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Value of Chemoresistant Testing for Cancer Treatment

Value of Chemoresistant Testing for Cancer Treatment. Dr. Kai Schulze-Forster. Introduction. Personalized Medicine. .... Because humans are different!. The Problem. The response to chemotherapy (solid tumors ) is about 30% !

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Value of Chemoresistant Testing for Cancer Treatment

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  1. Value of Chemoresistant Testingfor Cancer Treatment Dr. Kai Schulze-Forster

  2. Introduction Personalized Medicine .... Because humans are different!

  3. The Problem The responsetochemotherapy (solid tumors) isabout 30% ! Principlesand Practice ofOncology (Cancer: Principles & Practice (DeVita, 8thRevisededition (REV).Lippincott Williams & Wilkins, 1. Mai 2008

  4. Biomarker WhichDrug? Responder severeside effects Non-Responder

  5. Biomarker High need for predictive biomarkers! There is progress especially for biologicals:- Her2- K-RAS mutation- EGFR mutation - …..

  6. Chemoresistant Assay … but for chemotherapy ?? validated biomarkers are not available Solution: functional bioassays

  7. Chemoresistant Assay Well-known method in bacterial infections: Antibiogram Replace bacteria by tumor cells Oncobiogram = Chemoresistant (Chemosensitivity) Assay

  8. 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

  9. Chemoresistant Assay • 96 well Microtiter plate • 6 concentrations • Duplicates • Untreated control (negative control)

  10. Luciferase ATP + Luciferin + O2 AMP + 2P + CO2 + Light Chemoresistant Assay Method Readout: ATP determination using chemoluminescence Very sensitive: 40 cells/well also named ATP-TCA (ATP-Tumor Chemosensitivity Assay)

  11. Chemoresistant Assay Results: Chart

  12. Chemoresistant Assay Results: Table

  13. 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

  14. Chemoresistant Assay Advantages • Safe prediction of resistance • Avoidance of ineffective therapies • Avoidance of unnecessary side effects

  15. Publications Publication search in PubMed 11/2013 • Chemosensitivity Assay : 3089 entries • Chemosensitivity Testing Cancer: 534 entries • ATP-TCA: 60 entries

  16. 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

  17. 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).

  18. 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.

  19. 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

  20. 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. (…)

  21. 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.

  22. 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.

  23. Case Report Man, 59 year oldNasopharynx Carcinoma April 2010 Surgery and Radiation Mar 2011 Metastatic Prostate CaPSA > 500 ng/ml, Gleason 8, Start of antiandrogenic therapy (Fugerel, LHRH)

  24. 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

  25. 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

  26. 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

  27. 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.

  28. Case Report HT1 Woman, 72 years old GIST, rectum Pretreated with Glivec

  29. Hyperthermia

  30. Hyperthermia

  31. Hyperthermia

  32. Case Report HT2 Woman, 34 years old

  33. Hyperthermia

  34. Hyperthermia

  35. Summary Chemoresistant assaysare useful tools to exclude non-responding chemotherapies, especially in pretreated multiresistant patients.

  36. Zentrum für molekulare Onkologie GmbH Im Biotechnologiepark  14943 Luckenwalde Germany (near Berlin)

  37. Thank youfor yourattention !

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