HORMONAL THERAPY

IN BREAST CANCER
 BACKGROUND
EPIDEMIOLOGY

- Breast cancer is by far the most frequent

cancer among women with an estimated :
1.6 million new cases diagnosed with more than
500,000 deaths each year in the world1

- estimate 48,000 new cases diagnosed each

year in Indonesia, with incidence rate 40 per
100,000 women

Ref :
1. Globocan 2012
 ESTROGEN
- Estrogen are essential for the normal growth and proliferation of target cells,
such as breast epithelial cells, also stimulate growth of breast carcinoma.
- Their normal physiological effects by binding to specific nuclear proteins,
known as oestrogen receptors (ERs).
- Around two-thirds post menopausal patients diagnosed to have breast cancer
are Estrogen-Receptor positive, and around one-half of tumours found in
premenopausal women are oestrogen-sensitive.

Ref :
Annals of Oncology 14: 1017–1025, 2003
 ESTROGEN Estrogen Production in Premenopausal
PRODUCTION and Postmenopausal Patients
Hypothalamus

Premenopausal Pre / Postmenopausal

ovary is the main site of
oestrogen production at
Gonadotropins Adrenocorticotropic
premenopausal,
(FSH + LH) hormone (ACTH)
Pituitary gland
whereas in post-menopausal
women the adrenal glands
and peripheral tissues are the Ovary
Prolactin
Adrenal gland
main sources.1 Growth Hormone

Corticosteroids
Estrogens Progesterone
Progesterone Androgens
Estrogens

Ref :
1. NCCN Guidelines Version 1.2015
100 years in the development of endocrine therapy
Date of the first publication Type of therapy Principal author
1896 Oophorectomy Beatson
1922 Ovarian irradiation Courmelles
1939 Androgens Ulrich
1944 Synthetic oestrogens Haddow
1951 Progestins Esher
1952 Pituitary irradiation Douglas
1953 Adrenalectomy Huggins
1953 Hypophysectomy Luft
1971 Antioestrogens Cole
1973 Aromatase inhibitors Griffiths
1982 LHRH agonists Klijn
1987 Antiprogestins Romieu
1993 ‘Pure’ antioestrogens Howell

Reference: Howell, A. et al. Reviews on Endocrine-related Cancer. 1993; 43: 5-21

GUIDELINE
ENDOCRINE
THERAPY

Ref :
1. NCCN Guidelines Version 1.2015
Subsequent endocrine therapy for systemic disease

Ref :
1. NCCN Guidelines Version 1.2015
HORMONAL THERAPY
1. Ovarian ablation
For premenopausal breast cancer : ovary is the main site of oestrogen production at
premenopausal
Ovarian Ablation :
 Surgical oophorectomy : immediate and permanent drop in ovarian estrogen production
 Ovarian Irradiation : incomplete or reversible in some women
 Medical ovarian ablation : LHRHa (Goserelin and Leuprolide)  The possible advantages of
LHRH analogues are their ease of administration and reversible effects
 Cytotoxic chemotherapy : less than 50% of women under 40 years of age will be rendered
postmenopausal by standard adjuvant chemotherapy regimens,
whereas the majority of women aged 40 or more years of age will
become permanently menopausal
 Effect of ovarian ablation
for women < 50 years of age

Ovarian ablation significantly

increasing 15 years disease
free survival and 15 years
survival
 Ovarian functional suppression/ablation
significantly reduces recurrence rate and breast cancer death rate

Reference :
Adapted from EBCTG. Lancet. 2005. 365 : 1687-
Effect of LHRHa on LH and estradiol Levels

35 300

30

Oestradiol (pg/ml)
250
25
LH (mU/ml)

200
20
150
15 (n=7)
100
10
(n=7)
5 50

0 0
0 1 2 3 4 5 6 7 8 12 16 20 0 1 2 3 4 5 6 7 8 12 16 20

Time (weeks) Time (weeks)

1 2 3 4 5 6 1 2 3 4 5 6
‘Zoladex’ 3.6mg depot ‘Zoladex’ 3.6mg depot

LH = Luteinising hormone West CP, et al. Clin Endocrinol 1987; 26: 213–20.
LHRHa added to standard adjuvant therapy offers
survival advantage
 Evidence of ZOLADEX® in Early Breast Cancer

1.Castiglione-Gertsch M, et al. J Natl Cancer Inst 2003; 95: 1833–46. 4.Jakesz R, et al. J Clin Oncol 2002; 20: 4621–7.
2.Kaufmann M, et al. Eur J Cancer 2003; 39: 1711–1717. 5.Baum M, et al. Euro J Cancer 2006; 42: 895-904.
3.Davidson NE, et al. J Clin Oncol 2005; 23: 5973–82.
6.Baum M. Breast Cancer Res Treat 1999; 57: 30, Abstr 24.
7.Cuzick et al. Lancet 2007; 369: 1711–23.
2. Selective ER modulator (SERM) : Tamoxifen
In Pre menopausal and Post menopausal BC ER/PR +

Mechanism of Estrogen Mechanism of Tamoxifen

TAMOXIFEN

E T
E T
MEMBRANE MEMBRANE

E T
OESTROGEN OESTROGEN
E T
E E E E
E E
E T
RECEPTORS RECEPTORS
R R
E T
R R
NUCLEUS NUCLEUS
CYTOPLASM CYTOPLASM
3. Aromatase Inhibitor
For Postmenopausal BC ER/PR +

First-generation Second-generation Third-generation

Fadrozole Anastrozole
aminoglutethimide
Formestane Letrozole
Exemestane
Aromatase Inhibitor inhibit the production oestrogen in
peripheral tissue
The peripheral aromatase system is the main source of circulating oestrogenic steroids in
post-menopausal women.

Sites of peripheral aromatisation

Breast Fat Liver

tumour Muscle
Aromatase inhibition within the breast
tumour cell
P-450 Aromatase
tumour
+ NADPH-cytochrome P-450 reductase
growth
ANDROGENS OESTROGENS
(Testosterone, (Oestradiol, oestrone)
androstenedione,
16-OH-testosterone)

Aromatase Inhibitors
 Anastrozole Letrozole Exemestane
Drug classification1 Non steroid Non streoid Steroid

Indicated as upfront Yes Yes No

adjuvant therapy in breast
cancer with HR +ve2

Time to achieve steady- 7 days 60 days 7 days

state in plasma1

Androgenic properties1 No No Yes

Lipid profiles1 No change Increased total Decreased total

cholesterol, LDL and cholesterol, HDL, apoA1
apoB and TGA

Ref :
1.Buzdar A. et al. Cancer 2002:95:2006-2016 2. MIMS Indonesia January 2015
ARIMIDEX® upfront significantly lowers time to recurrence and time to distant recurrence
vs tamoxifen in HR+ breast cancer patient
Give the best and the right treatment
for our patient