Association of Circulating Tumor Cells with Late Recurrence of Estrogen Receptor-Positive Breast Cancer

A Secondary Analysis of a Randomized Clinical Trial

Joseph Sparano, Anne O'Neill, Katherine Alpaugh, Antonio C. Wolff, Donald W. Northfelt, Chau T. Dang, George W. Sledge, Kathy Miller

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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:.

Original languageEnglish (US)
JournalJAMA oncology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Circulating Neoplastic Cells
Estrogen Receptors
Randomized Controlled Trials
Breast Neoplasms
Recurrence
Hormones
Lymph Nodes
Paclitaxel
Doxorubicin
Cyclophosphamide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Association of Circulating Tumor Cells with Late Recurrence of Estrogen Receptor-Positive Breast Cancer : A Secondary Analysis of a Randomized Clinical Trial. / Sparano, Joseph; O'Neill, Anne; Alpaugh, Katherine; Wolff, Antonio C.; Northfelt, Donald W.; Dang, Chau T.; Sledge, George W.; Miller, Kathy.

In: JAMA oncology, 01.01.2018.

Research output: Contribution to journalArticle

Sparano, Joseph ; O'Neill, Anne ; Alpaugh, Katherine ; Wolff, Antonio C. ; Northfelt, Donald W. ; Dang, Chau T. ; Sledge, George W. ; Miller, Kathy. / Association of Circulating Tumor Cells with Late Recurrence of Estrogen Receptor-Positive Breast Cancer : A Secondary Analysis of a Randomized Clinical Trial. In: JAMA oncology. 2018.
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title = "Association of Circulating Tumor Cells with Late Recurrence of Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial",
abstract = "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:.",
author = "Joseph Sparano and Anne O'Neill and Katherine Alpaugh and Wolff, {Antonio C.} and Northfelt, {Donald W.} and Dang, {Chau T.} and Sledge, {George W.} and Kathy Miller",
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day = "1",
doi = "10.1001/jamaoncol.2018.2574",
language = "English (US)",
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T1 - Association of Circulating Tumor Cells with Late Recurrence of Estrogen Receptor-Positive Breast Cancer

T2 - A Secondary Analysis of a Randomized Clinical Trial

AU - Sparano, Joseph

AU - O'Neill, Anne

AU - Alpaugh, Katherine

AU - Wolff, Antonio C.

AU - Northfelt, Donald W.

AU - Dang, Chau T.

AU - Sledge, George W.

AU - Miller, Kathy

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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:.

AB - 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:.

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