1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Treatment in Breast Cancer

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Variables for Prognosis of Early Breast Cancer and for Adjuvant Treatment 1.Axillary Lymph Node Status 2.Estrogen Receptor 3. Her-2/neu Status 4. Treatment

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria * Neoadjuvant Treatment * Adjuvant Treatment * Palliative Treatment Treatment Modalities for Breast Cancer

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Variables for Decision of Adjuvant Therapy Adjuvant Therapy Node-Negative / -Positive ER-Positive / -Negative HER-2 as Predictive Marker

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Therapy of Early Breast Cancer A. Endocrine Interventions Ovarian Ablation Tamoxifen Aromatase Inhibitors B. Polychemotherapy

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effects of Adjuvant Therapy for Early Breast Cancer: 1990 -. Treatment Effectivity A. Endocrine Interventions Ovarian Ablation 10% Absolute Gain in 15 yr.-Survival Tamoxifen 8% Absolute Gain in 15 yr.-Survival 50% Reduction in Contralateral cancer Small Risk of Endometrial Cancer, DVT Aromatase Inhibitors First Data (47 Months Follow-Up)

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria A. ENDOCRINE TREATMENT 1. Role of hormone withdrawal in premenopausal patients. 2. Role of third generation aromatase inhibitors in postmenopausal patients. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria The Estrogen Receptor in Breast Cancer 1. Localised within the Tumour Cell. 2. Interaction with Estrogen Results in Signal Transduction and Tumour Cell Proliferation. 3. Blockade Results in Cancer Cell Death. Consequence No. 1: Competitive Inhibition of Estrogen.

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Reduction of Relapses and Mortality from Early Breast Cancer by 20 mg Tamoxifen for 5 Years. * Relapse Mortality 2p 42  3% 22  4% <.00001/.00001 * EBCTCG, LANCET 351: 1451, 1998 Reduction of

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Estrogen Withdrawal Modalities 1.Premenopausal Patients LH-RH Agonists + Tamoxifen (+ Aromatase Inhibitors?) 2. Postmenopausal Patients Aromatase Inhibitors

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I and II EBC: The ABCSG Trial. * 1.034 Premenopausal Patients Hormone-Responsive Disease Treatment: 3 yrs. Goserelin plus 5 yrs. Tamoxifen vs. 6 Cycles of CMF Analysis at 60-month Median Follow-Up * R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I and II EBC: The ABCSG Trial. * TreatmentRelapsesLocal Recurrences RFS at 5 yrs. Endocrine17.2% 4.7% 81% Cytotoxic20.8%8.0% 76% p0.0176 0.0029 0.037 * R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I and II EBC: The ABCSG Trial. * CONCLUSION „The Goserelin-Tamoxifen Combination is Significantly More Effective than CMF in Premenopausal Patients with Stage I and II ER-Positive EBC.“ * R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II EBC: The ZEBRA Trial. * Study Design 1640 Randomized Patients Goserelin for 2 Years (n=817) vs. 6x CMF (n=823) ER-Positive and ER-Negative Patients Median Follow-Up: 6 Years. * W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II EBC: The ZEBRA Trial. * Primary Efficacy of Goserelin vs. CMF DFSOS ER-positivep=0.94 (equal efficacy) p=0.92 (equal efficacy) ER-negativep=0.0006 in favor of CMF p=0043 in favor of CMF ER-unknownp=0.026 in favor of CMF p=0.14 * W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II EBC: The ZEBRA Trial. * CONCLUSION „Equal Efficacy of Goserelin Given for 2 Years and 6 Cycles of CMF in Patients with ER-Positive Stage II Breast Cancer.“ * W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Postmenopausal Patients with EBC: Design of the ATAC Trial*. Anastrozole (n=3125) vs. Tamoxifen (n=3116) vs. Anastrozole + Tamoxifen (n=3125) Median follow-up: 47 months for DFS * Arimidex, Tamoxifen, Alone or in Combination; A. Buzdar SABCC 2002, Abstr. #13

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Estrogen Withdrawal in Postmenopausal Patients with EBC: Results of the ATAC Trial*. Significance Anastrozole vs. Tamoxifen in ER+ Patients DFS Estimates at 4 Years 89% vs. 86.1% Disease-free Survival 0.014 Time to Recurrence0.007 Contralateral Breast Cancer 0.042 NB: Results of Anastrozole + Tamoxifen equal to Tamoxifen alone! * Arimidex, Tamoxifen, Alone or in Combination; A. Buzdar SABCC 2002, Abstr. #13

19. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Side Effects of Anastrozole vs. Tamoxifen in the ATAC Trial*. Hot Flushesp<0.0001 in favor of Anastrozole Vaginal Bleeding and Dischargep<0.0001 in favor of Anastrozole Thromboembolic Eventsp=0.0006 in favor of Anastrozole Ischemic Cerebrovascular Eventp=0.0006 in favor of Anastrozole Endometrial Cancerp=0.02 in favor of Anastrozole Osteoporotic Bone Fracturesp<0.0001 in favor of Tamoxifen Musculoskeletal Disorders p<0.0001 in favor of Tamoxifen * The ATAC Trialists´ Group: Lancet 359: 2131- 2139, 2002

20. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Endocrine Adjuvant Treatment of Early Breast Cancer in Premenopausal Patients. Nodal StatusER+ER- N0Goserelin +/- TamoxifenChemotherapy N1Chemotherapy TamoxifenChemotherapy (Goserelin + Tamoxifen)

21. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Endocrine Adjuvant Treatment of Early Breast Cancer in Postmenopausal Patients. Nodal StatusER+ER- N0TamoxifenChemotherapy (Aromatase Inhibitor) N1TamoxifenChemotherapy +/- Chemotherapy (Aromatase Inhibitor)

22. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Chemotherapy in Early Breast Cancer. * RELAPSE -23.5  2.1%<.00001 DEATH-15.3  2.4%<.00001 * EBCTCG, LANCET 352: 930, 1998. REDUCTION OF ANNUAL RISK OF RELAPSE AND DEATH BY CHEMOTHERAPY

23. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Early Breast Cancer Trialists Collaborative Group: Effect of Adjuvant Anthracycline- Based Chemotherapy: Reduction of Annual Hazards. * % of Reduction 2p Anthracycline-Based Chemotherapy vs. CMF Recurrences 12  4 <.006 Mortality 11  5 <.02 * EBCTCG, Lancet 352: 930, 1998.

24. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Polychemotherapy for Early Breast Cancer: 1990 -. Premenopausal Patients: 5-12% Absolute Gain in 10 yr.-Survival Postmenopausal Patients: 2-4% Absolute Gain in 10 yr.-Survival NIH 2000 Consensus Conference

25. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Anthracyclines in Adjuvant Therapy for Early Breast Cancer. 5 Years10 Years Additional Absolute Gain 1.7% 4% in OS with Anthracycline in N- Pats. in N+ Pats. -Based Chemotherapy NIH 2000 Consensus Conference

26. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria % Free of Recurrence Years Simulation of Impact of Adjuvant Chemotherapy in EBC. Annual Odds of Recurrence: Nil = 15% / Yr. CMF = 11.4% / Yr. (Reduced by 24%) AC = 10% / Yr. (Reduced by 12%) 0 20 40 60 80 100 0246810 AC CMF Nil

27. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria B. CHEMOTHERAPY 1. Role of Anthracyclines. 2. Role of Taxanes. 3. Dose density. 4. Combination with Endocrine Treatment. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

28. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 1. When is an Anthracycline-Based Regimen Preferable to CMF? 2. Which Anthracycline Should be Used? 3. Which Regimen? 2- or 3-Drug-Regimen? Dose? Schedule? 4. How Many Cycles? 4 or 6? Anthracyclines in the Adjuvant Therapy of Patients with Breast Cancer: Unresolved Questions 2003. Anthracyclines in the Adjuvant Therapy of Patients with Breast Cancer: Unresolved Questions 2003.

29. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Review of Anthracyclines in the Adjuvant Chemotherapy of Breast Cancer: The Dilemma. Authors Cytotoxics Results Fisher et al. 1989 (B-11) PF(T) vs. PAF(T) Sign. OS&DFS for PAF vs. PF Fisher et al. 1990 (B-15) CMF (6Mo.) vs. AC (2Mo.) n.s. Moliterini et al. 1991 CMF vs. CMF->A n.s. for DFS & OS Budd et al. 1995 CMFVP vs. FAC-M Sign. DFS for CMFVP Misset et al. 1996 CMF vs. AVCF Sign. OS & DFS Premenopause Coombes et al. 1996 CMF vs. FEC Sign. OS & DFS Premenopause Levine et al. 1998 CMF vs. CEF Sig. OS & DFS Premenopause Mouridsen et al. 1999 CMF vs. CEF Sign. OS Premenopause Piccart et al. 2001 CMF vs. EC No Advantage of EC vs. CMF Reconfirmation of Dose Response

30. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Anthracycline- Based Adjuvant Chemotherapy in Breast Cancer. Effectivity Analysed in Premenopausal Patients Only Misset et al. 1996 Levine et al. 1998 Mouridsen et al. 1999 No Advantage for Postmenopausal Patients Misset et al. 1996 Piccart et al. 2001 (41-44% Postmenopausal Patients Included)

31. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Chemotherapy of Primary Breast Cancer: Some general remarks... Adriamycin Doses < 40mg/m 2 are Inferior to 60 mg/m 2 (CALGB 8541). Cyclophosphamide Doses > 600 mg/m 2 are not Superior (NSABP B-22). Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG).

32. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria DRUG PUBLICATION RECOMMENDATION Adriamycin CALGB 9344 60mg/m 2 q. 3 wks. in the AC Regimen Epirubicin French Trial 100mg/m 2 q. 3 wks. in the EC and Belgian Trial FEC regimens for high risk (N+) women Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Dose Recommendations.

33. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Efficacy of Anthracycline-Based Adjuvant Chemotherapy in Her-2/neu Overexpressing Early Breast Cancer. STUDYAUTHOR RESULTS IN HER-2/neu POSITIVE NEGATIVE NSABP-B11PAIK et al. 1998 DFS & OS SIGN. n.s. (PF vs. PAF) (Advantage Anthracycline) NSABP-B15PAIK et al. 2000 DFS & OS BORDERLINE n. s. (AC vs. CMF vs. AC->CMF) (Advantage Anthracycline)

34. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria ENDOCRINE RESPONSIVEENDOCRINE-NON-RESPONSIVE Likelihood of Response Risk Profile Low High Average High FE(A)C d1 x6 AC x4 FE(A)C d1 x6 CE(A)F d1+8 x6 CE(A)F d1+8 x6 Proposed Algorithm for Anthracycline Use as Adjuvant Therapy in Patients with Breast Cancer. Proposed Algorithm for Anthracycline Use as Adjuvant Therapy in Patients with Breast Cancer. ? Her-2/neu +++

35. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria The use of anthracyclines increases DFS and OS, probably even more so in selected patient populations (premenopause, Her-2/neu overexpression, etc.), and is superior to CMF. The routine use of anthracycline-based regimens is recommended in appropriate patient populations, optimal schedule and frequency of administration, however, are not clear at the moment. Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Conclusions. Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Conclusions.

36. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Role of Taxanes Available Studies: CALGB 9344 NSABP-B27 NSABP-B28 BCIRG 001 M.D. ANDERSON Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

37. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 1. AC most active adjuvant chemotherapy. 2. Paclitaxel achieves responses in stage IV breast cancer in 52- 59% of patients (22-30% in anthraycyline resistant patients) 3. Sequential chemotherapy is reasonable. Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Lymphnode- Positive Breast Cancer (CALGB 9344): RATIONALE. * Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Lymphnode- Positive Breast Cancer (CALGB 9344): RATIONALE. * * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

38. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Paclitaxel-induced Apopotosis is Independent from p53 Mutation Status. * Paclitaxel-induced Apoptosis is  Dependent on ERK p38 MAP Kinase Cascades  Independent from p53 * BACUS et al., Oncogene 20: 147, 2001

39. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria THERAPY Doxorubicin 60, 75 or 90mg/m 2 + Cyclophosphamide (AC) x 4, then randomised to nil vs. sequential Paclitaxel (175mg/m 2 ) x 4 (+/- Tamoxifen 20mg, 5 Years) PATIENTS 3.170 Patients Randomised according to 3x2 factorial trial design Positive axillary lymph nodes (1 - >10 Lnn.), First Kaplan-Meier Analysis after 18 months Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node- Positive Breast Cancer (CALGB 9344) Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node- Positive Breast Cancer (CALGB 9344) * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

40. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node- Positive Breast Cancer (CALGB 9344): First Results. * * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998. AC AC->T p DFS 86  1.2% 90  1% 0.0077 (= 22% Reduction of Relapses) OS 95  0.7% 97  0.6% 0.039 (= 26% Reduction of Mortality)

41. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node- Positive Breast Cancer (CALGB 9344): Results January 2003. * * L. Norton, tAnGo Trialists‘ Meeting January 2003 p Overall Survival0.01 Survival Receptor Positive Tumours0.4808 Survival Receptor Negative Tumors0.0034 Disease Free Survival (DFS)0.0018 DFS Receptor Positive Tumors0.2501 DFS Receptor Negative Tumors0.0006

42. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CALGB 9344: TOXICITY. * CALGB 9344: TOXICITY. * * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998. Diagnosis % Patients Transient Myelosuppression 21 Chemotherapy-associated Cardiotoxicity 6 Neuropathy 5 Pain 5 Hyperglycemia 5

43. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria The NSABP B-28 Trial: Paclitaxel for Adjuvant Treatment of Breast Cancer. Sequential AC T 3060 Node-Positive Patients Median Follow-Up: 34 Months NO SURVIVAL ADVANTAGE

44. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria The MD Anderson Trial on Paclitaxel for Adjuvant Treatment of Breast Cancer. Sequential P FAC 524 Patients Median Follow-Up: 43 Months NO SURVIVAL ADVANTAGE

45. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast Cancer: Interim Analysis of BCIRG 001 Study. * * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002 Median Observation: 33 Months TAC (745 Patients) Taxotere (75mg/m 2 ), Doxorubicin (50mg/m 2 ), Cyclophosphamide (500mg/m 2 ) FAC (746 Patients) Fluorouracil (500mg/m 2 ), Doxorubicin (50mg/m 2 ), Cyclophosphamide (500mg/m 2 ) q. 21 Days x6 ER-Positivity: Tamoxifen for 5 Years

46. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002 TAC vs. FACP-VALUE Disease Free Survival Adjusted for Nodal Status 0.680.0011 1-3 Nodes 0.500.0002 4+ Nodes 0.860.33 Overall Survival Adjusted for Nodal Status 0.760.11 1-3 Nodes 0.460.006 4+ Nodes 1.080.75 Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast Cancer: Interim Analysis of BCIRG 001 Study. *

47. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Phase III Trial Comparing TAC with FAC in the Treatment of Node-Positive Breast Cancer (BCIRG 001 STUDY): Toxicity. * * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002 TACFAC Febrile Neutropenia24%2% Neutropenia Grades 3/43%1% Septic Deaths00 Nausea / Vomitus Grades 3/4n.a.16% Asthzenia11%5% Stomatitis7%n.a. Cardiomyopathy1%0.1%

48. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria The NSABP B-27 Trial: Efficacy of Docetaxel in Adjuvant Treatment of Breast Cancer. Sequential AC D, Neoadjuvant 2411 T1-T3 Patients with Operable Breast Cancer Median Follow-Up: 39 Months TOO EARLY FOR DFS AND OS

49. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Role of Taxanes …. is unclear, yet …. side effects? …. possible benefit weighed against risks …. in clinical trials only Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

50. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria DOSE DENSITY Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

51. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 1 10 2 10 4 10 6 10 8 10 10 12 10765432 “Normal” Dose Intensity vs. Increased Dose Density

52. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Months Cell Number 1 10 2 10 4 10 6 10 8 10 10 12 10765432 3&6 Sequential Therapy is Dose Dense.

53. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Intergroup/CALGB 9741: Node-Positive Stage II-IIIA Doxorubicin (A) 60 mg/m 2 Paclitaxel (T) 175 mg/m 2 Cyclophosphamide (C) 600 mg/m 2 3-Week Cycles2-Week Cycles (w/ G-CSF)

54. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CALGB 9741: 3-YEAR RESULTS OF DOSE-DENSITY vs. CONVENTIONAL DOSE AND SEQUENTIAL vs. COMBINATION CHEMOTHERAPY, 2205 PATIENTS WITH N+ DISEASE. * * CITRON et al., SABCC 2002 TREATMENT TREATMENT DURATION q. 2 wks. + G-CSF q. 3 wks. SEQUENTIAL A-T-C x4, resp.24 wks. 36 wks. CONCURRENT AC T x4, resp. 16 wks. 24 wks. DISEASE-FREE SURVIVAL82% 75% p=0.007 OVERALL SURVIVAL92% 90% p=0.014

55. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria INCREASE IN DOSE DENSITY …. Exciting, but not for Routine Use Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

56. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CHEMOTHERAPY PLUS ENDOCRINE TREATMENT Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

57. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria REDUCTION OF RECURRENCE AND MORTALITY BY TAMOXIFEN AND CHEMOTHERAPY IN BREAST CANCER.* RECURRENCE MORTALITY 5 YEARS TAMOXIFEN vs. 0 -46  4 -22  5 5 YEARS TAMOXIFEN + CHEMOTHERAPY vs. CHEMOTHERAPY-52  8 -47  9 * EBCTCG, LANCET 351: 1451, 1998 % REDUCTION OF

58. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Sequence of Chemotherapy and Tamoxifen in Early Breast Cancer. INT 0100 TRIALGEICAM TRIAL (n=1116) (n=485) Median Follow-Up8 Years4.5 Years ChemotherapyCAF x6EC x4 Disease-Free Survival CTX T67%64% CTX + T62%57% p-Value0.03n.s. Toxicities No Difference Overall SurvivalNo Difference

59. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COMBINED CHEMOTHERAPY AND ENDOCRINE TREATMENT …. should be Administered Sequentially Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.

60. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Effectivity of Adjuvant Chemotherapy in Breast Cancer: Conclusion and Review of Conflicting Issues. 1. Polychemotherapy significantly reduces the annual risk of relapse and mortality both for N0- as well as N1- breast cancers. 2. Anthracycline-based regimens have been shown to have a significant advantage over non-anthracycline- regimens in premenopausal patients. 3. Use of taxanes continues to be controversial. 4. Dose density is becoming a decisive issue and deserves attention in future trials.

61. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Adjuvant Therapy in Breast Cancer: Final Conclusion. Recruit Patients into Clinical Trials!