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Original Investigation
December 2018

Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor–Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
  • 2Department of Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts
  • 3Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 4Department of Oncology, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
  • 5Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona
  • 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 7Department of Medicine, Division of Oncology, Stanford Cancer Center, Palo Alto, California
  • 8Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis
JAMA Oncol. 2018;4(12):1700-1706. doi:10.1001/jamaoncol.2018.2574
Key Points

Question  Are circulating tumor cells associated with late recurrence of breast cancer?

Findings  In this secondary analysis of a randomized clinical trial, circulating tumor cells were detectable in 26 of 547 patients (4.8%) with localized breast cancer 5 or more years after diagnosis and were associated with a higher risk of recurrence among patients with hormone receptor–positive breast cancer.

Meaning  Circulating tumor cells may be used to stratify for risk of late recurrence among patients with hormone receptor–positive breast cancer.


Importance  Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor–positive breast cancer.

Objective  To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2–negative breast cancer.

Design, Setting, and Participants  This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2–negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018.

Interventions  A blood sample was obtained for identification and enumeration of CTCs.

Main Outcome and Measures  The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence.

Results  Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor–positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor–negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative).

Conclusions and Relevance  A single positive CTC assay result 5 years after diagnosis of hormone receptor–positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy.

Trial Registration  ClinicalTrials.gov identifier: NCT00433511