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The Breast Course Breast Cancer: Biologicals New Paradigms ---------------------------------

The Breast Course Breast Cancer: Biologicals New Paradigms ---------------------------------. Joseph Ragaz , Director , Oncology Program McGill University Hospital Center May 5 2006. The 1979 – 2000 BrCa Mortality Trends: UK, USA, Canada J.Ragaz, A.Coldman, ASCO 2005.

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The Breast Course Breast Cancer: Biologicals New Paradigms ---------------------------------

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  1. The Breast CourseBreast Cancer: BiologicalsNew Paradigms--------------------------------- Joseph Ragaz, Director, Oncology Program McGill University Hospital Center May 5 2006

  2. The 1979 – 2000 BrCa Mortality Trends: UK, USA, Canada J.Ragaz, A.Coldman, ASCO 2005

  3. Breast Cancer: Mortality Reduction • Education & screening & downstaging • Endocrine (Tamoxifen & AIs) • Chemotherapy • Radiotherapy • Can we cure more pts? • Molecular Biology

  4. Breast Cancer: Targeted Therapy • Tumor Biology • Biologicals

  5. Genesis of Human Breast Ca:Genes & Genetic markers

  6. Targeted Therapy

  7. Her-2/Neu

  8. The EGFR/HER Family HRG (NRG1) HB-EGF -cel Epi EGF HB-GF Amp TGF NRG1 NRG2 Epi NRG3 Ligand binding domain NRG4 Transmembrane Tyrosine kinase domain Erb-b2 HER2/Neu Erb-b3 HER3 Erb-b4 HER4 erb-b1 EGFR HER1 Mendelsohn and Baselga. Oncogene. 2000;19:6550. Olayioye et al. EMBO J. 2000;19:3159. Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1. Harari and Yarden. Oncogene. 2000;19:6102. Earp et al. Breast Cancer Res Treat. 1995;35:115.

  9. Her2/Neu and Breast Cancer Benign epithelial cells: 20,000 Her2 Receptors Her2+ve BrCa cells:2 million Her2 Receptors Her2/Neuexpression Breast Cancer, overall: 20 – 25% High Grade DCIS: 60 - 70%

  10. HER2 geneAmplification HER2 protein Overexpression Her2/Neu and Breast Cancer Shortened Median Survival HER 2/Neu +ve: 3 yrsHER 2/Neu -ve 6 - 7 yrs Slamon et al, 1987

  11. HER2 Protein Overexpression Associated with Poor Prognosis and Shortened Survival HER2 overexpression: • ER negative status • High S-phase fraction • Positive nodal status • Mutated p53 • High nuclear grade

  12. HER / NEU staining Protein expression IHC: 1+ or 2+ or 3+ Gene Copy: FISH +ve or -ve CISH +ve or -ve

  13. Herceptin: Humanized Anti-HER2 Antibody • Targets HER2 oncoprotein • High affinity (Kd = 0.1 nM) and specificity • 95% human, 5% murine • Decrease potential for immunogenicity • Increase potential for recruiting immune-effector mechanisms

  14. Herceptin:Mode of Action

  15. Herceptin and Chemotherapy • Additive effect • Synergistic effect

  16. Herceptin (Trastuzumab) st. IV : Response only in Her2+ve cases • Slamon et.al. , NEJM, 2001:significant benefit of Herceptin added to Taxol (Paclitaxel) in stage IV disease… • QUESTION: Cost benefit? • Adjuvant studies(NSABP, BCIRG, HERA)…

  17. Adjuvant Trastuzumab Trials NSABP B-31 BCIRG 006 H…x 52 H…x 52 H…x 52 NCCTG 9831 HERA No therapy Standard Chemo Rx H…x 52 H…x 1 years H…x 52 H…x 2 years

  18. NSABP B-31 Control: ACT Arm 1 Arm 2 NCCTG N9831 Arm A Investigational: ACT+H Arm B Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

  19. NSABP B-31: Herceptin trial. Her2/Neu +ve cases • ARM 1: AC – Taxol • ARM 2: AC – Taxol + Herceptin x 1 year

  20. Herceptin Adjuvant trials: NSABP B-31 & NCCTG N9831, NEJM, Oct 2005 ARMS: AC-T AC-T+ H* HR p ------------------------------------------------------------------ • 4 DFS%:85% 67% 0.48p<.00001 • 4 OS%:0.670.015 • CHF: 1%4%* • < 50 vs >50 years: (2 vs 5.5%) , CHF: most reversible * H=Herceptin

  21. Impact of Adjuvant Herceptin, DFS, NSABP-NCTCG analyses, NEJM Oct 2005 ACTaxol - Herceptin 85% 87% ACT % 75% AC-Taxol alone 67% HR=0.48 2P=<0.000001 Years From Randomization

  22. Targeting “Targeted Therapy” • Can we identify subsets who will benefit (from Herceptin) much more, and those who will benefit much less…

  23. HerceptinSensitivity Resistance(PTEN expression) (PTEN loss)

  24. Herceptin Response vs PTEN RR% to Herceptin • All pts (Her2+ve) N: 47 35-50% ------------------------------------------------------------------- • High PTEN (30 pts): 65% • Loss of PTEN: (17 pts): 10% p = <0.01 * Nagata Y, et.al., Cancer Cell, Aug. 2004, 6: 117-127

  25. Role of c-Myc

  26. NSABP B 31: Herceptin subanalysis according to cMyc, S. Paik et.al. • 1736 Her2+ve pts had cMyc analysis • 432 (30%) were Her2 + cMyc +ve

  27. NSABP B-31, according to cMyc: all are Her2+ve 432 pts ======================== • Recurrences: RR ALL: 0.48 ------------------------------------------- cMyc-: 0.63 cMyc+: 0.23 ------------------------------------------

  28. NSABP B-31, according to cMyc: all are Her2+ve cMyc-cMyc+ p 1,078 432 ======================== • Deaths:0.99 0.36 0.037

  29. San Antonio 2005 • DCIS and Her2/Neu expression

  30. Adjuvant Trastuzumab Trials NSABP B-31 BCIRG 006 H…x 52 H…x 52 H…x 52 NCCTG 9831 HERA No therapy Standard Chemo Rx H…x 52 H…x 1 years H…x 52 H…x 2 years

  31. BCIRG 006: Adj. 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACTax Her2+ (Central FISH) N+ or high riskN- 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACTax Herceptin 1 Year Trastuzumab 6 xDocetaxel and Carboplatin 75 mg/m2 AUC 6 N=3,222 TaxCarbo Herceptin Stratified by Nodes and Hormonal Receptor Status 1 Year Trastuzumab Slamon D., SABCS 2005

  32. Disease Free Survival 1.0 93% 0.9 91% 86% 84% 86% 80% 80% 0.8 77% % Disease Free 73% 0.7 Patients Events 0.6 1073 147 AC->T No Herceptin HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001 1074 77 AC->TH 1075 98 TCH HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002 0.5 0 1 2 3 4 5 Year from randomization

  33. CARDIAC TOXICITY

  34. Clinically significant cardiac eventsas per independent review panel P = 0.016 P = 0.11 P = 0.54

  35. Normal Amplified Deletion TOPO II region Topo II NonCo-Amplified Co-Amplified 744 pts (35%) HER2 and TOPO II in BCIRG 006 2120 of 3222 patients analyzed 17 q 12 17 q 21.1 17 q 21.2 HER2 Core region N=2120 1285 pts (60%) 91 pts (4%)

  36. DFS according to Topo II 1.0 0.9 Co-Amplified % Disease Free 0.8 Non Co-amplified 0.7 Patients Events Topo II 744 57 Co-Amplified Logrank P<0.001 1376 191 Non Co-amplified 0.6 0.5 1 2 3 4 5 0 Year from randomization

  37. Topo II and Human BrCa • Topo II is the target for anthracyclines • Topo II is associated with inferior outcome

  38. DFS according to Topo II: Topo II +ve 1.0 AC->TH AC->T 0.8 % Disease Free TCH Patients Events Treatment AC->T 227 23 Logrank P= 0.24 265 13 AC->TH 252 21 TCH 0.6 0.5 0 6 12 18 24 30 36 42 48 54 Months

  39. DFS according to Topo II: Topo II - ve 1.0 0.8 % Disease Free AC->TH TCH Patients Events Treatment 0.6 458 92 AC->T 472 45 AC->TH Logrank P= <0.001 AC->T 446 54 TCH 0.0 0 6 12 18 24 30 36 42 48 54 Months

  40. Conclusion: Outcome according to Topo II • Among Topo II+ve (35% case): Herceptin + Carbo Tax is inferior to Herceptin + Anththracyclines • Among Topo II-ve (65% cases): Herceptin + Carbo Tax is same as Herceptin + Anththracyclines

  41. Might 9 weeks of Herceptin be enough?

  42. Might 9 weeks of Herceptin be enough?H. Joensuu, et.al., Helsinki, Abstr. #2 1010 stage I-II BrCa, T>2 cm, Her2+ve 1st Randomization: • ARM 1: Docetaxel 100 mg/m2 x 3 wks x 3 over 9 wks followed by CEF x 3 (C600E60F600) • ARM 2: Navelbine 25 mg/m2 weekly x 8 over 9 weeks followed by CEF x 3 (C600E60F600) 2nd Randomization (232 CISH +ve pts): • ARM1: Herceptin weekly x 9 weeks • ARM 2: No Herceptin

  43. Might 9 weeks of Herceptin be enough?H. Joensuu, et.al., Helsinki, Abstr. #2 Herceptin vs not HR p ======================= • Any recurrence: 0.46* 0.008 • Distant DFS: 0.43 0.008 • Overall Survival: 0.43* 0.08 * 54% reduction of recurrences due to Herceptin * 57% reduction of mortality due to Herceptin

  44. 10.Cost & Benefit Of Adjuvant Herceptin / 1000 newly diagnosed (15% of all pts. treated); RR=0.5Underlying recurrence rate: 60%.

  45. 12. Cost Benefit of Adjuvant Herceptin: Dollars spent vs Recurrences avoided(15% of all pts. treated; underlying recurrence rate: 60%)

  46. 13. Cost Benefit of Adjuvant Herceptin: therapy according to the “PTEN” statusTreated are only Her2+ve PTEN cMyc +ve (9% of newly 1,000 dg)

  47. Protein: Immunohistochemistry (IHC): simpler, cheaper than FISH, 1st screening test Gene: Fluorescence in situ Hybridization ============================================================ IHC: –ve, 1+:No Herceptin: IHC 2+ :Possible Herceptin: FISH retesting: 20-30% are FISH +ve IHC 3+:Herceptin indicated (n.b. FISH retesting, 10-15% are FISH –ve) The 2006 guidelines: FISH required for all IHC 2+ and 3+ Elligibility for adjuvant Herceptin: Detemination of Her2/Neu status

  48. Tissue Micro-Arrays: • Validation of new genes & proteins ... • Stains of archival (paraffin embedded) tumor samples: • 300 pts / 1 plattform / long f/up…. Kononen J, Bubendorf L, Kallioniemi A, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Medicine 4:844-7, 1998

  49. the red dots are her2/neu gene copies. greenish small dots are the cept 17/ chr D.Huntsman, L.Brown, BCCA Her2/Neu: FISH , presently “Gold Standard”….

  50. Her-2/Neu testing: FISH ADVANTAGES: • Close to 100% specific • 96.5% sensitive • Low inter-laboratory variation DIS-ADVANTAGES: • High Cost and specialised equipment (Florescent microscopy) • Limited availability to community

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