title: Clinical significance of circulating tumor cells (CTCs) with respect to optimal cut-off value and tumor markers in advanced/metastatic breast cancer.
abstract: BACKGROUND
  Although carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) are useful tumor markers (TMs) in metastatic breast cancer (MBC), circulating tumor cells (CTCs) are also detected in patients with advanced or metastatic breast cancer. We analyzed CTCs in MBC patients in order to establish the optimal cut-off value, to evaluate the prognostic utility of CTC count, and to clarify whether CTC count could provide information in addition to CEA and CA15-3.
  
  
  METHODS
  We studied 98 MBC patients enrolled between June 2007 and March 2013. To quantify CTCs, 7.5 ml of blood was collected and CEA and CA15-3 were measured simultaneously. CTCs were counted using the CellSearch™ System. The CTC count was dichotomized as 0 (CTC-negative) or ≥1 (CTC-positive). The clinical significance of CTCs was evaluated in terms of its relationship with levels of CEA and CA15-3. Associations between qualitative variables were evaluated using the chi-square test. In order to evaluate the predictive value of CTCs for advanced or metastatic breast cancer, multivariate Cox proportional hazards modeling was used to calculate hazard ratios.
  
  
  RESULTS
  With a CTC cut-off value of 1, there were 53 (54.1 %) CTC-negative patients and 45 (45.9 %) CTC-positive patients. Patients in the CTC-positive group had worse survival than those in the CTC-negative group (p < 0.0001). Seventy-one patients (72.4 %) had TM data at the time of CTC testing. To study the relationship between CTCs and TMs, we divided patients into normal TM and high TM groups. In the normal TM group, the CTC-negative patients had statistically significant survival than the CTC-positive patients (p = 0.005). The data suggested that CTC count could provide additional prognostic information beyond TMs for advanced/metastatic breast cancer. In multivariate analysis, the only significant predictor of overall survival was CTC ≥ 1 (hazard ratio, 3.026; 95 % confidence interval 1.350-6.784).
  
  
  CONCLUSIONS
  We found that a CTC cut-off value of 1 is appropriate in patients with advanced/metastatic breast cancer. CTCs could yield additional information beyond CEA and CA15-3.
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shiomi-Mouri
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kousaka
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Ando
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Tetsuka
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan. snakano1@aichi-med-u.ac.jp.
authors.forename: Shogo
authors.initials: S
authors.lastname: Nakano
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Kimihito
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Akizuki
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Imai
authors.affiliation: Department of Breast and Endocrine Surgery, Aichi Medical University, 1-1Yazakokarimata, Nagakute-city, Aichi Prefecture, 4801195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukutomi
authors.affiliation: Department of Surgery, Sakura General Hospital, Niwa, Aichi, Japan.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D002452:Cell Count; D005260:Female; D006801:Humans; D008875:Middle Aged; D018396:Mucin-1 / Q000378:metabolism*; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D018396:Mucin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human
keywords: Breast cancer; CA15-3; CEA; CTC; Tumor marker