Transforming treatment and improving survival for ovarian cancer patients March 25, 2012
Overview Introduction to Clearity Foundation Clearity profiling panel Interpretation of results utilizing the Diane Barton Database Case studies – Patient in second recurrence that went on to receive chemotherapy – Patient in first recurrence that went onto a clinical trial of a molecular- targeted agent combined with chemotherapy – Recurrent vs primary specimens Utilizing the TCGA groupings for selection of clinical trials – Case study of BRCAness Q&A 2
The Clearity Foundation launched as a non-profit organization in 2008 to: Bring molecular profiling to the forefront of ovarian cancer diagnosis and treatment Assist doctors in priorizing therapy for recurrent ovarian cancer informed by their patient’s tumor molecular profile Expedite the clinical development of novel targeted agents for ovarian cancer Increase the probability of success by utilizing molecular profiling to select patients for clinical trials 3
Leading advisors and scientific findings presented Mol Cancer Ther; 11(2) February 2012: Scientific Advisory Board Treatment-related protein biomarker expression Beth Karlan, MD, Chair Cedars Sinai & UCLA differs between primary and recurrent ovarian Medical Center carcinomas DA Zajchowski, BY Karlan and LK Shawver Doug Levine, MD Memorial Sloan Kettering Cancer Center ASCO 2011: Expression Profiles in Matched Primary and Recurrent Ovarian Carcinomas Johnathan Lancaster, MD Moffitt Cancer Center DA Zajchowski, BY Karlan and LK Shawver, Julie Cherrington, PhD Pathway Therapeutics AACR 2011: Molecular Profiling in Recurrent Ovarian Cancer Patients DA Zajchowski, C Bentley, J Gross, BY Karlan and LK Shawver Ursula Matulonis, MD Dana Farber Cancer Center & Harvard Medical School AACR 2010 : Selecting Patients for Ovarian Deb Zajchowski, PhD Clearity Foundation Scientific Cancer Clinical Trials by Profiling Tumors Director against a Broad Panel of Molecular Markers DA Zajchowski, J Gross, BY Karlan, K Bloom, D Loesch, A Alarcon and LK. Shawver 4
Accomplishments in less than four years Developed diagnostic protocols with latest technologies and input from expert advisors Created the Diane Barton Database, a platform for: – Compiling test results from multiple labs – Tracking patient outcomes – Establishing assay cut-points to prioritize treatment options – Utilizing markers for clinical trial enrollment – Comparing tumor profiling results from patient to patient Formed web-based informational tools and patient support process Provided access to molecular profiling for ~200 women with ovarian cancer 5
How we work Clearity Profiling Services: • Physician and patient education Oncologists • Coordination with CLIA labs to test and Patients • Secure database for patient data • Data integration/ analysis • Results reporting Medical team utilizes molecular profiles to prioritize therapeutic options 6 6
Multiple choices for recurrent disease Can we inform the treatment decision? NCCN Guidelines for Epithelial Ovarian Cancer/Fallopian Tube Cancer/Peritoneal Cancer 2.2.2011 7
Use tumor molecular profiles to prioritize choice of chemotherapy and/or clinical trial Targeted Therapy Chemotherapy Marker Panel Marker Panel Prioritize Select chemo for Select clinical chemotherapy combination with trial with for next targeted agent in targeted agent treatment clinical trial 8
Current panel of tests Growth Factors/ Receptors EGFR* Her2* IGF1R c-Met VEGF PDGFR Cytoplasmic Signal Transducers and Apotosis Regulators K-ras** B-raf** PIK3CA** PTEN Bcl-2 Survivin Cox-2 Nuclear Signaling Proteins Hormone Receptors/Transcription Factors Cell Cycle ER AR PR HIF1A Ki67 p21 p16 Rb Chemotherapy Sensitivity Markers DNA Synthesis/Transcription ECM TLE3 Topo1 Top2A SPARC Chemotherapy Resistance Markers Drug Transporters DNA Repair/ Modification DNA Synthesis/Cell Division ERCC1 BCRP MRP1 MDR1/PGP MGMT RRM1 TS TUBB3 9 * DNA amplification ** DNA mutational analysis
Data stored and analyzed in Diane Barton Database UNK Stage Platinum Response 3% Refractory IV I 7% II 6% 8% 7% NA Resistant 25% 15% III 76% Sensitive 53% Histology Specimen Source Ad TC UNK SB 5% CS CC 1% 2% 1% 1% 6% Endo 8% GC 2% Mucin Ovary Peritoneal 2% 34% recurrence MMMT 41% 1% Primary Serous Mixed peritoneal 70% 3% 20% Distant Mets N=244 5% *196 patients, February, 2012 10
Example laboratory read-out for IHC 11
Data collected as histoscores Histoscore = % tumor stained x Intensity =92 12
Marker expression in all patients provides basis for interpretation of individual results 300 250 200 H Score 150 100 50 0 EGFR HER2 IGF1Rb PDGFR Alpha COX-2 Ki-67 TOPO1 TOP2A TS ERCC1 TUBB3 TLE3 PGP/MDR1 BCRP MRP1 c-MET PDGFR Beta VEGF ER AR PR RRM1 SPARC MGMT 13 Box, inter-quartile range; line, median; whiskers, maximum and minimum values
Chemotherapy selection using published evidence and expression cut-offs derived from current database 300 250 High Topo I Irinotecan, topotecan High Topo II Doxorubicin, etoposide 200 Low RRM1 Gemzar 150 H Score* Low TS Fluoropyrimidines 100 High SPARC nab-Paclitaxel High PGP No Taxane, no doxil 50 High BCRP No Topotecan 0 TOPO1 TOP2A TS RRM1 PGP SPARC BCRP 14 Low: <25 th percentile High: >75 th percentile
Case Study : profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma 300 3/2005 Carbo/tax x6 250 taxol 10 mos 200 recurrence 12/2008 H Score* carbo/tax x 6 150 carbo/tax/bev x3 100 12/2009 Doxil x3 50 Surgery 1/2010 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 15
Case Study : profile for patient diagnosed in 3/2005 High EGFR (98 th percentile) with stage IIIB papillary serous carcinoma EGFR inhibitors have been 300 ineffective in clinical trials 3/2005 Carbo/tax x6 250 although benefit seen in taxol 10 mos individual patients 200 Mutations can predict recurrence 12/2008 H Score* carbo/tax x 6 sensitivity and resistance to 150 carbo/tax/bev x3 EGFR inhibitors in lung 100 cancer 12/2009 Doxil x3 Follow up mutation analysis 50 Surgery 1/2010 conducted; patient was wt 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 16
Case Study : profile for patient diagnosed in 3/2005 High ER with stage IIIB papillary serous carcinoma Anti-estrogens and aromatase 300 inhibitors utilized in ovarian 3/2005 Carbo/tax x6 cancer patients but not approved 250 due to lack of efficacy in clinical taxol 10 mos 200 studies recurrence 12/2008 H Score* carbo/tax x 6 150 carbo/tax/bev x3 100 12/2009 Doxil x3 50 Surgery 1/2010 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 17
Case Study : profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma High SPARC Clinical trial for nab-paclitaxel 300 3/2005 (none at the time) or off-label Carbo/tax x6 250 use taxol 10 mos patient had long history of 200 recurrence 12/2008 taxane treatment H Score* carbo/tax x 6 150 carbo/tax/bev x3 100 12/2009 Doxil x3 50 Surgery 1/2010 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 18
Case Study : profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma 300 3/2005 Carbo/tax x6 250 taxol 10 mos 200 recurrence 12/2008 Low TS H Score* carbo/tax x 6 Fluoropyrimidines 150 carbo/tax/bev x3 and pemetrexed 100 12/2009 considered as a Doxil x3 reasonable option 50 Surgery 1/2010 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 19
Case Study : profile for patient diagnosed in 3/2005 with stage IIIB papillary serous carcinoma 300 Low RRM 3/2005 Carbo/tax x6 High RRM1 associated with 250 taxol 10 mos resistance to gemcitabine 200 Gemcitabine is an recurrence 12/2008 H Score* carbo/tax x 6 approved agent in recurrent 150 carbo/tax/bev x3 ovarian cancer Physician choice was 100 12/2009 Doxil x3 gemcitabine as next 50 Surgery 1/2010 treatment 0 Tumor Profiled EGFR HER2 IGF1Rb c-MET PDGFR Beta VEGF COX-2 ER AR TOP2A PGP/MDR1 SPARC MRP1 MGMT PDGFR Alpha PR Ki-67 TOPO1 TS RRM1 ERCC1 TUBB3 TLE3 BCRP 20
Recommend
More recommend
