Zhong Ye1, Chun Wang1, Shaogui Wan2, Zhaomei Mu3, Zhenchao Zhang1, Maysa M Abu-Khalaf1, Frederick M Fellin1, Daniel P Silver1, Manish Neupane1, Rebecca J Jaslow1, Saveri Bhattacharya1, Theodore N Tsangaris1, Inna Chervoneva4, Adam Berger5, Laura Austin1, Juan P Palazzo6, Ronald E Myers1, Neha Pancholy1, Darayus Toorkey1, Kaelan Yao1, Max Krall1, Xiuling Li7, Xiaobing Chen8, Xiuhong Fu9, Jinliang Xing10, Lifang Hou11, Qiang Wei12, Bingshan Li12, Massimo Cristofanilli13, Hushan Yang14. 1. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. 2. Institute of Pharmacy, Pharmaceutical College, Henan University, Kaifeng, Henan 475004, China. 3. Department of Medicine, Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 4. Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA. 5. Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA. 6. Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. 7. Department of Gastroenterology, People's Hospital of Henan Province, Zhengzhou, Henan 450003, China. 8. Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, China. 9. Center for Reproductive Medicine and Genetics, Central Hospital of Luohe, Luohe, Henan 462300, China. 10. Experimental Teaching Center, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. 11. Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA. 12. Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. 13. Department of Medicine, Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: massimo.cristofanilli@nm.org. 14. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: hushan.yang@jefferson.edu.
Abstract
BACKGROUND: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients. METHODS: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models. RESULTS: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level. CONCLUSIONS: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.
BACKGROUND: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancerpatient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients. METHODS: We collected 227 blood samples from 117 MBCpatients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models. RESULTS: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level. CONCLUSIONS: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBCpatients.
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