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Maintrac®
A tool for monitoring therapy success in solid tumors:
circulating epithelial tumor cells
Based on the presentation of Prof. Dr. med Katharina Pachmann MD Transfusion Medicine Center Bayreuth TZB, Germany
Circulating Tumor Cells from solid tumors
S Carcinomas are from epithelial origin
S Carcinomas dissiminate epithelial cells
⇒ CETCs (circulating epithelial tumor cells)
Y. Shiozawa, A M Havens, K J Pienta and R S Taichman, Leukemia (2008) 22, 941–950
Testing Microscope based semi-automated image evaluation
Recording of
S any solid tumor
S not for lymphoma or leukemia
Method Maintrac liquid biopsy cell staining allows quantitative detection of vital circulating tumor cells.
NO fixation.
NO isolation.
NO enrichment.
Fluorochrome labeled antibody FITC
Circulating tumor cell
Surface antigen EpCAM
=NO cell loss
Cell gallery of a patient
red stained nucleus = dead cell
S
Monitoring therapy success using Circulating Tumor Cells
monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve
improved safety or effectiveness.
(‚Companoin Diagnostics‘: FDA)
Monitoring Monitoring the Response of Circulating Epithelial TumorCells to Adjuvant Chemotherapy in Breast Cancer AllowsDetection of Patients at Risk of Early RelapseKatharina Pachmann, Oumar Camara, Andreas Kavallaris, Sabine Krauspe, Nele Malarski,Mieczyslaw Gajda, Torsten Kroll, Cornelia Jorke, Ulrike Hammer, Annelore Altendorf-Hofmann,Carola Rabenstein, Ulrich Pachmann, Ingo Runnebaum, and Klaus Hoffken
From the Clinic for Internal Medicine II,Institution for Pathology, and Women’sHospital, Friedrich Schiller University;Tumorzentrum, Jena; and Transfu-sionsmedizinisches Zentrum, Bayreuth,Germany.
Submitted July 25, 2007; acceptedNovember 2, 2007.
Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.
Corresponding author: Katharina Pach-mann, MD, PhD, Department of Experi-mental Hematology and Oncology,Clinic for Internal Medicine II, FriedrichSchiller Universitat Jena, Erlanger Allee101, D-07747, Jena, Germany; e-mail:[email protected].
© 2008 by American Society of ClinicalOncology
0732-183X/08/2608-1208/$20.00
DOI: 10.1200/JCO.2007.13.6523
A B S T R A C T
PurposeTo demonstrate that it is possible to monitor the response to adjuvant therapy by repeated analysisof circulating epithelial tumor cells (CETCs) and to detect patients early who are at risk of relapse.
Patients and MethodsIn 91 nonmetastatic primary breast cancer patients, CETCs were quantified using laser scanningcytometry of anti–epithelial cell adhesion molecule–stained epithelial cells from whole unsepa-rated blood before and during adjuvant chemotherapy.
ResultsNumbers of CETCs were analyzed before therapy, before each new cycle, and at the end ofchemotherapy. The following three typical patterns of response were observed: (1) decrease incell numbers (! 10-fold); (2) marginal changes in cell numbers (" 10-fold); and (3) an (sometimessaw-toothed) increase or an initial decrease with subsequent reincrease (! 10-fold) in numbers ofCETCs. Twenty relapses (22%) were observed within the accrual time of 40 months, including oneof 28 patients from response group 1, five of 30 patients from response group 2, and 14 of 33patients from response group 3. The difference in relapse-free survival was highly significant forCETC (hazard ratio # 4.407; 95% CI, 1.739 to 9.418; P " .001) between patients with decreasingcell numbers and those with marginal changes and between patients with marginal changes andthose with an increase of more than 10-fold (linear Cox regression model).
ConclusionThese results show that peripherally circulating tumor cells are influenced by systemic chemotherapyand that an increase (even after initial response to therapy) of 10-fold or more at the end of therapy isa strong predictor of relapse and a surrogate marker for the aggressiveness of the tumor cells.
J Clin Oncol 26:1208-1215. © 2008 by American Society of Clinical Oncology
INTRODUCTION
Solid malignant tumors of the breast are the mostfrequent cause of death in women in the devel-oped world. Although early detection, precise sur-gery with wide margins, and adjuvant therapyhave improved results,1 relapse is not infrequent.In premenopausal women, a first narrow peakoccurs approximately 8 to 10 months after mas-tectomy, and a second peak occurs at 28 to 30months. Postmenopausal patients display a peakat approximately 18 to 20 months.2 After diagno-sis of metastatic disease, the outcome is fatal. Todate, there is no tool to monitor the effect ofadjuvant treatment apart from statistical analy-ses3; however, prediction for the individual pa-tient is restricted.
Solid tumors can seed tumor cells into the pe-ripheral blood, which may, even after complete re-section of the tumor, eventually grow intometastases. Detection of such circulating tumor cellshas been reported in patients with primary4-6 andmetastatic7 breast cancer, with a shorter survival inpatients with cells in bone marrow8 or in patientswith metastatic disease with higher cell numbers inblood.7 In metastatic disease, the clinical conse-quence of this result is questionable because there isno indication that treatment will lead to improvedsurvival in patients with poor prognosis.9 In patientswith primary tumor, only 40% of patients carryingisolated tumor cells in bone marrow experiencerecurrence,6 indicating that a portion of the circu-lating epithelial tumor cells (CETCs) may be bio-logically irrelevant and tumor cells may differ in
JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T
VOLUME 26 ! NUMBER 8 ! MARCH 10 2008
1208
Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved. Information downloaded from jco.ascopubs.org and provided by F Delbanco on March 9, 2008 from 141.35.226.179.
J Clin Oncol 2008, 26 (8): 1208-1215
Monitoring the Response of Circulating Epithelial Tumor Cells (CETC) to Adjuvant Chemotherapy in Breast Cancer Allows Detection of Patients at Risk of Early Relapse
Good prognosis
Pachmann et al, J Clin Oncol, 2008, 26 (8): 1208-‐1215
Decrease of the cell number more than 10 fold good prognosis
c)
Pachmann et al, J Clin Oncol, 2008, 26 (8): 1208-‐1215
No change of the cell number
Medium prognosis (could be better)
Pachmann et al, J Clin Oncol, 2008, 26 (8): 1208-‐1215
Increase of the cell number more than 10fold bad prognosis
Bad prognosis
150012009006003000days
1,0
0,8
0,6
0,4
0,2
0,0
cum
. sur
viva
l
marginal change-censored
increase>10fold-censored
decrease>10fold-censored
marginal changeincrease>10folddecrease>10fold
relapse free survival
Clinical outcome
Increasing cell numbers correlate highly significant with a poor prognosis
log rank p < 0.001
K . Pachmann, et al. J Clin Oncol 2008, 26 (8): 1208-‐1215
S
Increasing cell numbers What can you do?
Chemo-sensitivity identify patients who are most likely to benefit from a particular therapeutic product
(‚Companoin Diagnostics‘: FDA)
Chemo-sensitivity J Cancer Therapy 2013, 4:597-605
Chemosensitivity Testing of Circulating Epithelial Tumor Cells (CETC) in Vitro: Correlation to in Vivo Sensitivity and Clinical Outcome.
Chemo- sensitivity • Exposing the blood sample
to different drugs and concentrations
• Determin the rate of dying circulating epithelial tumor cells to identify the most effective drug for the patient
Typical pictures
Epithelial cells (green staining), with red nucleus as marker for beginning cell death.
Cells dying under drug effect
Highly effective
Low effective
N. Rüdiger et al, J Cancer Therapy, 2013, 4, 597-‐605
no drug 1 /10 concentration blood equivalent 10 fold concentration
Relapse free survial of patients with ovarian cancer
N. Rüdiger et al, J Cancer Therapy, 2013, 4, 597-‐605
log rank p≤0.007 Sensitive vs. resistant tumor cells to standard therapy (carboplatin and paclitaxel)
10
100
1000
10000
100000
1000000
21.0
6.10
10.0
8.10
29.0
9.10
18.1
1.10
07.0
1.11
cells
/ml b
lood
CarboPac
Caelyx/ Doxo
Pro-
gres
s
0102030405060708090
100
Jun 10 Jul 10 Aug 10 Sep 10 Okt 10 Nov 10 Dez 10 Jan 11
% of
cells
dying
off
CarboPacDoxo
Guideline therapy
Effect following change of
therapy
Diagnosis
Surgery
maintrac cell counting
1. cycle guidelines
2. cycle guidelines
maintrac cell counting
Increase in cell numbers
maintrac chemosensitivity
3. cycle adapted
4. cycle adapted
maintraccell couning
5. cycle adapted
6. cycle adapted
maintrac cell counting
Decrease in cell numbers
3. cycle guidelines
4. cycle guidelines
maintrac cell counting
Increase in cell numbers
maintrac chemosensitivity
5. cycle adapted
6. cycle adapted
maintrac cell counting
Decrease in cell numbers
5. cycle guidelines
6. cycle guidelines
maintrac cell counting
OPTIONAL:maintrac chemosensitivity
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If cell numbers are increasing,
chemosensitivity testing can be considered to
determine the drug with the best efficiency.
S
Maintenance therapy
Good prognosis
Gradual decrease in cell numbers
during Tamoxifen therapy
10
100
1.000
10.000
100.000
1.000.000
-‐400 -‐200 0 200 400 600 800 1000 1200 1400
cells/m
l
days
Tamoxifen
Bad prognosis
Continious increase
during Tamoxifen therapy
may proceed to recurrence
10
100
1.000
10.000
100.000
1.000.000
-‐400 -‐200 0 200 400 600 800 1000 1200 1400
cells/m
l
days
Tamoxifen
Relapse after 849d
Relapse after 1112d
Relapse after 627d
K. Pachmann et al, J Cancer Res Clin Oncol 2011, 137:821-‐828
Patients with increasing cell numbers have
a higher risk of recurrence
Clinical outcome
maintenance therapy
maintrac cell counting
every 3 month
Increase in cell numbers
take change of therapyinto consideration
maintrac cell counting
every 3 month
Decrease in cell numbers
go on with therapy
maintrac cell countingevery 3 month
If cell numbers increase,
change of therapy may be considered
monitor every 3 months
S
Long term surveillance
Good prognosis
Bad prognosis
Long term surveillance
Clinical Outcome
P=0,029
Patients with increasing cell numbers
after the end of maintenance therapy
have an increased risk of recurrence
Discussion
There is already a discussion going on, if it would be better taking tamoxifen 10 years instead of stopping after 5 years.
hWp://am.asco.org/ extending-‐adjuvant-‐tamoxifen-‐reduces-‐breast-‐cancer-‐recurrence-‐mortality
Effect of therapy switch
10
100
1000
10000
100000
1000000
08.05.04
20.09.05
02.02.07
16.06.08
29.10.09
13.03.11
Anz
ahl Z
elle
n pr
o m
L B
lut
4 4R
Tam LetrZol
OP
after end of therapy
maintrac cell countingafter 3 month
Increase in cell numbers
restart maintenance herapy
Decreasing or stable
cell numbers
maintrac cell countingafter 3 month
Decreasing or stable
cell numbers
maintrac cell countingevery 6 month
If cell numbers increase,
restart therapy
and monitor
S
Thank you for your attention
Association Transfusion Medicine Center in Bayreuth - TZB
SIMFO Specialized Immunology Science + Development GmbH & Laboratory Dr. Ulrich Pachmann
Peter Pachmann Laboratory Dr. Pachmann Kattjahren 8 Kurpromenade 2 22359 Hamburg 95448 Bayreuth Germany Germany
www.maintrac.de
