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Principles of Hormonal Therapy

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. History. Beatson 1896: Palliation by oophorectomy 1950’s: DES

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Principles of Hormonal Therapy

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

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

  4. 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 The MammaClinic

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

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

  7. Tamoxifen Adjuvant The MammaClinic

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

  9. 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 The MammaClinic

  10. Disease-free survival (HR+) HR+ ITT A 424 575 T 497 651 HR 0.83 0.87 95% CI (0.73–0.94) (0.78–0.97) p-value 0.005 0.01 25 Patients (%) 20 15 Anastrozole (A) 10 Tamoxifen (T) 5 Absolute difference: 1.6% 2.6% 2.5% 3.3% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 The MammaClinic

  11. The MammaClinic

  12. Additional effect of Anastrozole on recurrences at 5 years 38% risk of recurrence with no adjuvant treatment1 50% risk reduction with tamoxifen1 Further 26% risk reduction with anastrozole2 1. EBCTCG. Lancet 1998; 351: 1451-1467 2. ATAC Trialists’ Group. Lancet 2005; 365: 60-62 The MammaClinic

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

  14. Change in lumbar spine BMD over time p<0.0001 Change from baseline lumbar spine BMD in % 4 p<0.0001 3 2 1 0 -1 -2 -3 1 year 2 year -4 -5 -6 Anastrozole Tamoxifen Combination Control Patient no: 71 58 69 64 64 51 39 32 The MammaClinic

  15. Other Hormonal Therapies • Fulvestrant • Androgens • Progestagens The MammaClinic

  16. 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? The MammaClinic

  17. Principles of Hormonal Therapy Justus Apffelstaedt University of Stellenbosch

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