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AGA/ASCO/ASTRO/SSO Gastrointestinal Cancers Symposium Orlando, FL January 26, 2008

Circulating tumor cells: are they predictive markers?. AGA/ASCO/ASTRO/SSO Gastrointestinal Cancers Symposium Orlando, FL January 26, 2008. Neal J. Meropol, M.D. Fox Chase Cancer Center. “Predictive” vs. “Prognostic”. Predictive : explains variability in response to treatment

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AGA/ASCO/ASTRO/SSO Gastrointestinal Cancers Symposium Orlando, FL January 26, 2008

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  1. Circulating tumor cells: are they predictive markers? AGA/ASCO/ASTRO/SSO Gastrointestinal Cancers Symposium Orlando, FL January 26, 2008 Neal J. Meropol, M.D. Fox Chase Cancer Center

  2. “Predictive” vs. “Prognostic” • Predictive: explains variability in response to treatment • Traditional application before treatment • Prognostic: explains variability irrespective of treatment

  3. Natural History of Circulating Tumor Cells Paterlini-Brechot and Benali, Cancer Letters, 2007

  4. Potential advantages of circulating tumor cells (CTCs) compared to other blood markers • Representative of tumor access to circulation • Permits multiple simultaneous analyses • Enumerate, phenotype, gene expression • Cytopathology • in vivo pharmacodynamic assessment, gene expression profiling • Sensitivity/Specificity

  5. Why Study CTCs? • Prognosis • Monitor disease course • Minimal residual disease • Early relapse • Response to therapy • Treatment selection • Drug development (pharmacodynamics) • Target acquisition • Down stream effects

  6. Methods for CTC Detection • Density gradient • Immunomagnetic separation (beads, ferrofluid) • Size-based filtration Count Cytopathology RT-PCR Genotyping 20%-70% of patients with colorectal cancer have detectable CTCs

  7. Stations 2 & 3 7.5 ml Plasma Magnetic Primary Addition of Blood + Aspiration & Incubations Magnetic Cytokeratin-PE 6.5mL Addition of Separation & CD45-APC, & Buffer EPCAM Ferrofluid Resuspension DAPI Immunomagnetic Separation Station 1 Station 4 Station 5 Centrifuge Place on Instrument - - Described in: WJ Allard et al, Clin Cancer Res 10: 6897-6904, 2004

  8. Staining Incubation, Final Magnetic Wash & Resuspension Free Particle Removal Immunomagnetic Separation Image Gallery Stations 6,7, & 8 Station 9a Station 9b Automatic Transfer of Sample for Fluorescent Image Analysis

  9. Characterization of CTCs by Flow Cytometry SJ Cohen et al. Clin Colorectal Cancer, 2006 CTC, green and red EGFR+, red WBC, blue Beads, yellow

  10. Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer ASCO 2007 N. J. Meropol, S. J. Cohen, N. Iannotti, B. H. Saidman, K. D. Sabbath, M. C. Miller, G. V. Doyle, H. Tissing, L. W.M.M. Terstappen, C.J.A. Punt Fox Chase Cancer Center, Philadelphia, PA; Hematology Oncology Associates, Port St. Lucie, FL; Medical Oncology Associates, Kingston, PA; Medical Oncology and Hematology, PC, Waterbury, CT; Immunicon Corporation, Huntingdon Valley, PA; Radboud University Medical Center, Nijmegen, The Netherlands

  11. Objectives and Eligibility Overall Objective To determine the association between circulating tumor cell number and clinical outcomes in patients with metastatic colorectal cancer Eligibility Adults with measurable metastatic colorectal cancer, initiating first-, second-, or third-line therapy

  12. Methods • Multicenter international study • Radiographic tumor measurement at baseline and every 6-12 weeks after treatment initiation (RECIST criteria) • Peripheral blood was collected for CTC enumeration at baseline and subsequently at 1-2, 3-5, 6-12, and 13-20 weeks after treatment initiation • Blood mailed overnight at room temperature, and processed at 1 of 4 laboratories within 96 hours

  13. 26 24 22 20 18 16 Median OS from Baseline (Months) 14 12 10 8 6 4 2 53% 47% 33% 26% 21% 18% 16% 14% 13% 12% 11% 0 0 >= 1 >= 2 >= 3 >= 4 >= 5 >= 6 >= 7 >= 8 >= 9 >= 10 CTC / 7.5mL of Blood (Baseline Draw) Median OS for Patients with Metastatic Colorectal Cancer Based Upon number of CTC Prior to the Initiation of Therapy (N=413) ASCO 2007

  14. Baseline CTC: Progression Free Survival 100% CTC/7.5 mL Median in Months (95% CI) <3 CTCs 7.9 (7.0 - 8.6) ≥3 CTCs 4.5 (3.7 - 6.3) 90% 80% 70% 60% 50% P = 0.0002 % Progression Free 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Baseline Blood Draw (Months) <3 CTCs 305 269 229 187 138 88 44 32 20 15 8 6 3 0 0 0 ≥3 CTCs 108 84 60 42 28 16 8 3 2 2 1 0 0 0 0 0 ASCO 2007

  15. Baseline CTC: Overall Survival CTC/7.5 mL Median in Months (95% CI) <3 CTC 18.5 (15.5 - 21.2) ≥3 CTC 9.4 (7.5 - 11.6) 100% 90% 80% 70% P < 0.0001 60% 50% % Survival 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Baseline Blood Draw (Months) <3 CTC 305 289 276 252 227 180 134 107 78 60 43 32 22 11 4 2 ≥3 CTC 108 102 86 66 49 36 24 13 12 11 7 4 2 1 1 0 ASCO 2007

  16. CTC During Treatment: PFS 100% N Median PFS in Months (95% CI) <3 CTC ≥3 CTC 1-2 wks 315 7.3 (6.5 - 8.1) 3.8 (1.9 - 5.1) 3-5 wks 329 6.8 (6.1 - 7.6) 1.9 (1.2 - 4.4) 6-12 wks 284 6.5 (5.8 - 7.7) 2.0 (0.5 - 2.5) 90% 80% 70% 60% 50% P < 0.0001 at each timepoint %Probability of Progression Free Survival 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Blood Draw (Months) ASCO 2007

  17. CTC During Treatment: Overall Survival Median OS in Months (95% CI) N <3 CTC ≥3 CTC 1-2 wks 357 15.7 (14.3 - 18.4) 6.1 (4.9 - 8.9) 3-5 wks 333 16.4 (14.1 - 18.3) 4.4 (2.6 - 8.7) 6-12 wks 310 15.8 (13.8 - 19.2)3.3 (1.8 - 5.6) 100% 90% 80% 70% P < 0.0001 at each timepoint 60% %Probability of Survival 50% 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Blood Draw (Months) ASCO 2007

  18. Predictors of PFS and OS:Multivariable Model – Baseline (N=373) ASCO 2007

  19. Predictors of PFS and OS:Multivariable Model – 3-5 Weeks (N=302) ASCO 2007

  20. Circulating Tumor Cells at Time of 1st Followup Image Add Prognostic Information CTC Response N OS in Months (95% CI) <3 CTC S/PR/CR 271 18.8 (17.0 - 25.1) <3 CTC PD/Death 64 8.3 (5.8 - 11.2) >3 CTC S/PR/CR 13 7.1 (5.4 - 10.8) >3 CTC PD/Death 16 3.1 (2.0 - 4.4) 100% 90% 80% 70% vs. P < 0.0001 60% 50% %Probability of Survival 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Baseline Blood Draw (Months) ASCO 2007

  21. Circulating Tumor Cells at Time of 1st Followup Image Add Prognostic Information CTC Response N OS in Months (95% CI) <3 CTC S/PR/CR 271 18.8 (17.0 - 25.1) <3 CTC PD/Death 64 8.3 (5.8 - 11.2) >3 CTC S/PR/CR 13 7.1 (5.4 - 10.8) >3 CTC PD/Death 16 3.1 (2.0 - 4.4) 100% 90% 80% 70% 60% 50% %Probability of Survival vs. P = 0.0001 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Baseline Blood Draw (Months) ASCO 2007

  22. Circulating Tumor Cells at Time of 1st Followup Image Add Prognostic Information CTC Response N OS in Months (95% CI) <3 CTC S/PR/CR 271 18.8 (17.0 - 25.1) <3 CTC PD/Death 64 8.3 (5.8 - 11.2) >3 CTC S/PR/CR 13 7.1 (5.4 - 10.8) >3 CTC PD/Death 16 3.1 (2.0 - 4.4) 100% 90% 80% 70% 60% 50% %Probability of Survival 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 6 10 12 30 4 Time from Baseline Blood Draw (Months) ASCO 2007

  23. Decrease in CTC at 3-5 Weeks is Associated with Improved PFS in Patients with > 3 CTC at Baseline 100% Baseline 3-5 wks N Med PFS (95% CI) ≥3 CTC <3 CTC 52 6.2 (4.6 - 7.0) ≥3 CTC ≥3 CTC 28 1.6 (1.2 - 2.7) P = 0.02 90% 80% 70% 60% 50% % Probability of Progression Free Survival 40% 30% 20% 10% 0% 0 8 14 16 18 20 22 24 26 28 2 4 6 10 12 30 Time from 3-5 Week Blood Draw (Months) ASCO 2007

  24. CTC Association with PFS and OS by Lines of Therapy 1st line HR=2.22 (1.49-3.30) HR=1.44 (1.04-1.98) PFS OS HR=1.90 (1.26-2.85) 2nd line HR=2.98 (1.85-4.77) Cohen et al. AGA/ASCO/ASTRO/SSO GI Cancers Symposium, 2008

  25. Conclusions • In patients with metastatic colorectal cancer, CTC number before and after initiation of treatment is a significant independent predictor of progression free survival and overall survival • CTC enumeration is complementary to imaging, and may provide early evidence of treatment success or failure • Further research is required to determine whether change in therapy based upon elevated CTC number at early followup will improve patient outcomes

  26. Are CTCs Predictive Markers? Maybe • Traditional application before treatment • no data yet regarding role of phenotyping/genotyping CTCs and response to therapy • Alternative application early after treatment initiation • suggestive evidence that CTCs indicate resistance to treatment

  27. Clinical validation study design requirements • Standardized assay platform for clinical decision making • Prospective randomized trial • archival well-annotated clinical specimens do not exist • Randomized population of adequate size to answer clinical question • Requires previous validation with assay platform

  28. Continue Treatment A Favorable CTCs? Yes* Continue Treatment A No R Change to Treatment B Metastatic disease study design:early change in therapy Assess at 1-3 weeks Begin Treatment A *assumes that continuation of Treatment A is best in Favorable CTC group

  29. Standard initial therapy Yes* Standard initial therapy No R More aggressive initial therapy Metastatic disease study design:selection of initial therapy Favorable CTCs? *assumes that standard therapy is “best” in Favorable CTC group

  30. Routine surveillance R Routine surveillance + CTC evaluation, with aggressive intervention if CTC “recurrence” Surveillance study design 1: randomize early Resected patients at risk for recurrence

  31. Continue routine surveillance R CTC “Recurrence” Aggressive intervention Surveillance study design 2: randomize later Resected patients at risk for recurrence Routine surveillance plus CTC evaluation

  32. Many Questions Remain • What are “circulating tumor cells”? • Are CTCs the same as in situ cancer? • How does cell separation process affect gene expression? • How can CTCs be used in the drug development process? • How can CTCs be integrated into routine patient care?

  33. The End

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