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Value of Chemoresistant Testingfor Cancer Treatment
Dr. Kai Schulze-Forster
.... Because humans are different!
Personalized Medicine
Introduction Introduction
The Problem The Problem
The response to chemotherapy (solid tumors) is about
30% !
Principles and Practice of Oncology (Cancer: Principles &
Practice (DeVita, 8th Revised edition (REV).
Lippincott Williams & Wilkins, 1. Mai 2008
Biomarker Biomarker
WhichDrug?
Responder
Non-Respondersevere
side effects
Biomarker Biomarker
High need for predictive biomarkers!
There is progress especially for biologicals:
- Her2
- K-RAS mutation
- EGFR mutation
- …..
Chemoresistant Assay Chemoresistant Assay
… but for chemotherapy ??
validated biomarkers are not available
Solution: functional bioassays
Chemoresistant Assay Chemoresistant Assay
Well-known method in bacterial infections:
Antibiogram
Replace bacteria by tumor cells
Oncobiogram
= Chemoresistant (Chemosensitivity) Assay
Chemoresistant Assay Chemoresistant Assay
Method
1. Collect tumor cells (from primary tumor, metastases
or ascites during surgery, biopsy or punction)
2. Prepare single cell suspension
3. Perform proliferation assay with drugs 1-3 days
4. Determine number of living cells
5. Calculate growth inhibition
96 well Microtiter plate
- 6 concentrations
- Duplicates
- Untreated control (negative control)
ABCDEFGH
1 2 3 4 5 6 7 8 9 10 11 12
D rug1 P os itive C ontro l B uffer
D rug2 N egative C on tro l
Chemoresistant Assay Chemoresistant Assay
Chemoresistant Assay Chemoresistant Assay
Method
Readout: ATP determination using chemoluminescence
Very sensitive: 40 cells/well
also named ATP-TCA (ATP-Tumor Chemosensitivity Assay)
LuciferaseATP + Luciferin + O2 AMP + 2P + CO2 + Light
Chemoresistant Assay Chemoresistant Assay
Results: Chart
0
20
40
60
80
100
120
200 100 50 25 12,5 6,25
Test Drug Concentration %
Tu
mo
r G
row
th In
hib
itio
n %
Carboplatin
Docetaxel
Chemoresistant Assay Chemoresistant Assay
Results:
Table
Chemoresistant Assay Chemoresistant Assay
Advantages
1. In vitro-testing does not affect the patient
2. several drugs and combinations can be tested in
parallel
3. hyperthermia can be included
Chemoresistant Assay Chemoresistant Assay
Advantages
Safe prediction of resistanceAvoidance of ineffective therapiesAvoidance of unnecessary side effects
Publications Publications
Publication search in PubMed 11/2013
Chemosensitivity Assay : 3089 entries
Chemosensitivity Testing Cancer: 534 entries
ATP-TCA: 60 entries
Publications Publications
Cancer Chemotherapy and Pharmacology May 2012, Volume 69, Issue 5, pp 1307-1314
Predicting platinum resistance in primary advanced ovarian cancer patients with an in vitro resistance index
Thea Eline Hetland, Janne Kærn, Martina Skrede, Berit Sandstad, Claes Tropé, Ben Davidson,Vivi Ann Flørenes
Departement of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, 0424 Oslo, Norway. theaeline@gmail.com
Publications Publications
PURPOSE: We aimed to identify primary platinum resistance in epithelial ovarian cancer (OC) patients with FIGO stage III-IV disease by an in vitro drug-response assay and to correlate the findings with clinical response. (…)METHODS: We combined the ATP-based tumor-chemosensitivity and the extreme drug resistance assays for testing of 85 biopsies from 58 patients. Tumors were classified as sensitive or resistant by a resistance index (RI). (…) Results were analyzed for association with clinical platinum resistance, progression-free survival (PFS), and overall survival (OS).
Publications Publications
RESULTS: RI <= 250 predicted primary platinum resistance, without misclassification of sensitive patients. The test sensitivity for primary tumors was 15/15, specificity 3/10, negative predictive value 3/3, and positive predictive value 15/22. Patients with in vitro platinum-resistant samples had shorter PFS compared with patients with sensitive samples (3.4 vs. 10.0 months, p = 0.02). Comparing patient-matched primary and metastatic samples, there was about 1/3 mismatch in resistance. RI for platinum was lower in primary tumors exposed to neoadjuvant chemotherapy than in chemo-naïve tumors (p < 0.01).
CONCLUSIONS: This in vitro assay predicted primary platinum resistance, without misclassification of sensitive OC patients, and the results were significantly associated with PFS. We suggest that samples from primary tumor and metastatic samples have different responses to chemotherapy and that exposure to chemotherapy might induce in vitro platinum resistance.
Publications Publications
Recent Results Cancer Res. 2003;161:221-30.
ATP chemosensitivity testing in ovarian and breast cancer: early clinical trials.
Kurbacher CM, Grecu OM, Stier U, Gilster TJ, Janát MM, Untch M, Konecny G, Bruckner HW, Cree IA.
Division of Clinical and Experimental Gynecologic Oncology, Department of Gynecology and Obstetrics, University of Cologne Medical Center, Kerpener Strasse 34, 50931 Köln, Germany. Christian.Kurbacher@medizin.uni-koeln.de
Publications Publications
ABSTRACT(…) Currently, the ATP-based tumor chemosensitivity assay (ATP-TCA) can be regarded as the most sophisticated assay to investigate both solid samples and effusions derived from patients with various organ tumors. (…)Clinical trials that have been set up in heavily pretreated patients with recurrent ovarian or breast cancer have convincingly confirmed the high activity of these combinations previously demonstrated in preclinical investigations using the ATP-TCA. In a recent phase II trial performed in 59 patients with relapsed ovarian carcinoma, ATP-TCA-directed therapy was able to triple the response rate and to double the survival time, compared with published empirical chemotherapy regimes.
(…)
Publications Publications
Methods Mol Med. 2005;110:101-20.
Chemosensitivity testing using microplate adenosine triphosphate-based luminescence measurements.
Kurbacher CM, Cree IA.
Department of Gynecology and Obstertrics, University of Cologne, Cologne, Germany.
Publications Publications
ABSTRACT(…) Among these, the ATP-TCA has gained particular merits for ex vivo chemosensitivity testing of native nonhematological tumors including cancers of the breast, ovary, gastrointestinal tract, cervix and corpus uteri, and lung; malignant melanomas; gliomas; sarcomas; and mesotheliomas. For this indication, the ATP-TCA can now be considered the best documented and validated technology. (…)In ovarian and breast carcinomas, the predictive accuracy is > 90%, with a positive predictive value of 85-90% and a negative predictive value near 100%, respectively. In primary ovarian cancers, the ATP-TCA has been found to accurately predict both clinical response and survival.
Case Report Case Report
Man, 59 year old
Nasopharynx Carcinoma
April 2010 Surgery and Radiation
Mar 2011 Metastatic Prostate Ca
PSA > 500 ng/ml, Gleason 8, Start of antiandrogenic
therapy (Fugerel, LHRH)
Case Report Case Report
April 2011 Estracyt, Zometa, PSA decreased to 21,
good general condition
May-July 2011 Zometa and hormons, PSA = 9
Aug 2011 Zometa, well-being, PSA = 22
Oct 2011 PSA=296, start Second line chemotherapy
Taxotere/ Zometa/ Prednisolon
Case Report Case Report
Dec 2011 Therapy well tolerated, EPO
Jan 2012 Relapse Nasopharynx Ca
Feb 2012 Chemoresistant assay:
Cisplatin / 5-FU / Taxans found as effective drugs
Mar 2012 Start chemotherapy (Cisplatin/5-FU/Taxotere)
Aug 2012 After 6 cycles good general condition
Case Report Case Report
Sep 2012 Progression of Nasopharynx Ca
Oct 2012 Patient dead
Summary: using the chemoresistant assay a well
tolerated chemotherapy could be found for a multiple
treated patient.
About 6 month of life prolongation
Hyperthermia Hyperthermia
To simulate a hyperthermia we included a 1 hour
treatment at 42 °C at incubation start.
In parallel the same drugs were tested without
hyperthermia.
Case Report HT1 Case Report HT1
Woman, 72 years old
GIST, rectum
Pretreated with Glivec
Hyperthermia Hyperthermia
Hyperthermia Hyperthermia
Hyperthermia Hyperthermia
Case Report HT2 Case Report HT2
Woman, 34 years old
Hyperthermia Hyperthermia
Hyperthermia Hyperthermia
Summary Summary
Chemoresistant assays are useful tools to exclude non-responding chemotherapies, especially in pretreated multiresistant patients.
Zentrum für molekulare Onkologie GmbHIm Biotechnologiepark 14943 Luckenwalde
Germany (near Berlin)
Thank you
for your
attention !
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