.tif (2.8 mb)
Supplementary material 6 (TIF 2853 KB)

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefGoogle Scholar
  2. 2.
    Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.CrossRefGoogle Scholar
  3. 3.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687 – 97.CrossRefGoogle Scholar
  4. 4.
    Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.CrossRefGoogle Scholar
  5. 5.
    McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013;2:662–73.Google Scholar
  6. 6.
    Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98–106.CrossRefGoogle Scholar
  7. 7.
    Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.CrossRefGoogle Scholar
  8. 8.
    Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561.CrossRefGoogle Scholar
  9. 9.
    Lote H, Cafferkey C, Chau I. PD-1 and PD-L1 blockade in gastrointestinal malignancies. Cancer Treat Rev. 2015;41:893–903.CrossRefGoogle Scholar
  10. 10.
    Wainberg ZA, Jalal S, Muro K, Yoon HH, Garrido M, Golan T, et al. LBA28_PRKEYNOTE-059 Update: Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer. Ann Oncol. 2017;28:mdx440.020–mdx440.020.CrossRefGoogle Scholar
  11. 11.
    Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol. 2016;2:1217–22.CrossRefGoogle Scholar
  12. 12.
    Yuasa T, Masuda H, Yamamoto S, Numao N, Yonese J. Biomarkers to predict prognosis and response to checkpoint inhibitors. Int J Clin Oncol. 2017;22:629 – 34.CrossRefGoogle Scholar
  13. 13.
    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.CrossRefGoogle Scholar
  14. 14.
    Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer. 2016;52:1–9.CrossRefGoogle Scholar
  15. 15.
    Luo M, Fu L. The effect of chemotherapy on programmed cell death 1/programmed cell death 1 ligand axis: some chemotherapeutical drugs may finally work through immune response. Oncotarget. 2016;7:29794–803.Google Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Boger C, Behrens HM, Mathiak M, Kruger S, Kalthoff H, Rocken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7:24269–83.CrossRefGoogle Scholar
  18. 18.
    Meng X, Huang Z, Teng F, Xing L, Yu J. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 2015;41:868–76.CrossRefGoogle Scholar
  19. 19.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.CrossRefGoogle Scholar
  20. 20.
    Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389:67–76.CrossRefGoogle Scholar
  21. 21.
    Schatton T, Schutte U, Frank NY, Zhan Q, Hoerning A, Robles SC, et al. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 2010;70:697–708.CrossRefGoogle Scholar
  22. 22.
    Shen JK, Cote GM, Choy E, Yang P, Harmon D, Schwab J, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2:690–8.CrossRefGoogle Scholar
  23. 23.
    Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, et al. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther. 2015;23:717–27.CrossRefGoogle Scholar
  24. 24.
    Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y, et al. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep. 2016;6:20090.CrossRefGoogle Scholar
  25. 25.
    Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. 2008;45:1470–6.CrossRefGoogle Scholar
  26. 26.
    Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M, et al. Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res. 2010;12:R48.CrossRefGoogle Scholar
  27. 27.
    Kim JW, Nam KH, Ahn SH, Park do J, Kim HH, Kim SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2016;19:42–52.CrossRefGoogle Scholar
  28. 28.
    Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108:19–24.CrossRefGoogle Scholar
  29. 29.
    Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66:3381–5.CrossRefGoogle Scholar
  30. 30.
    Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, et al. B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA. 2007;104:19458–63.CrossRefGoogle Scholar
  31. 31.
    Thompson ED, Zahurak M, Murphy A, Cornish T, Cuka N, Abdelfatah E, et al. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut. 2017;66:794–801.CrossRefGoogle Scholar
  32. 32.
    Jiang W, Liu K, Guo Q, Cheng J, Shen L, Cao Y, et al. Tumor-infiltrating immune cells and prognosis in gastric cancer: a systematic review and meta-analysis. Oncotarget. 2017;8:62312–29.Google Scholar
  33. 33.
    Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–39.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Ji Hyun Yang
    • 1
  • Hyunho Kim
    • 1
  • Sang Young Roh
    • 1
    • 6
  • Myung Ah Lee
    • 1
    • 7
  • Jae Myung Park
    • 2
    • 6
  • Han Hee Lee
    • 2
    • 6
  • Cho Hyun Park
    • 3
    • 6
  • Han Hong Lee
    • 3
    • 6
  • Eun Sun Jung
    • 4
    • 6
  • Sung Hak Lee
    • 4
    • 6
  • Young Joon Lee
    • 5
    • 6
  • Moon Hyung Choi
    • 5
    • 6
  • Okran Kim
    • 7
  • In-Ho Kim
    • 1
    • 6
    • 7
  1. 1.Department of Internal Medicine, Division of Medical Oncology, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  2. 2.Department of Internal Medicine, Division of Gastroenterology, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  3. 3.Department of Surgery, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  4. 4.Department of Clinical Pathology, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  5. 5.Department of Radiology, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  6. 6.Department of Gastric Cancer Centre, Seoul St. Mary’s HospitalThe Catholic University of Korea College of MedicineSeoulSouth Korea
  7. 7.Cancer Research InstituteThe Catholic University of Korea College of MedicineSeoulSouth Korea

Personalised recommendations