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In vivo detection of circulating tumor cells predicts high-risk features in patients with bladder cancer

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Abstract

Previous studies have suggested the potential diagnostic value of circulating tumor cells (CTCs). This study aims to validate the efficacy of in vivo detection of CTCs in bladder cancer (BC) patients. A total of 216 BC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as a baseline parameter. The results of CTCs were associated with different clinicopathological features including molecular subtypes. PD-L1 expression on CTCs was also assessed and compared with its expression on tumors. CTC positive was defined as > 2 CTCs detected. Among all 216 patients, 49 (23%) were detected as CTC positive (> 2 CTCs) at baseline. Positive detection of CTCs was associated with multiple high-risk clinicopathological features including the multiplicity of the tumor (P = 0.02), tumor size (P < 0.01), tumor stage (P < 0.01), tumor grade (P < 0.01) and tumor PD-L1 expression (P = 0.01). The expression of PD-L1 on tumor and CTCs were not coordinated. Only 55% (74/134) matched the same status of PD-L1 expression on tumor and CTCs, along with 56 CTC (+) Tissue (−) and 4 CTC (−) Tissue (+) (P < 0.01). Our study has demonstrated the efficacy of in vivo detection of CTCs. The positive detection of CTCs is associated with multiple clinicopathological features. PD-L1 expression on CTCs has the potential to be a supplementary biomarker for immunotherapy.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. https://doi.org/10.3322/caac.21708.

    Article  PubMed  Google Scholar 

  2. Lenis AT, Lec PM, Chamie K, Mshs MD. Bladder cancer: a review. JAMA. 2020;324(19):1980–91. https://doi.org/10.1001/jama.2020.17598.

    Article  CAS  PubMed  Google Scholar 

  3. Babjuk M, Burger M, Compérat EM, et al. European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and Carcinoma in situ)—2019 update. Eur Urol. 2019;76(5):639–57. https://doi.org/10.1016/j.eururo.2019.08.016.

    Article  CAS  PubMed  Google Scholar 

  4. Witjes JA, Bruins HM, Cathomas R, et al. European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol. 2021;79(1):82–104. https://doi.org/10.1016/j.eururo.2020.03.055.

    Article  CAS  PubMed  Google Scholar 

  5. International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171–7. https://doi.org/10.1200/JCO.2010.32.3139.

    Article  PubMed Central  Google Scholar 

  6. Ritch CR, Velasquez MC, Kwon D, et al. Use and validation of the AUA/SUO risk grouping for nonmuscle invasive bladder cancer in a contemporary cohort. J Urol. 2020;203(3):505–11. https://doi.org/10.1097/JU.0000000000000593.

    Article  PubMed  Google Scholar 

  7. Huguet J, Crego M, Sabaté S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol. 2005;48(1):53–9. https://doi.org/10.1016/j.eururo.2005.03.021.

    Article  CAS  PubMed  Google Scholar 

  8. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol. 2001;19(3):666–75. https://doi.org/10.1200/JCO.2001.19.3.666.

    Article  CAS  PubMed  Google Scholar 

  9. Bianco FJ Jr, Justa D, Grignon DJ, Sakr WA, Pontes JE, Wood DP Jr. Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol. 2004;22(4):290–4. https://doi.org/10.1016/S1078-1439(03)00144-3.

    Article  PubMed  Google Scholar 

  10. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26. https://doi.org/10.1056/NEJMoa1613683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Powles T, Csőszi T, Özgüroğlu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7):931–45. https://doi.org/10.1016/S1470-2045(21)00152-2.

    Article  CAS  PubMed  Google Scholar 

  12. Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706–14. https://doi.org/10.1038/s41591-019-0628-7.

    Article  CAS  PubMed  Google Scholar 

  13. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol. 2018;36(34):3353–60. https://doi.org/10.1200/JCO.18.01148.

    Article  CAS  PubMed  Google Scholar 

  14. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102–14. https://doi.org/10.1056/NEJMoa2034442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018;48(3):434–52. https://doi.org/10.1016/j.immuni.2018.03.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao Q, Xie R, Lin S, You X, Weng X. Anti-PD-1/PD-L1 antibody therapy for pretreated advanced or metastatic nonsmall cell lung carcinomas and the correlation between PD-L1 expression and treatment effectiveness: an update meta-analysis of randomized clinical trials. Biomed Res Int. 2018;2018:3820956. https://doi.org/10.1155/2018/3820956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Small AC, Gong Y, Oh WK, Hall SJ, van Rijn CJ, Galsky MD. The emerging role of circulating tumor cell detection in genitourinary cancer. J Urol. 2012;188(1):21–6. https://doi.org/10.1016/j.juro.2012.02.2558.

    Article  PubMed  Google Scholar 

  18. Ahn JC, Teng PC, Chen PJ, et al. Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology. 2021;73(1):422–36. https://doi.org/10.1002/hep.31165.

    Article  PubMed  Google Scholar 

  19. Jiang H, Gu X, Zuo Z, Tian G, Liu J. Prognostic value of circulating tumor cells in patients with bladder cancer: a meta-analysis. PLoS ONE. 2021;16(7):e0254433. https://doi.org/10.1371/journal.pone.0254433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hong B, Zu Y. Detecting circulating tumor cells: current challenges and new trends. Theranostics. 2013;3(6):377–94. https://doi.org/10.7150/thno.5195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vermesh O, Aalipour A, Ge TJ, et al. An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. Nat Biomed Eng. 2018;2(9):696–705. https://doi.org/10.1038/s41551-018-0257-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Budna-Tukan J, Świerczewska M, Mazel M, et al. Analysis of circulating tumor cells in patients with non-metastatic high-risk prostate cancer before and after radiotherapy using three different enumeration assays. Cancers (Basel). 2019;11(6):802. https://doi.org/10.3390/cancers11060802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22. https://doi.org/10.1038/nature12965.

    Article  CAS  Google Scholar 

  24. Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540-556.e25. https://doi.org/10.1016/j.cell.2017.09.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kamoun A, de Reyniès A, Allory Y, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2020;77(4):420–33. https://doi.org/10.1016/j.eururo.2019.09.006.

    Article  PubMed  Google Scholar 

  26. Choi W, Czerniak B, Ochoa A, et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol. 2014;11(7):400–10. https://doi.org/10.1038/nrurol.2014.129.

    Article  CAS  PubMed  Google Scholar 

  27. Chen S, Tauber G, Langsenlehner T, et al. In vivo detection of circulating tumor cells in high-risk non-metastatic prostate cancer patients undergoing radiotherapy. Cancers (Basel). 2019;11(7):933. https://doi.org/10.3390/cancers11070933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cohen SJ, Punt CJ, Iannotti N, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20(7):1223–9. https://doi.org/10.1093/annonc/mdn786.

    Article  CAS  PubMed  Google Scholar 

  29. Hodgson A, Liu SK, Vesprini D, Xu B, Downes MR. Basal-subtype bladder tumours show a “hot” immunophenotype. Histopathology. 2018;73(5):748–57. https://doi.org/10.1111/his.13696.

    Article  PubMed  Google Scholar 

  30. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91. https://doi.org/10.1056/NEJMoa040766.

    Article  CAS  PubMed  Google Scholar 

  31. Abrahamsson J, Aaltonen K, Engilbertsson H, et al. Circulating tumor cells in patients with advanced urothelial carcinoma of the bladder: association with tumor stage, lymph node metastases, FDG-PET findings, and survival. Urol Oncol. 2017;35(10):606.e9-606.e16. https://doi.org/10.1016/j.urolonc.2017.05.021.

    Article  CAS  PubMed  Google Scholar 

  32. Gazzaniga P, de Berardinis E, Raimondi C, et al. Circulating tumor cells detection has independent prognostic impact in high-risk non-muscle invasive bladder cancer. Int J Cancer. 2014;135(8):1978–82. https://doi.org/10.1002/ijc.28830.

    Article  CAS  PubMed  Google Scholar 

  33. Rink M, Chun FK, Dahlem R, et al. Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol. 2012;61(4):810–7. https://doi.org/10.1016/j.eururo.2012.01.017.

    Article  CAS  PubMed  Google Scholar 

  34. Guzzo TJ, McNeil BK, Bivalacqua TJ, Elliott DJ, Sokoll LJ, Schoenberg MP. The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy. Urol Oncol. 2012;30(1):44–8. https://doi.org/10.1016/j.urolonc.2009.10.008.

    Article  PubMed  Google Scholar 

  35. Jordan B, Meeks JJ. T1 bladder cancer: current considerations for diagnosis and management. Nat Rev Urol. 2019;16(1):23–34. https://doi.org/10.1038/s41585-018-0105-y.

    Article  PubMed  Google Scholar 

  36. Gorin MA, Verdone JE, van der Toom E, Bivalacqua TJ, Allaf ME, Pienta KJ. Circulating tumour cells as biomarkers of prostate, bladder, and kidney cancer. Nat Rev Urol. 2017;14(2):90–7. https://doi.org/10.1038/nrurol.2016.224.

    Article  CAS  PubMed  Google Scholar 

  37. Bergmann S, Coym A, Ott L, et al. Evaluation of PD-L1 expression on circulating tumor cells (CTCs) in patients with advanced urothelial carcinoma (UC). Oncoimmunology. 2020;9(1):1738798. https://doi.org/10.1080/2162402X.2020.1738798.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hwang DM, Albaqer T, Santiago RC, et al. Prevalence and heterogeneity of PD-L1 expression by 22C3 assay in routine population-based and reflexive clinical testing in lung cancer. J Thorac Oncol. 2021;16(9):1490–500. https://doi.org/10.1016/j.jtho.2021.03.028.

    Article  CAS  PubMed  Google Scholar 

  39. Inman BA, Longo TA, Ramalingam S, Harrison MR. Atezolizumab: a PD-L1-blocking antibody for bladder cancer. Clin Cancer Res. 2017;23(8):1886–90. https://doi.org/10.1158/1078-0432.CCR-16-1417.

    Article  CAS  PubMed  Google Scholar 

  40. Boorjian SA, Sheinin Y, Crispen PL, et al. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res. 2008;14(15):4800–8. https://doi.org/10.1158/1078-0432.CCR-08-0731.

    Article  CAS  PubMed  Google Scholar 

  41. de Kruijff IE, Beije N, Martens JWM, de Wit R, Boormans JL, Sleijfer S. Liquid biopsies to select patients for perioperative chemotherapy in muscle-invasive bladder cancer: a systematic review. Eur Urol Oncol. 2021;4(2):204–14. https://doi.org/10.1016/j.euo.2020.01.003.

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (82173076, 82103485), Shanghai Natural Science Foundation (20Y11904900), Young Talent Project in Healthcare of Shanghai Municipal Health Commission (2022YQ014), Shanghai Hospital Development Center (SHDC2022CRD034) and Innovative Research Team of High-level Local Universities in Shanghai.

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Authors and Affiliations

  1. Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Di Jin, Lei Qian, Ruiyun Zhang, Guoliang Yang, Lianhua Zhang, Wei Xue, Ming Cao, Liang Dong & Haige Chen

  2. Department of Pathology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Jun Xia

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Contributions

DJ, LD, and HC designed studies, analyzed data, and wrote the manuscript. DJ, LQ, JX, and MC conducted the experiments and data analysis. GY, RZ, LZ and WX collected the patient samples, followed up with patients, and performed data analysis. LQ and LD prepared figures and tables. All authors reviewed and approved the final manuscript.

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Correspondence to Ming Cao, Liang Dong or Haige Chen.

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The authors have no relevant financial or non-financial interests to disclose.

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The study complies with the Declaration of Helsinki and was conducted following the approval from Renji Hospital Ethics Committee. Written informed consent was obtained from all the patients.

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The authors Di Jin and Lei Qian are contributed equally to this work.

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Jin, D., Qian, L., Xia, J. et al. In vivo detection of circulating tumor cells predicts high-risk features in patients with bladder cancer. Med Oncol 40, 113 (2023). https://doi.org/10.1007/s12032-023-01977-z

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