Detection of circulating cytokeratin-19 mRNA-positive cells in the blood and the mitotic index of the primary tumor have independent prognostic value in early breast cancer

Clin Breast Cancer. 2014 Dec;14(6):442-50. doi: 10.1016/j.clbc.2014.04.001. Epub 2014 Jun 2.


Background: Previous studies showed that molecular detection of CK-19 mRNA in peripheral blood and the mitotic index of primary tumors have prognostic value in early breast cancer. The aim of this study was to assess the association between these variables.

Patients and methods: The primary tumors of 223 operable breast cancer patients (92 premenopausal and 131 postmenopausal) were evaluated for the MAI classified as either ≤ 5 per 10, 6 to 10 per 10 and > 10 per 10 or < 10 per 10 and ≥ 10 per 10 mitoses per high power field using a standardized protocol previously reported. Peripheral blood was also collected before and after the end of adjuvant chemotherapy for detection of CK-19 mRNA-positive cells using reverse transcription polymerase chain reaction previously described.

Results: After a median follow-up of 118 months, 75 patients (33.6%) experienced disease relapse and 56 (25.1%) died of breast cancer. MAI was strongly associated with disease-free survival (DFS) and overall survival (OS) (P < .001 for DFS and OS together). Detecting CK-19 mRNA-positive cells in the peripheral blood before but not after adjuvant chemotherapy was associated with marginally worse DFS (P = .055) and OS (P = .059). Cox regression analysis revealed that MAI and CK-19 mRNA-positive cell detection before adjuvant chemotherapy were independent variables associated with decreased DFS (P < .001 and P = .038, respectively) and OS (P < .001 and P = .029, respectively). There was no significant interaction between MAI and detection of CK-19 mRNA-positive cells.

Conclusion: MAI of the primary tumor and detection of CK-19 mRNA-positive cells in the blood before adjuvant chemotherapy in early breast cancer patients are 2 independent prognostic factors associated with clinical outcome.

Keywords: Adjuvant chemotherapy; Circulating tumor cells; Early breast cancer; Mitotic activity index; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Carcinoma, Lobular / drug therapy
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / mortality
  • Carcinoma, Lobular / pathology*
  • Chemotherapy, Adjuvant
  • Female
  • Follow-Up Studies
  • Humans
  • Keratin-19 / genetics*
  • Middle Aged
  • Mitotic Index*
  • Neoplasm Grading
  • Neoplasm Staging
  • Neoplastic Cells, Circulating / pathology*
  • Prognosis
  • RNA, Messenger / genetics*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate


  • Biomarkers, Tumor
  • Keratin-19
  • RNA, Messenger