1. Current Situation of Breast Cancer Treatment in US Stefan Glück MD PhD Professor of Medicine Clinical Director Braman Family Breast Cancer Institute UMSylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine

3. Available Regimens (Level I Evidence) ~Equivalent RegimensCMFACCAFFEC50 StudyBonadonnaNSABP-B15, 23SECSG, SpainICCG Improvement CEF120 (E - CMF) AC - T DDTACFEC100 RR~20-35%~30%~20%~30% StudyNCIC MA.05CALGB9741BCIRG001FASG05 Further Improvement DD EC - TDD AC - TGE-T-C DD and DI FEC100  Doc StudyNCIC MA.21NSABP-B38AGOPACS01

4. + TAM if >50 yrs. AC x 4 Operable Breast Cancer Stratification Age Clinical Tumor Size Clinical Nodal Status Operation + TAM if >50 yrs. AC x 4 Operation NSABP B-18: Trial Design Fisher et al. J Clin Oncol. 1998;16(8):2672-2685.

5. NSABP B-18 Conclusions  Survival benefit was equivalent for pre-operative or post-operative therapy  pCR correlates with a significant increase in disease free survival (p=0.00005) and overall survival (p=0.0008)  Pre-operative chemotherapy increases the rate of breast conserving surgeries

6. Primary Outcomes Neoadjuvant vs adjuvant therapy NSummary risk ratio % (95% CI), random effects analysis p-value Death 1.0 (0.90-1.12) – Disease progression 0.99 (0.88-1.11) – Distant recurrences 0.94 (0.83-1.06) – Locoregional recurrences 1.22 (1.03-1.44) 0.018 Mauri D et al. J Natl Cancer Inst 2005;97(3):188-94.

7. NSABP B-27: Design Operable Breast Cancer Randomization Surgery AC X 4 Tam X 5 yrs AC X 4 Tam X 5 yrs AC X 4 Tam X 5 yrs Docetaxel X 4 I II III Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

8. NSABP B-27: Pathologic Complete Responses in Breast Percentage ( % ) *P < 0.001 for test of heterogeneity across groups (n=764) (n=767) 12.8%* 26.1%* 14.3%* (n=775) Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

9. NSABP B-27: Overall Survival pCR versus non-pCR Patients % Surviving Years after surgery TreatmentNDeaths Non pCR1899396 pCR40931HR=0.33P<0.0001 Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26. 40 50 60 70 80 90 100 012345

10. ErbB Family of Tyrosine Kinase Receptors  Family of evolutionarily conserved type I receptor tyrosine kinases  Four members: – ErbB-1 (EGFR/HER1) – ErbB-2 (HER2) – ErbB-3 (HER3) – ErbB-4 (HER4) Extracellular Domain (Binds Ligand) TM Domain Cytoplasmic Domain (Kinase Activity)

11. ErbB-2 or HER2  Also known as HER2/neu  No known ligands  Activation thought to occur through heterodimerization with other ErbB family members  ErbB-2 is the preferred heterodimerization partner with other family members  Most resistant to intracellular degradation, slower to inactivate compared to other family members  ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival times

12. Poorer Survival of Patients With HER2+ Primary Breast Cancer 0246810121416 Years 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion surviving P<0.0001 HER2 – HER2+ 0 0.1 Witton et al. J Pathol. 2003;200:290. N=220 (majority >1 cm); all patients received standard therapy

13. 4 cycles Dox/Cyc Pax HD q 3 wk Trastuzumab Pax HD q 3 wk 4 cycles 52 wks NSABP B-31 NCCTG 9831 Dox/Cyc Pax LD/wk Trastuzumab Pax LD/wk Trastuzumab Pax LD/wk 12 wks 52 wks 64 wks HERA Trastuzumab No therapy Standard ChemoRx 1 Yr 2 Yr BCIRG 006 Dox/Cyc 4 cycles Docetaxel Trastuzumab Docetaxel Carboplatin Trastuzumab Summary of Adjuvant Trastuzumab Trials

14. Combined Analysis: Overall Survival AC  TH 94% 91% 87% 92% AC  T NDeaths AC  T167992 AC  TH167262 HR=0.67, 2P=0.015 Years From Randomization B31/N9831

15. Complexity of HER Signaling Adapted from Yarden and Sliwkowski. Nat Rev Mol Cell Biol. 2001;2:127. MycSp1 Jun FosElkEgr1Stat MigrationApoptosisGrowthAdhesionDifferentiation Src Cbl PLC  PI(3)K Shp2 GAP Shc Nck Vav Grb7 Crk Jak Grb2 Sos Rac Transcription factors Cascades Adaptors and enzymes Receptor dimers Ligands Signal-processing layer Input layer Output layer Ras-GDP PKC Bad Akt S6K RAF MER MAPK PAK Abl JNKK JNK LPA, thrombin, ET, etc TGF  (1) EGF (1) Epiregulin (1,4)  -cellulin (1) HB-EGF (1,4) Amphi- regulin (1) NRG1 (3,4)   NRG2 (4)   NRG3 (4) Cytokines NRG4 (4) Multiple pathway interactions (eg, ER)

16. Summary and Conclusion  There is increased clarity regarding adjuvant treatment of node-positive breast cancer – Use of an anthracycline and taxane is a standard if not THE standard – Adjuvant trastuzumab improves outcomes and became standard  Neoadjuvant treatment is the treatment of choice for patients with locally advanced breast cancer, and a resonable option for patients with operable breast cancer  Novel combinations hold promise for improving outcomes for women in high risk settings  Genomic data and DNA microarray analysis will gain increasing importance in clinical investigation as well as clinical management of breast cancer