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Biomarkers predicting the response to chemotherapy and the prognosis in patients with esophageal squamous cell carcinoma

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Abstract

Background

The prognosis of patients with esophageal squamous cell carcinoma (ESCC) has been improved by multidisciplinary therapy with chemoradiotherapy and surgery, but it remains poor. Advanced stage, malignant potential, and chemo-resistance contribute to the poor prognosis. Here, we attempted to identify predictive factors of the response to chemotherapy and the prognosis of ESCC patients.

Patients and methods

We examined 51 ESCC patients who were treated with chemotherapy followed by radical surgery, and 23 patients who were treated with chemotherapy alone. We conducted quantitative reverse transcription-polymerase chain reaction gene expression analysis using RNA extracted from 74 tumor tissue samples collected before chemotherapy and 67 tumor tissue samples collected after chemotherapy, focusing on PIK3CA, AKT-1, mTOR, 4E-BP1, p70S6K, PD-L1, and PD-L2.

Results

The proportions of patients with high expressions of AKT-1 and PD-L1 before chemotherapy were significantly higher among the non-responders than among the responders (p = 0.034, p = 0.020, respectively). Multivariate analyses revealed that high PD-L1 expression before chemotherapy was associated with poor response to chemotherapy (odds ratio 2.998; 95% CI 1.043–8.619; p = 0.042) and high p70S6K expression before chemotherapy was a poor prognostic factor (hazard ratio 2.518; 95% CI 1.058–5.988; p = 0.037). In addition, the patients with high expression of PD-L1 and PD-L2 in the tumors after chemotherapy had significantly worse survival than those with low expression of these genes (p = 0.012, p = 0.007, respectively).

Conclusion

These results demonstrated that PD-L1 and p70S6K in the primary ESCC tissues were related to a poor response to chemotherapy and poor prognosis, respectively.

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References

  1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14):2137–50.

    Article  Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics. CA Cancer J Clin. 2015;65(2):87–108.

    Article  Google Scholar 

  3. Kitagawa Y, Uno T, Oyama T, Kato K, Kato H, Kawakubo H, et al. Esophageal cancer practice guidelines 2017 edited by the japan esophageal society: part 1. Esophagus. 2019;16(1):1–24.

    Article  Google Scholar 

  4. Wu N, Du Z, Zhu Y, Song Y, Pang L, Chen Z. The expression and prognostic impact of the PI3K/AKT/mTOR signaling pathway in advanced esophageal squamous cell carcinoma. Technol Cancer Res Treat. 2018. https://doi.org/10.1177/1533033818758772.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ui T, Fujii H, Hosoya Y, Nagase M, Mieno MN, Mori M, et al. Comparison of preoperative chemotherapy using docetaxel, cisplatin and fluorouracil with cisplatin and fluorouracil in patients with advanced carcinoma of the thoracic esophagus. Dis Esophagus. 2015;28(2):180–7.

    Article  CAS  Google Scholar 

  6. Ben O, Rosalind JC, Yuan L, Sarah H, Xin H, Kerry F, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–403.

    Article  Google Scholar 

  7. Yoshida T, Miyoshi T, Seike J, Yamai H, Takechi H, Yuasa Y, et al. Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. Anticancer Res. 2009;29:1163–8.

    CAS  PubMed  Google Scholar 

  8. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.

    Article  CAS  Google Scholar 

  9. Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev. 2009;35(2):148–59.

    Article  CAS  Google Scholar 

  10. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000;19:6680–6.

    Article  CAS  Google Scholar 

  11. Panwalkar A, Verstovsek S, Giles GJ. Manmmalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer. 2004;100:657–66.

    Article  CAS  Google Scholar 

  12. Li B, Li J, Wen Xu, Guan XY, Qin YR, Zhang LY, et al. Suppression of esophageal tumor growth and chemo-resistance by directly targeting the PI3K/AKT pathway. Oncotarget. 2014;5(22):11576–87.

    Article  Google Scholar 

  13. Hatogai K, Kitano S, Fujii S, Kojima T, Daiko H, Nomura S, et al. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget. 2016;7(30):47252–64.

    Article  Google Scholar 

  14. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–12.

    Article  CAS  Google Scholar 

  15. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (checkmate 017 and checkmate 057). J Clin Oncol. 2017;35(35):3924–33.

    Article  CAS  Google Scholar 

  18. Zhao L, Li C, Liu F, Zhao Y, Liu J, Hua Y, et al. A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway. Onco Targets Ther. 2017;10:2115–26.

    Article  CAS  Google Scholar 

  19. Yoshida T, Seike J, Miyoshi T, Yamai H, Takechi H, Yuasa Y, et al. Preoperative chemotherapy with weekly docetaxel plus low-dose cisplatin and 5-fluorouracil for stage II/III squamous cell carcinoma of the esophagus. Esophagus. 2010;7:95–100.

    Article  Google Scholar 

  20. Nishino T, Yoshida T, Inoue S, Fujiwara S, Goto M, Minato T, et al. Gender differences in clinicopathological features and prognosis of squamous cell carcinoma of the esophagus. Esophagus. 2017;14:122–30.

    Article  Google Scholar 

  21. Japan Esophageal Society. Japanese Classification of esophageal cancer, 11th edition: part II and III. Esophagus. 2017;14:37–65.

    Article  Google Scholar 

  22. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.

    Article  CAS  Google Scholar 

  23. Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:121–30.

    Article  CAS  Google Scholar 

  24. Li SH, Chen CH, Lu HI, Huang WT, Tien WY, Lan YC, et al. Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma. Surgery. 2015;157(3):570–80.

    Article  Google Scholar 

  25. Malinowsky K, Nitsche U, Janssen KP, Barder FG, Spath C, Drecoll E, et al. Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer. Br J Cancer. 2014;110(8):2081–9.

    Article  CAS  Google Scholar 

  26. Ying J, Xu Q, Liu B, Zhang G, Chen L, Pan H. The expression of the PI3K/AKT/mTOR pathway in gastric cancer and its role in gastric cancer prognosis. Onco Targets Ther. 2015;8:2427–33.

    Article  CAS  Google Scholar 

  27. Goncharenko-Khaider N, Lane D, Matte I, Rancourt C, Piche A. The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells. Oncogene. 2010;29:5523–36.

    Article  CAS  Google Scholar 

  28. Simioni C, Martelli AM, Cani A, Cetin-Atalay R, McCubrey JA, Capitani S, et al. The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy. Oncotarget. 2013;4:1496–506.

    Article  Google Scholar 

  29. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018. https://doi.org/10.1136/bmj.k793.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11(8):2947–53.

    Article  CAS  Google Scholar 

  31. Shin J, Chung JH, Kim SH, Lee KS, Suh KJ, Lee JY, et al. Effect of platinum-based chemotherapy on PD-L1 expression on tumor cells in non-small cell lung cancer. Cancer Res Treat. 2019;51(3):1086–97.

    Article  CAS  Google Scholar 

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Acknowledgements

Grant support: This work was supported by a First JATS Award for Young Investigators in 2018. We thank Ms. Kana Tominaga for technical assistance.

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Authors and Affiliations

  1. Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Seiya Inoue, Takahiro Yoshida, Takeshi Nishino, Masakazu Goto, Mariko Aoyama, Naoya Kawakita, Yota Yamamoto, Furukita Yoshihito, Hiromitsu Takizawa & Akira Tangoku

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  1. Seiya Inoue
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  2. Takahiro Yoshida
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  3. Takeshi Nishino
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Correspondence to Seiya Inoue.

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All procedures were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. All patients provided informed consent for the use of their data and materials.

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Inoue, S., Yoshida, T., Nishino, T. et al. Biomarkers predicting the response to chemotherapy and the prognosis in patients with esophageal squamous cell carcinoma. Gen Thorac Cardiovasc Surg 69, 525–533 (2021). https://doi.org/10.1007/s11748-021-01586-5

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