Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor-positive breast cancer.
BACKGROUND
Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC.


METHODS
The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC.


RESULTS
The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90-0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues.


CONCLUSIONS
CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial.
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Costanza
C
Paoletti
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Maria C
MC
Muñiz
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Dafydd G
DG
Thomas
Center for Cancer Biostatistics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
Kent A
KA
Griffith
Center for Cancer Biostatistics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
Kelley M
KM
Kidwell
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Nahomi
N
Tokudome
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Martha E
ME
Brown
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Kimberly
K
Aung
Janssen Pharmaceutical, a Johnson & Johnson Co., Huntingdon Valley, Pennsylvania.
M Craig
MC
Miller
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Dorothy L
DL
Blossom
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
Anne F
AF
Schott
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
N Lynn
NL
Henry
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan.
James M
JM
Rae
Janssen Pharmaceutical, a Johnson & Johnson Co., Huntingdon Valley, Pennsylvania.
Mark C
MC
Connelly
Janssen Pharmaceutical, a Johnson & Johnson Co., Huntingdon Valley, Pennsylvania.
David A
DA
Chianese
Breast Oncology Program of the Comprehensive Cancer Center and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan. hayesdf@umich.edu.
Daniel F
DF
Hayes
D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000097:blood / Q000235:genetics*; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics*; D011960:Receptors, Estrogen / Q000097:blood / Q000235:genetics*
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human