Principles of Hormonal Therapy

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Principles of Hormonal Therapy

• Justus Apffelstaedt
• University of Stellenbosch

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History

• Beatson 1896 Palliation by oophorectomy
• 1950s DES
• 1961 Estrogen receptor
• 1970s Tamoxifen
• 1980s SERMS
• 1990 Selective Aromatase Inhibitors

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Principles of Hormonal Therapy

• Estrogen Deprivation
• Ovarian manipulation
• Radiation
• Oophorectomy
• LHRH agonists
• Aromatase inhibitors
• Receptor Approaches
• Competitive inhibition
• Non-competivitive inhibition

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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

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Ovarian Manipulation Adjuvant

• 25 risk of recurrence reduction (EBTCG)
• Absolut 6 mortality reduction
• Note HR unknown
• In combination with Tamoxifen?

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Tamoxifen

• Principle
• Reversible inhibition of singnal transduction at
  HR receptor
• Metastatic
• Response rate 30 - 45
• Response duration 6 18 months

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Tamoxifen Adjuvant
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Tamoxifen Prevention

• 30 49 reduction in breast cancer rate
• Questions
• 98.2 no benefit
• Economics?

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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

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Disease-free survival (HR)
HR 0.83 0.87
HR ITT
95 CI (0.730.94) (0.780.97)
p-value 0.005 0.01
A 424 575
T 497 651
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
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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
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ATAC Adverse events
Completion analysis
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
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
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Change in lumbar spine BMD over time
plt0.0001
Change from baseline lumbar spine BMD in
4
plt0.0001
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
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Other Hormonal Therapies

• Fulvestrant
• Androgens
• Progestagens

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Current Issues in Hormonal Therapy

• Sequencing
• Metastatic setting
• Sequencing AI -gt Tam -gt Fulvestrant?
• Adjuvant setting
• Duration of treatment
• How long AIs after tamoxifen? How long ovarian
  suppression?
• Combination therapies
• Ovarian ablation with AIs?
• Chemotherapy with AIs?
• AI and tamoxifen?
• Receptor issues
• ER, PR- disease
• Reactivation of receptor negative disease
• Interaction with biologicals?

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Principles of Hormonal Therapy

• Justus Apffelstaedt
• University of Stellenbosch