title: Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer.
abstract: Circulating tumor cell (CTC) is a well-established prognosis predictor for metastatic breast cancer (MBC), and CTC-cluster exhibits significantly higher metastasis-promoting capability than individual CTCs. Because measurement of CTCs and CTC-clusters at a single time point may underestimate their prognostic values, we aimed to analyze longitudinally collected CTCs and CTC-clusters in MBC prognostication.
  
  
  
  CTCs and CTC-clusters were enumerated in 370 longitudinally collected blood samples from 128 MBC patients. The associations between baseline, first follow-up, and longitudinal enumerations of CTCs and CTC-clusters with patient progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models.
  
  
  
  CTC and CTC-cluster counts at both baseline and first follow-up were significantly associated with patient PFS and OS. Time-dependent analysis of longitudinally collected samples confirmed the significantly unfavorable PFS and OS in patients with ≥5 CTCs, and further demonstrated the independent prognostic values by CTC-clusters compared to CTC-enumeration alone. Longitudinal analyses also identified a link between the size of CTC-clusters and patient OS: compared to the patients without any CTC, those with 2-cell CTC-clusters and ≥3-cell CTC-clusters had a hazard ratio (HR) of 7.96 [95 % confidence level (CI) 2.00-31.61, P = 0.003] and 14.50 (3.98-52.80, P < 0.001), respectively.
  
  
  
  In this novel time-dependent analysis of longitudinally collected CTCs and CTC-clusters, we showed that CTC-clusters added additional prognostic values to CTC enumeration alone, and a larger-size CTC-cluster conferred a higher risk of death in MBC patients.
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Chun
authors: C
authors: Wang
authors: Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors: Zhaomei
authors: Z
authors: Mu
authors: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Inna
authors: I
authors: Chervoneva
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Laura
authors: L
authors: Austin
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Zhong
authors: Z
authors: Ye
authors: Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors: Giovanna
authors: G
authors: Rossi
authors: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Juan P
authors: JP
authors: Palazzo
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Carl
authors: C
authors: Sun
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Maysa
authors: M
authors: Abu-Khalaf
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Ronald E
authors: RE
authors: Myers
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Zhu
authors: Z
authors: Zhu
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Yanna
authors: Y
authors: Ba
authors: Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA.
authors: Bingshan
authors: B
authors: Li
authors: Robert H Lurie Comprehensive Cancer Center, Division of Hematology & Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors: Lifang
authors: L
authors: Hou
authors: Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. massimo.cristofanilli@nm.org.
authors: Massimo
authors: M
authors: Cristofanilli
authors: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. hushan.yang@jefferson.edu.
authors: Hushan
authors: H
authors: Yang
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000401:mortality* / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis
keywords: Circulating tumor cell clusters (CTC-clusters); Circulating tumor cells (CTCs); Metastatic breast cancer (MBC); Prognosis; Time-dependent analysis