Prognostic value of circulating tumor cells in determining prognosis of patients operated for gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Chuang , LIANG Wenquan , LU Yixun , GAO Yunhe , ZHUANG Ziwei , WANG Lili , XI Hongqing ,  CHEN Lin

Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Institute of General Surgery, Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, P. R. China;

Corresponding?author：

CHEN Lin, Email: chenlinbj@.sina.com

Keywords：

circulating tumor cells; gastric cancer; prognosis

DOI：

10.7507/1007-9424.202104113

Video：

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Objective To investigate the clinical significance of circulating tumor cells (CTC) in gastric cancer patients treated with surgery and to assess its prognostic value for gastric cancer patients. Methods A case-control study was conducted to retrospectively collect the clinicopathological data of gastric cancer patients who underwent radical gastric cancer surgery at the Department of General Surgery, First Medical Center of the Chinese People’s Liberation Army General Hospital between April 2015 and July 2017, and who underwent postoperative CTC examination. The optimal cut-off value was determined by drawing a receiver operating characteristic (ROC) curve based on CTC levels and patient survival, and patients were divided into CTC-positive and negative groups based on this cut-off value to investigate the differences in clinicopathological characteristics between the two groups. Patients with gastric cancer were followed up and survival was recorded until September 30, 2020. The Kaplan-Meier method was used to calculate the 3-year overall survival rate and plot survival curves, and Cox regression models were used to conduct univariate and multifactorial analyses of patient prognostic factors to explore the factors affecting the survival of patients after gastric cancer surgery. Results A total of 242 patients with gastric cancer were included in this study. The results of ROC curve analysis showed that the most statistically significant CTC cut-off value for patient survival difference was 1, which meant that patients were considered positive when CTC was detected in their blood. Forty-nine cases (20.2%) in the CTC positive group had a positive cell count of 1 to 32 cells/7.5 mL, with a median of 2 cells/ 7.5 mL, and 193 cases (79.8%) in the negative group. Comparison of baseline data between the two groups showed that there were no statistically significant differences in patients’ age, gender, tumor site, surgical method, type of resection, anastomosis, tumor diameter, lymph node metastasis and nerve invasion (all P>0.05), and statistically significant differences in body mass index, choroidal carcinoma embolus, degree of tumor differentiation, tumor pathological type, and tumor TNM stage (all P<0.05). The median follow-up time after surgery for 242 gastric cancer patients was 42 (3–67) months, and the 3-year survival rates were 49.0% and 72.5% in the CTC-positive and -negative groups, respectively, with statistically significant difference (χ²=17.129, P<0.001). The results of univariate analysis showed that age, tumor site, type of resection, anastomosis, tumor diameter, lymph node metastasis, choroidal carcinoma embolism, nerve invasion, degree of tumor differentiation, tumor TNM stage, and whether CTC was positive or not were the important factors affecting the overall survival rate of gastric cancer patients (all P<0.05). The results of multivariate analysis showed that age >60 years old [HR=3.009, 95%CI(1.807, 5.010), P<0.001], tumor TNM Ⅲ–Ⅳ stage [HR=3.082, 95%CI (1.504, 6.317), P=0.002] and positive CTC [HR=2.488, 95%CI (1.475, 4.197), P=0.001] were independent risk factors affecting the survival of gastric cancer patients. Conclusion CTC is correlated with the prognosis of gastric cancer patients and can be used as a potential indicator to determine the prognosis of gastric cancer patients.

Citation： WANG Chuang, LIANG Wenquan, LU Yixun, GAO Yunhe, ZHUANG Ziwei, WANG Lili, XI Hongqing, CHEN Lin. Prognostic value of circulating tumor cells in determining prognosis of patients operated for gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(1): 17-23. doi: 10.7507/1007-9424.202104113 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Feng RM, Zong YN, Cao SM, et al. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer commun (London), 2019, 39(1): 22.
3.	Shen L, Shan YS, Hu HM, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol, 2013, 14(12): e535-e547.
4.	Rosa F, Alfieri S, Tortorelli AP, et al. Trends in clinical features, postoperative outcomes, and long-term survival for gastric cancer: a Western experience with 1 278 patients over 30 years. World J Surg Oncol, 2014, 12: 217.
5.	Siravegna G, Marsoni S, Siena S, et al. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol, 2017, 14(9): 531-548.
6.	Praharaj PP, Bhutia SK, Nagrath S, et al. Circulating tumor cell-derived organoids: current challenges and promises in medical research and precision medicine. Biochim Biophys Acta Rev Cancer, 2018, 1869(2): 117-127.
7.	Li Y, Ma G, Zhao P, et al. Improvement of sensitive and specific detection of circulating tumor cells using negative enrichment and immunostaining-FISH. Clin Chim Acta, 2018, 485: 95-102.
8.	Qin L, Zhou W, Zhang S, et al. Highly efficient isolation of circulating tumor cells using a simple wedge-shaped microfluidic device. IEEE Trans Biomed Eng, 2019, 66(6): 1536-1541.
9.	Eyles J, Puaux AL, Wang X, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest, 2010, 120(6): 2030-2039.
10.	Zhang Q, Shan F, Li Z, et al. A prospective study on the changes and clinical significance of pre-operative and post-operative circulating tumor cells in resectable gastric cancer. J Transl Med, 2018, 16(1): 171.
11.	Sun S, Yang S, Hu X, et al. Combination of immunomagnetic separation with aptamer-mediated double rolling circle amplification for highly sensitive circulating tumor cell detection. ACS Sens, 2020, 5(12): 3870-3878.
12.	de Miguel-Pérez D, Bayarri-Lara CI, Ortega FG, et al. Post-surgery circulating tumor cells and axl overexpression as new poor prognostic biomarkers in resected lung adenocarcinoma. Cancers (Basel), 2019, 11(11): 1750.
13.	Normanno N, Cervantes A, Ciardiello F, et al. The liquid biopsy in the management of colorectal cancer patients: Current applications and future scenarios. Cancer Treat Rev, 2018, 70: 1-8.
14.	郗洪慶, 張珂誠, 衛勃, 等. 胃癌 TNM 分期第八版更新在臨床診斷治療中的意義和思考. 中華胃腸外科雜志 , 2017, 20(2): 166-170.
15.	中國研究型醫院學會微創外科學專業委員會, 《腹腔鏡外科雜志》. 循環腫瘤細胞檢測在結直腸癌中的應用專家共識(2018). 腹腔鏡外科雜志, 2019, 24(1): 74-80.
16.	Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res, 2004, 10(20): 6897-6904.
17.	Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells—mechanisms of immune surveillance and escape. Nat Rev Clin Oncol, 2017, 14(3): 155-167.
18.	Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell, 2013, 23(5): 573-581.
19.	Hu B, Tian X, Li Y, et al. Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer Med, 2020, 9(8): 2686-2697.
20.	Wu S, Liu S, Liu Z, et al. Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One, 2015, 10(4): e0123976.
21.	Li TT, Liu H, Li FP, et al. Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: relevance to therapy response. World J Gastroenterol, 2015, 21(47): 13259-13267.
22.	Sun W, Huang T, Li G, et al. The advantage of circulating tumor cells over serum carcinoembryonic antigen for predicting treatment responses in rectal cancer. Future Oncol, 2013, 9(10): 1489-1500.
23.	Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer, 2004, 4(6): 448-456.
24.	Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 2007, 25(33): 5287-5312.
25.	唐林, 陳巍魏, 管曉翔. AJCC第8版乳腺癌分期系統更新的解讀. 臨床腫瘤學雜志, 2017, 22(11): 1038-1040.
26.	郭迎雪, 李貴新, 李方超, 等. 胃癌中循環腫瘤細胞與臨床特征的關系. 濰坊醫學院學報, 2016, 38(1): 73-75.
27.	朱瑩, 易善永, 郭云霞, 等. HER-2陰性晚期胃癌外周血循環腫瘤細胞檢測及臨床意義. 中國腫瘤外科雜志, 2018, 10(3): 153-155.
28.	Uenosono Y, Arigami T, Kozono T, et al. Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer. Cancer, 2013, 119(22): 3984-3991.
29.	Lee SJ, Lee J, Kim ST, et al. Circulating tumor cells are predictive of poor response to chemotherapy in metastatic gastric cancer. Int J Biol Markers, 2015, 30(4): e382-e386.
30.	Okabe H, Tsunoda S, Hosogi H, et al. Circulating tumor cells as an independent predictor of survival in advanced gastric cancer. Ann Surg Oncol, 2015, 22(12): 3954-3961.
31.	Cao W, Yang W, Li H, et al. Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. J Surg Oncol, 2011, 103(2): 110-115.
32.	Cheng B, Tong G, Wu X, et al. Enumeration and characterization of circulating tumor cells and its application in advanced gastric cancer. Onco Targets Ther, 2019, 12: 7887-7896.
33.	Abdallah EA, Braun AC, Flores BCTCP, et al. The potential clinical implications of circulating tumor cells and circulating tumor microemboli in gastric cancer. Oncologist, 2019, 24(9): e854-e863.
34.	Pernot S, Badoual C, Terme M, et al. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: prognostic value and early assessment of therapeutic effects. Eur J Cancer, 2017, 79: 15-22.
35.	Thanh Huong P, Gurshaney S, Thanh Binh N, et al. Emerging role of circulating tumor cells in gastric cancer. Cancers (Basel), 2020, 12(3): 695.
36.	Li M, Zhang B, Zhang Z, et al. Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer. Biomed Res Int, 2014, 2014: 981261.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Feng RM, Zong YN, Cao SM, et al. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer commun (London), 2019, 39(1): 22.
3. Shen L, Shan YS, Hu HM, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol, 2013, 14(12): e535-e547.
4. Rosa F, Alfieri S, Tortorelli AP, et al. Trends in clinical features, postoperative outcomes, and long-term survival for gastric cancer: a Western experience with 1 278 patients over 30 years. World J Surg Oncol, 2014, 12: 217.
5. Siravegna G, Marsoni S, Siena S, et al. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol, 2017, 14(9): 531-548.
6. Praharaj PP, Bhutia SK, Nagrath S, et al. Circulating tumor cell-derived organoids: current challenges and promises in medical research and precision medicine. Biochim Biophys Acta Rev Cancer, 2018, 1869(2): 117-127.
7. Li Y, Ma G, Zhao P, et al. Improvement of sensitive and specific detection of circulating tumor cells using negative enrichment and immunostaining-FISH. Clin Chim Acta, 2018, 485: 95-102.
8. Qin L, Zhou W, Zhang S, et al. Highly efficient isolation of circulating tumor cells using a simple wedge-shaped microfluidic device. IEEE Trans Biomed Eng, 2019, 66(6): 1536-1541.
9. Eyles J, Puaux AL, Wang X, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest, 2010, 120(6): 2030-2039.
10. Zhang Q, Shan F, Li Z, et al. A prospective study on the changes and clinical significance of pre-operative and post-operative circulating tumor cells in resectable gastric cancer. J Transl Med, 2018, 16(1): 171.
11. Sun S, Yang S, Hu X, et al. Combination of immunomagnetic separation with aptamer-mediated double rolling circle amplification for highly sensitive circulating tumor cell detection. ACS Sens, 2020, 5(12): 3870-3878.
12. de Miguel-Pérez D, Bayarri-Lara CI, Ortega FG, et al. Post-surgery circulating tumor cells and axl overexpression as new poor prognostic biomarkers in resected lung adenocarcinoma. Cancers (Basel), 2019, 11(11): 1750.
13. Normanno N, Cervantes A, Ciardiello F, et al. The liquid biopsy in the management of colorectal cancer patients: Current applications and future scenarios. Cancer Treat Rev, 2018, 70: 1-8.
14. 郗洪慶, 張珂誠, 衛勃, 等. 胃癌 TNM 分期第八版更新在臨床診斷治療中的意義和思考. 中華胃腸外科雜志 , 2017, 20(2): 166-170.
15. 中國研究型醫院學會微創外科學專業委員會, 《腹腔鏡外科雜志》. 循環腫瘤細胞檢測在結直腸癌中的應用專家共識(2018). 腹腔鏡外科雜志, 2019, 24(1): 74-80.
16. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res, 2004, 10(20): 6897-6904.
17. Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells—mechanisms of immune surveillance and escape. Nat Rev Clin Oncol, 2017, 14(3): 155-167.
18. Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell, 2013, 23(5): 573-581.
19. Hu B, Tian X, Li Y, et al. Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer Med, 2020, 9(8): 2686-2697.
20. Wu S, Liu S, Liu Z, et al. Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One, 2015, 10(4): e0123976.
21. Li TT, Liu H, Li FP, et al. Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: relevance to therapy response. World J Gastroenterol, 2015, 21(47): 13259-13267.
22. Sun W, Huang T, Li G, et al. The advantage of circulating tumor cells over serum carcinoembryonic antigen for predicting treatment responses in rectal cancer. Future Oncol, 2013, 9(10): 1489-1500.
23. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer, 2004, 4(6): 448-456.
24. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 2007, 25(33): 5287-5312.
25. 唐林, 陳巍魏, 管曉翔. AJCC第8版乳腺癌分期系統更新的解讀. 臨床腫瘤學雜志, 2017, 22(11): 1038-1040.
26. 郭迎雪, 李貴新, 李方超, 等. 胃癌中循環腫瘤細胞與臨床特征的關系. 濰坊醫學院學報, 2016, 38(1): 73-75.
27. 朱瑩, 易善永, 郭云霞, 等. HER-2陰性晚期胃癌外周血循環腫瘤細胞檢測及臨床意義. 中國腫瘤外科雜志, 2018, 10(3): 153-155.
28. Uenosono Y, Arigami T, Kozono T, et al. Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer. Cancer, 2013, 119(22): 3984-3991.
29. Lee SJ, Lee J, Kim ST, et al. Circulating tumor cells are predictive of poor response to chemotherapy in metastatic gastric cancer. Int J Biol Markers, 2015, 30(4): e382-e386.
30. Okabe H, Tsunoda S, Hosogi H, et al. Circulating tumor cells as an independent predictor of survival in advanced gastric cancer. Ann Surg Oncol, 2015, 22(12): 3954-3961.
31. Cao W, Yang W, Li H, et al. Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. J Surg Oncol, 2011, 103(2): 110-115.
32. Cheng B, Tong G, Wu X, et al. Enumeration and characterization of circulating tumor cells and its application in advanced gastric cancer. Onco Targets Ther, 2019, 12: 7887-7896.
33. Abdallah EA, Braun AC, Flores BCTCP, et al. The potential clinical implications of circulating tumor cells and circulating tumor microemboli in gastric cancer. Oncologist, 2019, 24(9): e854-e863.
34. Pernot S, Badoual C, Terme M, et al. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: prognostic value and early assessment of therapeutic effects. Eur J Cancer, 2017, 79: 15-22.
35. Thanh Huong P, Gurshaney S, Thanh Binh N, et al. Emerging role of circulating tumor cells in gastric cancer. Cancers (Basel), 2020, 12(3): 695.
36. Li M, Zhang B, Zhang Z, et al. Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer. Biomed Res Int, 2014, 2014: 981261.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Prognostic value of circulating tumor cells in determining prognosis of patients operated for gastric cancer

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