A Paradigm Shift in Cancer Staging - Seeing the Unseen with Circulating Tumor Cell Measurement

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Akbar Khan


The U.S. National Cancer Institute (NCI) defines the stage of cancer as the extent of cancer, with categories that reflect tumor size and tumor spread. Staging is meant to assist physicians to understand the seriousness of the cancer (for example chance of survival), and to select the best treatment plan to achieve optimal outcomes. By way of clinical experience, physicians understand that there are significant limitations of the current staging system. It is not unusual, for example, to see patients deemed to have a favorable prognosis or limited disease (by standard accepted staging), who develop early disease recurrence and distant spread. By examining the staging model more closely, it becomes clear that there is a serious omission: modern staging systems only factor in local invasion, micro and macroscopic lymphatic spread and macroscopic spread, while failing entirely to measure hematogenous spread. In recent years, new techniques have been developed that measure and quantify microscopic hematogenous spread, namely circulating tumor cell (CTC) identification and quantification. Hematogenous spread is a well-recognized phenomenon, and extensive data already exists which correlates CTC counts with disease recurrence and patient survival for many solid tumor types. Therefore a revision to the cancer staging system to include hematogenous spread is proposed. It is suggested that the new classification category "Hematogenous" (H) be adopted and measured through the routine use of CTC testing. This addition could result in a significant impact on patient survival for a wide range of cancer types.

Keywords: cancer, staging, TNM, carcinoma, circulating tumor cells, CTC, liquid biopsy, EpCAM, hematogenous, metastases, invasion

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How to Cite
KHAN, Akbar. A Paradigm Shift in Cancer Staging - Seeing the Unseen with Circulating Tumor Cell Measurement. Medical Research Archives, [S.l.], v. 12, n. 3, mar. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5065>. Date accessed: 13 apr. 2024. doi: https://doi.org/10.18103/mra.v12i3.5065.
Review Articles


1. National Cancer Institute. Cancer Staging. National Cancer Institute. Published 2022. https://www.cancer.gov/about-cancer/diagnosis-staging/staging, Accessed Jan 2, 2024

2. Park H, Dahlberg SE, Lydon CA, et al. M1b Disease in the 8th Edition of TNM Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcome. Oncologist. 2019;24(8):e749-e754. doi:10.1634/theoncologist.2018-0596

3. See Reference 1

4. Brierley J, Gospodarowicz M, O'Sullivan B. The principles of cancer staging. Ecancermedicalscience. 2016; 10:ed61. Published 2016 Nov 24. doi:10.3332/ecancer. 2016.ed61

5. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog. 2013;18 (1-2):43-73. doi:10.1615/critrevoncog.v18.i1-2.40

6. Zhou H, Lei PJ, Padera TP. Progression of Metastasis through Lymphatic System. Cells. 2021;10(3):627. Published 2021 Mar 12. doi:10.3390/cells10030627

7. Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide?. Cell Cycle. 2006;5(8):812-817. doi:10.4161/cc.5.8.2646

8. Seeberg LT, Brunborg C, Waage A, et al. Survival Impact of Primary Tumor Lymph Node Status and Circulating Tumor Cells in Patients with Colorectal Liver Metastases. Ann Surg Oncol. 2017;24(8):2113-2121. doi:10. 1245/s10434-017-5818-2

9. Rami-Porta R. Future Perspectives on the TNM Staging for Lung Cancer. Cancers (Basel). 2021;13(8):1940. Published 2021 Apr 17. doi:10.3390/cancers13081940

10. van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010;31(11):1913-1921. doi:10.1093/carcin/bgq187

11. Pachmann K, Camara O, Kavallaris A, Schneider U, Schünemann S, Höffken K. Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring. Breast Cancer Res. 2005;7(6):R97 5-R979. doi:10.1186/bcr1328

12. Smerage JB, Hayes DF. The measurement and therapeutic implications of circulating tumour cells in breast cancer. Br J Cancer. 2006;94(1):8-12. doi:10.1038/sj.bjc.6602871

13. Ma YC, Wang L, Yu FL. Recent advances and prospects in the isolation by size of epithelial tumor cells (ISET) methodology. Technol Cancer Res Treat. 2013;12(4):295-309. doi:10.7785/tcrt.2012.500328

14. See Reference 7

15. Gold M, Pachmann K, Kiani A, Schobert R. Monitoring of circulating epithelial tumor cells using the Maintrac® method and its potential benefit for the treatment of patients with colorectal cancer. Mol Clin Oncol. 2021;15(4):201. doi:10.3892/mco.2021.2363

16. Garrido Castillo LN, Mejean A, Vielh P, et al. Predictive Value of Circulating Tumor Cells Detected by ISET® in Patients with Non-Metastatic Prostate Cancer Undergoing Radical Prostatectomy. Life (Basel). 2022;12 (2):165. Published 2022 Jan 22. doi:10.3390 /life12020165

17. Wang Z, Zhang XC, Feng WN, et al. Circulating tumor cells dynamics during chemotherapy predict survival and response in advanced non-small-cell lung cancer patients. Ther Adv Med Oncol. 2023;15: 17588359231167818. Published 2023 Apr 22. doi:10.1177/17588359231167818

18. Hwang SB, Bae JW, Lee HY, Kim HY. Circulating Tumor Cells Detected by RT-PCR for CK-20 before Surgery Indicate Worse Prognostic Impact in Triple-Negative and HER2 Subtype Breast Cancer. J Breast Cancer. 2012;15(1):34-42. doi:10.4048/jbc. 2012.15.1.34

19. Diaz, M.T.d., Abdallah, E.A., Tariki, M.S. et al. Circulating tumor cells as marker of poor prognosis in metastatic lung cancer: a pilot study. Appl Cancer Res 38, 8 (2018). doi:10.1186/s41241-018-0059-7

20. Huang X, Gao P, Song Y, et al. Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch System in colorectal cancer. BMC Cancer. 2015;15:202. Published 2015 Mar 30. doi:10.1186/s12885-015-1218-9

21. Rolle A, Günzel R, Pachmann U, Willen B, Höffken K, Pachmann K. Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC(R) is a predictor for relapse: A preliminary report. World J Surg Oncol. 2005;3(1):18. Published 2005 Mar 31. doi:10.1186/1477-7819-3-18

22. Yang C, Shi D, Wang S, Wei C, Zhang C, Xiong B. Prognostic value of pre- and post-operative circulating tumor cells detection in colorectal cancer patients treated with curative resection: a prospective cohort study based on ISET device. Cancer Manag Res. 2018;10:4135-4144. Published 2018 Oct 4. doi:10.2147/CMAR.S176575

23. Truini A, Alama A, Dal Bello MG, et al. Clinical Applications of Circulating Tumor Cells in Lung Cancer Patients by CellSearch System. Front Oncol. 2014;4:242. Published 2014 Sep 4. doi:10.3389/fonc.2014.00242

24. Mäurer M, Pachmann K, Wendt T, Schott D, Wittig A. Prospective Monitoring of Circulating Epithelial Tumor Cells (CETC) Reveals Changes in Gene Expression during Adjuvant Radiotherapy of Breast Cancer Patients. Current Oncology. 2021; 28(5):3507-3524. doi:10.3390/curroncol28050302

25. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018;32(19-20):1267-1284. doi:10.1101/ gad.314617.118

26. Castle J, Morris K, Pritchard S, Kirwan CC. Challenges in enumeration of CTCs in breast cancer using techniques independent of cytokeratin expression. PLoS One. 2017;12 (4):e0175647. Published 2017 Apr 19. doi:10. 1371/journal.pone.0175647

27. Gorges, T.M., Tinhofer, I., Drosch, M. et al. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer 12, 178 (2012). https://doi.org/10.1186/1471-2407-12-178

28. See Reference 15

29. Gajda M, Camara O, Oppel S, et al. Monitoring circulating epithelial tumor cells (CETCs) during primary systemic chemotherapy including trastuzumab for early prediction of outcome in patients with Her2/neu-positive tumors. Ann Oncol. 2008;19(12):2090-2091. doi:10.1093/annonc/mdn648

30. Pachmann K, Schuster S. The Value of Monitoring the Behavior of Circulating Tumor Cells at the End of Endocrine Therapy in Breast Cancer Patients. Cancers (Basel). 2018;10 (11):407. Published 2018 Oct 29. doi:10.3390/cancers10110407

31. Kwei KA, Kung Y, Salari K, Holcomb IN, Pollack JR. Genomic instability in breast cancer: pathogenesis and clinical implications. Mol Oncol. 2010;4(3):255-266. doi:10.1016/j. molonc.2010.04.001

32. Feng Y, Wang P, Chen Y, Dai W. 18 F-FDG PET/CT for evaluation of metastases in nonsmall cell lung cancer on the efficacy of immunotherapy. Nucl Med Commun. 2023;44 (10):900-909. doi:10.1097/MNM.0000000000001737

33. Umemura Y, Wang D, Peck KK, et al. DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy. J Neurooncol. 2020;146 (2):339-346. doi:10.1007/s11060-019-03379-6

34. Lagalla R, Caruso G, Finazzo M. Monitoring treatment response with color and power Doppler. Eur J Radiol. 1998;27 Suppl 2:S149-S156. doi:10.1016/s0720-048x(98)00056-4

35. Ried K, Eng P, Sali A. Screening for Circulating Tumour Cells Allows Early Detection of Cancer and Monitoring of Treatment Effectiveness: An Observational Study. Asian Pac J Cancer Prev. 2017;18(8):2275-2285. Published 2017 Aug 27. doi:10.22034/APJCP.2017.18.8.2275

36. Garcés JJ, Cedena MT, Puig N, et al. Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma. J Clin Oncol. 2022;40(27):3151-3161. doi:10.1200/JCO.21.01365

37. Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients [published correction appears in J Natl Cancer Inst. 2014 Sep;106(9):doi/10.1093/jnci/dju 273]. J Natl Cancer Inst. 2014;106(5):dju066. Published 2014 May 15. doi:10.1093/jnci/dju066

38. Chinniah C, Aguarin L, Cheng P, et al. Early Detection of Recurrence in Patients With Locally Advanced Non-Small-Cell Lung Cancer via Circulating Tumor Cell Analysis. Clin Lung Cancer. 2019;20(5):384-390.e2. doi:10.1016/j.cllc.2019.04.011

39. See Reference 37

40. Ju L, Yang J, Zhai C, Chai S, Dong Z, Li M. Survival, Chemotherapy and Chemosensitivity Predicted by CTC Cultured In Vitro of SCLC Patients. Front Oncol. 2021;11:683318. Published 2021 Jun 25. doi: 10.3389/fonc. 2021.683318

41. Sun Y, Wu G, Cheng KS, et al. CTC phenotyping for a preoperative assessment of tumor metastasis and overall survival of pancreatic ductal adenocarcinoma patients. EBioMedicine. 2019;46: 133-149. doi:10.1016 /j.ebiom.2019.07.044

42. Hugenschmidt H, Labori KJ, Borgen E, et al. Preoperative CTC-Detection by CellSearch® Is Associated with Early Distant Metastasis and Impaired Survival in Resected Pancreatic Cancer. Cancers (Basel). 2021;13 (3):485. Published 2021 Jan 27. doi:10.3390/ cancers 13030485

43. Lugassy C, Zadran S, Bentolila LA, et al. Angiotropism, pericytic mimicry and extravascular migratory metastasis in melanoma: an alternative to intravascular cancer dissemination. Cancer Microenviron. 2014;7(3):139-152. doi:10.1007/s12307-014-0156-4

44. Pizon M, Schott D, Pachmann U, Pachmann K. The number of tumorspheres cultured from peripheral blood is a predictor for presence of metastasis in patients with breast cancer. Oncotarget. 2016;7(30):48143-48154. doi:10.18632/oncotarget.10174