1. Principles of Hormonal Therapy Justus Apffelstaedt University of Stellenbosch These Power Point presentations are free to download only for academic purposes, with due acknowledgements to authors and this website.

2. Prof. J. ApffelstaedtThe MammaClinic History Beatson 1896: Palliation by oophorectomy 1950’s: DES 1961: Estrogen receptor 1970’s: Tamoxifen 1980’s: SERMS 1990: Selective Aromatase Inhibitors

3. Prof. J. ApffelstaedtThe MammaClinic Principles of Hormonal Therapy Estrogen Deprivation: –Ovarian manipulation Radiation Oophorectomy LHRH agonists –Aromatase inhibitors Receptor Approaches –Competitive inhibition –Non-competivitive inhibition

4. Prof. J. ApffelstaedtThe MammaClinic Ovarian Manipulation Metastatic Response rate: 30% unselected HR+ disease: –60% ER+, PR+ –30% either positive Vs Tamoxifen: ? Combination with Tamoxifen: –Probably better N.b.: Chemotherapy effect –43% ovarian failure

5. Prof. J. ApffelstaedtThe MammaClinic Ovarian Manipulation Adjuvant 25% risk of recurrence reduction (EBTCG); Absolut 6% mortality reduction –Note: HR unknown In combination with Tamoxifen?

6. Prof. J. ApffelstaedtThe MammaClinic Tamoxifen Principle: –Reversible inhibition of singnal transduction at HR receptor Metastatic –Response rate: 30 - 45% –Response duration: 6 – 18 months

7. Prof. J. ApffelstaedtThe MammaClinic Tamoxifen Adjuvant

8. Prof. J. ApffelstaedtThe MammaClinic Tamoxifen Prevention 30 – 49% reduction in breast cancer rate Questions: –98.2 % no benefit –Economics?

9. Prof. J. ApffelstaedtThe MammaClinic Aromatase inhibitors Principle: Inhibition of peripheral aromatization Side effect profile: –Antiestrogenic effects –Musculoskeletal pains –BMD loss Metastatic setting: –Response rate: 30% –Response duration: 40 – 50 weeks

10. Prof. J. ApffelstaedtThe MammaClinic Disease-free survival (HR+) At risk: A261825402448235522682014830 T259825162398230421891932774 Follow-up time (years) 0 5 10 15 20 25 0123456 Absolute difference:1.6%2.6%2.5%3.3% Patients (%) Anastrozole (A) Tamoxifen (T) HR 0.83 0.87 HR+ ITT 95% CI (0.73–0.94) (0.78–0.97) p-value 0.005 0.01 A 424 575 T 497 651

11. Prof. J. ApffelstaedtThe MammaClinic

12. Prof. J. ApffelstaedtThe MammaClinic Additional effect of Anastrozole on recurrences at 5 years 38% risk of recurrence with no adjuvant treatment 1 50% risk reduction with tamoxifen 1 Further 26% risk reduction with anastrozole 2 1. EBCTCG. Lancet 1998; 351: 1451-1467 2. ATAC Trialists’ Group. Lancet 2005; 365: 60-62

13. Prof. J. ApffelstaedtThe MammaClinic T 40.9 10.2 13.2 0.8 2.8 4.5 2.4 29.4 7.7 A 35.7 5.4 3.5 0.2 2.0 2.8 1.6 35.6 11.0 Completion analysis p-value <0.0001 0.02 0.03 0.0004 0.02 <0.0001 Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures ATAC Adverse events ATAC Trialists’ Group. Lancet 2005; 365: 60-62

14. Prof. J. ApffelstaedtThe MammaClinic Change in lumbar spine BMD over time Change from baseline lumbar spine BMD in % 4 Patient no: Anastrozole 7158 Tamoxifen 6964 Combination 6451 1 year 2 year 3 2 1 0 -2 -3 -4 -5 -6 p<0.0001 Control 3932

15. Prof. J. ApffelstaedtThe MammaClinic Other Hormonal Therapies Fulvestrant Androgens Progestagens

16. Prof. J. ApffelstaedtThe MammaClinic Current Issues in Hormonal Therapy Sequencing: –Metastatic setting: Sequencing: AI -> Tam -> Fulvestrant? –Adjuvant setting: Duration of treatment: –How long AI’s after tamoxifen? How long ovarian suppression? Combination therapies: –Ovarian ablation with AI’s? –Chemotherapy with AI’s? –AI and tamoxifen? Receptor issues: –ER+, PR- disease –Reactivation of receptor negative disease –Interaction with biologicals?

17. Principles of Hormonal Therapy Justus Apffelstaedt University of Stellenbosch