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Adjuvant Treatment in Breast Cancer

Adjuvant Treatment in Breast Cancer. Variables for Prognosis of Early Breast Cancer and for Adjuvant Treatment. Axillary Lymph Node Status Estrogen Receptor 3. Her-2/neu Status 4. Treatment. Treatment Modalities for Breast Cancer.

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Adjuvant Treatment in Breast Cancer

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  1. Adjuvant Treatment in Breast Cancer

  2. Variables for Prognosisof Early Breast Cancer and for Adjuvant Treatment • Axillary Lymph Node Status • Estrogen Receptor • 3. Her-2/neu Status • 4. Treatment

  3. Treatment Modalities for Breast Cancer * Neoadjuvant Treatment* Adjuvant Treatment* Palliative Treatment

  4. Variables for Decision of Adjuvant Therapy Node-Negative / -Positive ER-Positive / -Negative Adjuvant Therapy HER-2 as Predictive Marker

  5. Adjuvant Therapy of Early Breast Cancer A. Endocrine Interventions Ovarian Ablation Tamoxifen Aromatase Inhibitors B. Polychemotherapy

  6. 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. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. A. ENDOCRINE TREATMENT1. Role of hormone withdrawal in premenopausal patients. 2. Role of third generation aromatase inhibitors in postmenopausal patients.

  8. 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. Reduction of Relapses and Mortality from Early Breast Cancer by 20 mg Tamoxifen for 5 Years. * Reduction of Relapse Mortality 2p 42  3% 22  4% <.00001/.00001 * EBCTCG, LANCET 351: 1451, 1998

  10. Estrogen Withdrawal Modalities • Premenopausal Patients • LH-RH Agonists • + Tamoxifen • (+ Aromatase Inhibitors?) • 2. Postmenopausal Patients • Aromatase Inhibitors

  11. 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. Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I and II EBC: The ABCSG Trial. * TreatmentRelapsesLocal RecurrencesRFS at 5 yrs. Endocrine 17.2% 4.7% 81% Cytotoxic 20.8% 8.0% 76% p 0.0176 0.0029 0.037 * R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002

  13. 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. 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. Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II EBC: The ZEBRA Trial. * Primary Efficacy of Goserelin vs. CMF DFSOS ER-positive p=0.94 (equal efficacy) p=0.92 (equal efficacy) ER-negative p=0.0006 in favor of CMF p=0043 in favor of CMF ER-unknown p=0.026 in favor of CMF p=0.14 * W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002

  16. 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. 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. 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 Recurrence 0.007 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. Side Effects of Anastrozole vs. Tamoxifen in the ATAC Trial*. Hot Flushes p<0.0001 in favor of Anastrozole Vaginal Bleeding and Discharge p<0.0001 in favor of Anastrozole Thromboembolic Events p=0.0006 in favor of Anastrozole Ischemic Cerebrovascular Event p=0.0006 in favor of Anastrozole Endometrial Cancer p=0.02 in favor of Anastrozole Osteoporotic Bone Fractures p<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. Endocrine Adjuvant Treatment of Early Breast Cancer in Premenopausal Patients. Nodal StatusER+ER- N0 Goserelin +/- Tamoxifen Chemotherapy N1 Chemotherapy Tamoxifen Chemotherapy (Goserelin + Tamoxifen)

  21. Endocrine Adjuvant Treatment of Early Breast Cancer in Postmenopausal Patients. Nodal StatusER+ER- N0 Tamoxifen Chemotherapy (Aromatase Inhibitor) N1 Tamoxifen Chemotherapy +/- Chemotherapy (Aromatase Inhibitor)

  22. Adjuvant Chemotherapy in Early Breast Cancer. * REDUCTION OF ANNUAL RISK OF RELAPSE AND DEATH BY CHEMOTHERAPY RELAPSE -23.5  2.1% <.00001 DEATH -15.3  2.4% <.00001 * EBCTCG, LANCET 352: 930, 1998.

  23. Early Breast Cancer Trialists Collaborative Group: Effect of Adjuvant Anthracycline-Based Chemotherapy: Reduction of Annual Hazards. * % of Reduction 2pAnthracycline-Based Chemotherapy vs. CMFRecurrences 12  4 <.006 Mortality 11  5 <.02 * EBCTCG, Lancet 352: 930, 1998.

  24. 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. Anthracyclines in Adjuvant Therapy for Early Breast Cancer. 5 Years 10 Years Additional Absolute Gain 1.7% 4% in OS with Anthracycline in N- Pats. in N+ Pats. -Based Chemotherapy NIH 2000 Consensus Conference

  26. Simulation of Impact of Adjuvant Chemotherapy in EBC. 100 Annual Odds of Recurrence: Nil= 15% / Yr. CMF= 11.4% / Yr. (Reduced by 24%) AC= 10% / Yr. (Reduced by 12%) 80 60 % Free of Recurrence 40 AC CMF 20 Nil 0 0 2 4 6 8 10 Years

  27. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. B. CHEMOTHERAPY1. Role of Anthracyclines. 2. Role of Taxanes. 3. Dose density. 4. Combination with Endocrine Treatment.

  28. Anthracyclines in the Adjuvant Therapy of Patients with Breast Cancer: Unresolved Questions 2003. 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?

  29. Review of Anthracyclines in the Adjuvant Chemotherapy of Breast Cancer: The Dilemma. AuthorsCytotoxicsResultsFisher 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 & OSBudd et al. 1995 CMFVP vs. FAC-M Sign. DFS for CMFVPMisset et al. 1996 CMF vs. AVCF Sign. OS & DFS PremenopauseCoombes et al. 1996 CMF vs. FEC Sign. OS & DFS PremenopauseLevine et al. 1998 CMF vs. CEF Sig. OS & DFS PremenopauseMouridsen et al. 1999 CMF vs. CEF Sign. OS PremenopausePiccart et al. 2001 CMF vs. EC No Advantage of EC vs. CMF Reconfirmation of Dose Response

  30. 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 PatientsMisset et al. 1996 Piccart et al. 2001 (41-44% Postmenopausal Patients Included)

  31. Adjuvant Chemotherapy of Primary Breast Cancer: Some general remarks... • Adriamycin Doses < 40mg/m2 are Inferior to 60 mg/m2 (CALGB 8541). • Cyclophosphamide Doses > 600 mg/m2 are not Superior (NSABP B-22). • Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG).

  32. Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Dose Recommendations. DRUGPUBLICATIONRECOMMENDATIONAdriamycinCALGB 9344 60mg/m2q. 3 wks. in the AC RegimenEpirubicin French Trial 100mg/m2q. 3 wks. in the EC and Belgian Trial FEC regimens for high risk (N+) women

  33. Efficacy of Anthracycline-Based Adjuvant Chemotherapy in Her-2/neu Overexpressing Early Breast Cancer. STUDYAUTHORRESULTS IN HER-2/neuPOSITIVENEGATIVENSABP-B11 PAIK et al. 1998 DFS & OS SIGN. n.s.(PF vs. PAF) (Advantage Anthracycline)NSABP-B15 PAIK et al. 2000 DFS & OS BORDERLINE n. s.(AC vs. CMF vs. AC->CMF) (Advantage Anthracycline)

  34. Proposed Algorithm for Anthracycline Use as Adjuvant Therapy in Patients with Breast Cancer. ENDOCRINE RESPONSIVEENDOCRINE-NON-RESPONSIVELikelihood of ResponseRisk Profile Low High Average High FE(A)C d1 x6 AC x4 FE(A)C d1 x6CE(A)F d1+8 x6 CE(A)F d1+8 x6 ? Her-2/neu +++

  35. Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Conclusions. 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.

  36. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Role of TaxanesAvailable Studies: CALGB 9344 NSABP-B27 NSABP-B28 BCIRG 001 M.D. ANDERSON

  37. Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Lymphnode-Positive Breast Cancer (CALGB 9344): RATIONALE. * 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. * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

  38. 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. Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Positive Breast Cancer (CALGB 9344) THERAPY Doxorubicin 60, 75 or 90mg/m2 + Cyclophosphamide (AC) x 4, then randomised to nil vs. sequential Paclitaxel (175mg/m2) x 4 (+/- Tamoxifen 20mg, 5 Years) PATIENTS3.170 Patients Randomised according to 3x2 factorial trial design Positive axillary lymph nodes (1 - >10 Lnn.), First Kaplan-Meier Analysis after 18 months * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

  40. Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Positive Breast Cancer (CALGB 9344): First Results. * AC AC->Tp DFS86  1.2% 90  1% 0.0077 (= 22% Reduction of Relapses) OS95  0.7% 97  0.6% 0.039 (= 26% Reduction of Mortality) * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

  41. Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Positive Breast Cancer (CALGB 9344): Results January 2003. * p Overall Survival 0.01 Survival Receptor Positive Tumours 0.4808 Survival Receptor Negative Tumors 0.0034 Disease Free Survival (DFS) 0.0018 DFS Receptor Positive Tumors 0.2501 DFS Receptor Negative Tumors 0.0006 * L. Norton, tAnGo Trialists‘ Meeting January 2003

  42. CALGB 9344: TOXICITY. * Diagnosis% Patients Transient Myelosuppression 21 Chemotherapy-associated Cardiotoxicity 6 Neuropathy 5Pain 5 Hyperglycemia 5 * I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.

  43. 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. 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. Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast Cancer: Interim Analysis of BCIRG 001 Study. * Median Observation: 33 Months TAC (745 Patients) Taxotere (75mg/m2), Doxorubicin (50mg/m2), Cyclophosphamide (500mg/m2) FAC (746 Patients) Fluorouracil (500mg/m2), Doxorubicin (50mg/m2), Cyclophosphamide (500mg/m2) q. 21 Days x6 ER-Positivity: Tamoxifen for 5 Years * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002

  46. Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast Cancer: Interim Analysis of BCIRG 001 Study. * TAC vs. FACP-VALUE Disease Free Survival Adjusted for Nodal Status 0.68 0.0011 1-3 Nodes 0.50 0.0002 4+ Nodes 0.86 0.33 Overall Survival Adjusted for Nodal Status 0.76 0.11 1-3 Nodes 0.46 0.006 4+ Nodes 1.08 0.75 * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002

  47. Phase III Trial Comparing TAC with FAC in the Treatment of Node-Positive Breast Cancer (BCIRG 001 STUDY): Toxicity. * TAC FAC Febrile Neutropenia 24% 2% Neutropenia Grades 3/4 3% 1% Septic Deaths 0 0 Nausea / Vomitus Grades 3/4 n.a. 16% Asthzenia 11% 5% Stomatitis 7% n.a. Cardiomyopathy 1% 0.1% * J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002

  48. 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. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. Role of Taxanes…. is unclear, yet …. side effects? …. possible benefit weighed against risks …. in clinical trials only

  50. Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003. DOSE DENSITY

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