Download CA 15-3, circulating tumor cells

The NEW ENGLNAD JOURNAL of MEDICINE 368;18 MARCH 28, 2013
R4 박지윤/Prof . 김시영
INTRODUCTION
• Breast cancer
- most common cancer and the leading cause of cancer related death
in women worldwide
• Monitoring of treatment response of metastatic breast cancer
- essential to determine benefit of therapies
- treatment response : generally assessed with serial imaging
 but often fail to detect changes in tumor burden
 urgent need for biomarkers that measure tumor burden
• Cancer antigen 15-3 (CA 15-3)
- useful biomarker in metastatic breast cancer(sensitivity : 60-70%)
- circulating tumor cells :emerged promising biomarker
elevated levels of circulating tumor cells (≥ 5 cells per 7.5 ml of blood)
 associated with a worse prognosis
• Studies using circulating tumor DNA to monitor tumor dynamics
 few cases of breast cancer have been analyzed
PURPOSE
To compare between circulating tumor DNA
and other circulating biomarkers (CA 15-3, circulating tumor cells)
and medical imaging
for the noninvasive monitoring of metastatic breast cancer
METHOD
 Patients and Sample Collection
- prospective, single-center study, between April 2010 and April 2012
- metastatic breast cancer undergoing active treatment
- 52 women recruited
 Identification of Somatic Genomic Alterations
- sequencing from breast-cancer specimens
- sequencing methods
1. tagged-amplicon deep sequencing for PIK3CA & TP53
2. paired-end whole-genome sequencing
 Isolation and Quantification of Circulating Tumor DNA
- DNA extracted with QIAamp circulating nucleic acid kit (Qiagen)
- digital PCR or direct plasma sequencing by means of tagged-amplicon
deep sequencing to measure genomic alterations
 Assay of CA 15-3 and Circulating Tumor Cells
- CA 15-3 level : ADVIA Centaur immunoassay system
- circulating tumor cells : CellSearch System
RESULT
 Quantification of Circulating Tumor DNA in Plasma
1. Digital PCR assay
- circulating tumor DNA detected in 18 of the 19 patients,
in 80 of the 97 plasma samples (82%)
2. Tagged-amplicon deep sequencing
- circulating tumor DNA identified in 11 patients,
in 35 of the 44 plasma samples (80%)
 Tagged-amplicon deep sequencing or digital PCR assay : agreement
 Concurrent Monitoring of
Multiple Somatic Genomic Alterations in Plasma
Mutations or structural variants
in tumor tissue
 similar dynamic pattern in plasma
Multiple mutations identified
in tumor tissue
 similar dynamic patterns in plasma
 Sensitivity of Circulating Tumor DNA and CA 15-3
Median Difference in Sensitivity : 26%(P< 0.002)
 Sensitivity of Circulating Tumor DNA and CTC
Median Difference in Sensitivity : 27%(P< 0.002)
 CT and Circulating Biomarkers for Tumor Monitoring
ctDNA, CA 15-3, CTC : Correlating with Treatment Response
Circulating tumor DNA increased average 5 months
before PD by imaging in 53% patients
Overall Survival
P = 0.03
P < 0.001
P = 0.52
 Prognostic Use of Circulating Biomarkers
Increasing of circulating tumor cells and circulating tumor DNA
increased hazard
CONCLUSION
This proof-of-concept analysis showed that
circulating tumor DNA is an informative, inherently specific,
and highly sensitive biomarker of metastatic breast cancer.