Circulating tumor cells predict survival in early average-to-high risk breast cancer patients.
BACKGROUND
Circulating tumor cells (CTCs) have been shown to predict reduced survival outcomes in metastatic breast cancer.


METHODS
CTCs were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0-54). Kaplan-Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided.


RESULTS
Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio [HR] = 2.11; 95% confidence interval [CI] = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30 mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06) CONCLUSIONS: These results suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ). brigitte.rack@med.uni-muenchen.de.
Brigitte
B
Rack
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Christian
C
Schindlbeck
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Julia
J
Jückstock
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Ulrich
U
Andergassen
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Philip
P
Hepp
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Thomas
T
Zwingers
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Thomas W P
TW
Friedl
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Ralf
R
Lorenz
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Hans
H
Tesch
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Peter A
PA
Fasching
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Tanja
T
Fehm
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Andreas
A
Schneeweiss
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Werner
W
Lichtenegger
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Matthias W
MW
Beckmann
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Klaus
K
Friese
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Klaus
K
Pantel
Affiliations of authors: Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany (BR, JJ, UA, KF); Department of Gynecology and Obstetrics, Clinical Center Traunstein, Traunstein, Germany (CS); Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany (PH, TF); Augsburg, Germany (TZ); Braunschweig, Germany (RL); Frankfurt, Germany (HT); National Center for Tumor Diseases, University Hospital, Heidelberg, Germany (AS); Charité University Hospital Campus Virchow, Berlin, Germany (WL); Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg, Erlangen, Germany (PAF, MWB); Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (KP); Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany (TWPF, WJ).
Wolfgang
W
Janni
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology*; D011446:Prospective Studies; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D000093542:Gemcitabine