Principles of Hormonal Therapy

Justus Apffelstaedt University of Stellenbosch

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History

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

Principles of Hormonal Therapy

Estrogen Deprivation:

– –

Ovarian manipulation

• Radiation • Oophorectomy • LHRH agonists

Aromatase inhibitors Receptor Approaches

–

Competitive inhibition

–

Non-competivitive inhibition Prof. J. Apffelstaedt The 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 Prof. J. Apffelstaedt The MammaClinic

Ovarian Manipulation Adjuvant

25% risk of recurrence reduction (EBTCG); Absolut 6% mortality reduction

–

Note: HR unknown In combination with Tamoxifen? Prof. J. Apffelstaedt The MammaClinic

Tamoxifen

Principle:

–

Reversible inhibition of singnal transduction at HR receptor Metastatic

–

Response rate: 30 - 45%

–

Response duration: 6 – 18 months Prof. J. Apffelstaedt The MammaClinic

Tamoxifen Adjuvant

Prof. J. Apffelstaedt The MammaClinic

Tamoxifen Prevention

30 – 49% reduction in breast cancer rate Questions:

–

98.2 % no benefit

–

Economics?

Prof. J. Apffelstaedt The 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 Prof. J. Apffelstaedt The MammaClinic

Disease-free survival (HR+)

Patients (%) 25 20 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

15 Anastrozole (A) Tamoxifen (T) 10 5 0 0 At risk: A T 2618 2598 Prof. J. Apffelstaedt Absolute difference: 1.6% 1 2540 2516 2 2448 2398 3 Follow-up time (years) 2355 2304 2.6% 4 2268 2189 2.5% 5 3.3% 6 2014 1932 830 774 The MammaClinic

Prof. J. Apffelstaedt The 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 Prof. J. Apffelstaedt 1. EBCTCG. Lancet 1998; 351: 1451-1467 2. ATAC Trialists’ Group. Lancet 2005; 365: 60-62 The MammaClinic

ATAC Adverse events

Completion analysis p-value Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures 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

<0.0001

<0.0001

<0.0001

0.02

0.03

0.0004

0.02

< 0.0001

<0.0001

Prof. J. Apffelstaedt

Change in lumbar spine BMD over time

Change from baseline lumbar spine BMD in % Patient no: 1 -1 0 4 3 2 -2 -3 -4 -5 -6 p<0.0001

p<0.0001

Anastrozole 71 58 Tamoxifen 69 64 Combination 64 51 1 year 2 year Control 39 32 Prof. J. Apffelstaedt The MammaClinic

Other Hormonal Therapies

Fulvestrant Androgens Progestagens Prof. J. Apffelstaedt The 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? Prof. J. Apffelstaedt The MammaClinic

Principles of Hormonal Therapy

Justus Apffelstaedt University of Stellenbosch