1) Endocrine therapy targets the estrogen receptor and is effective in treating hormone receptor positive breast cancers. Tamoxifen has been the standard adjuvant treatment since the 1970s. 2) Guidelines recommend 5 years of tamoxifen therapy for postmenopausal patients and those with hormone receptor positive cancers. Longer durations do not provide additional benefits and may cause harms. 3) While tamoxifen is not effective for hormone receptor negative cancers, some low response may occur due to indirect effects. 20mg daily is the standard tamoxifen dose.

1. HORMONE THERAPY IN
BREAST CANCER
Dr. Kiran Kumar BR

2. Background
Henri Francois Le Dran (1685–1770) gave the hypothesis
that breast cancer spread was in a orderly fashion. The
concept was carried to it’s logical conclusion by Halsted.
The Halstedian theory was based upon:
Local and regional nodes were the first echelon of metastatic
Spread.
They were effective barriers against further spread.
The concept was challenged by the Fisher brothers (Edward
and Bernard), who showed in a series of trials conducted
by the NSABP that:
Lymph nodes were not effective as barriers against systemic
Spread.
Hematogenous dissemination was as important as lymphatic
Dissemination.
Systemic therapy is therefore believed to be effective in
this disease.

3. • History
Schinzinger was the first person to propose that
oophorectomy might be of benefit in breast
cancer:
Post menopausal breast atrophy
More virulent tumor growth in premenopausal
The first reported series of surgical oophorectomy
for breast cancer was reported by Thomas Beatson
(1896)
Showed significant tumor regression by castration
Better sense of well being
Regression of cutaneous metastasis
Best above age of 40
No effect on osseous metastatsis

9. Mechanism of action
All endocrine therapies target the estrogen
receptor at one level or other.
While the PR receptor doesn't act as a target
directly it does indicate a functional ER
pathway as it is a ER induced gene.

10. SERM
The SERMs are chemically diverse compounds that lack the steroid
structure of estrogens but possess a tertiary structure that allows them
to bind to the estrogen receptor.
Examples:
Tamoxifen
Raloxifen
Tormifen
Selective modulation explained by:
Differential estrogen-receptor expression in a given target tissue
Differential estrogen-receptor conformation on ligand binding
Differential expression and binding to the estrogen receptor of coregulator
proteins

11. Tamoxifen
• Chemically a triphenylethylene.
• The trans isomer is used as a citrate salt.
• MOA: Competitive binding to the estrogen receptor
resulting in reduction of transcription of estrogen
regulated genes.
• Dimethylaminoethoxy side chain and the trans
configuration are crucial for the antiestrogenic activity
of tamoxifen
• The net result is a block in the G1 phase of the cell cycle
and a slowing of cell proliferation.
• Tamoxifen is thus, a cytostatic drug.

12. Pharmacokinetics
• Long t1/2 : 7 -14 days.
• OD dose can be used
• Reduced bioavailability is not a cause for resistance.
• False negative receptor assays for several months
• after stopping Rx in tumor tissue.
• Metabolism in liver and excretion in feces
► Renal dysfunction not a contraindication.
• Metabolized by CYP 450 3A4 enzyme:
• Can reduce warfarin metabolism.
• Careful INR monitoring needed in patients receiving
• warfarin with tamoxifen.

13. Mechanisms of action
Binding and inactivation of estrogen receptor in
cancerous cell : Predominant mode of action
Other postulated mechanisms:
Initiation of apoptosis in malignant cells
Reduction of serum IGF-1 and increase in IGF-1
binding proteins are another potential mechanism of action.
Other actions:
Increased sex hormone binding globulin ( Reduced estrogen
bioavailability)
Increased TGF β (Increased pulm fibrosis / breast fibrosis if used
concurrently with RT)
Selective activation / inactivation of corepessors and coactivators
responsible for selective agonist / antagonist activity

14. Toremifene
Structure identical to that of tamoxifen, except for a
chorine atom
Less likely to form DNA adducts or induce liver tumors
in animals
Prospective randomized clinical trials demonstrate that
response rates, TTPs, OS, and toxicities of toremifene are
equivalent to those of tamoxifen
One reported adjuvant trial did not indicate that
toremifene is associated with a lower risk of endometrial
cancer
Toremifene displays crossresistance with tamoxifen and
should not be used in tamoxifen resistant disease

15. Aromatase Inhibitors
Include a class of drugs which prevent peripheral conversion of androgens
to estrogen.
Also cause selective impairment of gonadal steroidogenesis.
Thus are capable of selective estrogen deprivation without impairment of
adrenal androgen synthesis.
Two types exist:
Type I : Enzyme inactivators (Steroidal)
Type II : Competitive antagonists ( Non steroidal)
3 generations exist:
1st generation: Aminoglutethemide
2nd generation: Formestane (Type I) , Fadrazole
3rd generation: Exemestane (Type I) , Anastrazole ,
Letrozole, Vorozole

16. 3rd generation AI
These drugs inhibit the Aromatase enzyme selectively
by blocking the heme moiety of the enzyme.
Active sites of other steroidogenic enzymes remain
free.
3rd generation AIs are 3 times more potent than
aminoglutethemide.
Dose:
Letrozole (Femara) – 2.5 mg OD
Anastrazole (Arimidex) – 1 mg OD
Exemestane (Aromasin) – 25 mg OD

17. Special Properties
Anastrazole:
Less than 10% of the drug is cleared as unchanged
drug because of its extensive metabolism.
Letrozole:
Only 5% is excreted in the urine, letrozole can be
safely used in patients with renal insufficiency.
Used with caution when patients have severe liver
impairment.
Produces the greatest suppression of estrogen
synthesis
Exemestane:
Weakly androgenic metabolite (17-hydroexemestane)
that may ameliorate bone loss associated with
estrogen deprivation

18. Fulvestrant
Classified as a steroidal antiestrogen.
Considerably higher affinity for ER than tamoxifen
Promotes accelerated ER turnover,
Suppression of ER protein levels,
Inhibition of ER dimerization,
Reduced shuttling of the ER from the cytoplasm to the nucleus
Developed for clinical use as a 250-mg intramuscular monthly depot
injection
Developed to counter the estrogenic effects of Tamoxifen on uterus
and the bone related effects of AIs.

19. Ovarian Ablation/ Suppression
Ovarian ablation classically includes techniques that cause
permanent cessation of menstruation.
Techniques:
Surgical oophorectomy
Radiation induced oophorectomy
Ovarian suppression on the other hand refers to the suppression of
ovarian function through the use of LHRH analogues.
Uses:
Treatment of breast cancer:
Adjuvant setting
Metastatic cancer
Prevention of hereditary breast cancer syndromes

20. Radiation oophorectomy
First series reported by Foveau de Courmelles in 1922
Radiation oophorectomy:
Non invasive and cheap procedure.
Low dose carries little additional morbidity.
However takes time for effect to appear usually 2-3
months
For such reason best avoided when prompt relief is
needed.
Also best reserved for the patient with slow progression
of disease.

21. Technique
Position: Supine
Field selection: Parallel opposing two field technique
Energy : Co60 or 6 MV LINAC
Dose Schedules:
In a younger women 10 – 12 Gy in 5 -6 divided fractions is preferred.
In older women shorter course of radiation can give equivalent ovarian
ablation.
Field borders:
The volume of interest is the entire true pelvis
10 x 15 cm field is opened.
Lower border is placed just below the superior border
of pubic symphysis.

22. Results
Treves in 1957 showed that following ovarian
irradiation 10 yrs survival improved from
33.8% to 42.3%.
Benefit was greater in patients who had node
negative disease as compared to patients with
node positive disease.
Paterson and Russel (1959) also found that
survival improved from 54.9% to 62.6% after
addition of ovarian irradiation.

23. • Endocrine therapy in the adjuvant setting

24. Background
The gold standard of treatment in the adjuvant setup is tamoxifen.
Adjuvant Tamoxifen has been used for treating breast cancer since
1970s
Some authors have attributed the 25% reduction in breast cancer
mortality in western countries over the past decade to tamoxifen use.
Issues that need to be answered are:
Optimal duration and dose
Patient selection criteria
Combination with chemotherapy
Risks of tamoxifen therapy
Additional benefits of tamoxifen therapy
Place of the newer agents like AIs

25. Guidelines
5 yrs of tamoxifen is the standard therapy in all hormone
receptor +ve patients.
5 yrs of tamoxifen therapy is also standard in post
menopausal females.
In females with unknown receptor status tamoxifen is
usually added specially if patient is post menopausal.
Adjuvant endocrine Rx is of little benefit in ER -ve females.
Except selected stage I patients without significant risk
factors all most all can be considered for adjuvant hormone
therapy.
Present evidence doesn't support 1st line use of AI in
adjuvant setting.
However it can be used after 3 -5 yrs of Tmx therapy after
careful consideration of the cost benefit ratio.

30. Longer Tamoxifen Rx
3 trials including one large NSABP trial have compared 5yrs
of Tamoxifen treatment with longer treatment:
There is no convincing evidence that treatment lasting longer than 5
years is beneficial.
In two of these trials there was a trend, (statistically significant in
one), toward a detrimental effect with treatment for more than 5
years
Problems evaluating longer tamoxifen therapy:
Significant carryover effect of tamoxifen beyond 5 yrs.
A 1% increase in risk of endometrial cancer expected is
Counter balanced by 1% decrease in risk of contralateral breast
cancer.
Trials evaluating these question now:
ATLAS trial (Adjuvant Tamoxifen—Longer Against Shorter)
aTTom trial (Adjuvant Tamoxifen Treatment Offer More?)

31. Dose of tamoxifen
• 20 mg once daily dose of tamoxifen is the
standard dose.
• Higher doses are not more effective
• Also lead to greater incidence of side effects.

32. Tamoxifen & ER status
ER receptor –ve tumors in tissue cultures are non
responsive to tamoxifen therapy.
However problems interpreting the results of tamoxifen therapy in ER –
ve tumors are:
Variable assay quality and reference values
Variable assay sensitivity
Possible paracrine loop action of tamoxifen (Few ER +ve tumors affecting
surrounding ER –ve tumors)
Systemic effects of Tamoxifen (e.g. IGF -1 concentrations)
The low response rates observed with tamoxifen in ER -ve metastatic
disease (5% to 10%) argue that these ancillary effects of tamoxifen are
clinically unimportant

96. Thank You