1. Hormone therapy is an important treatment for hormone receptor positive breast cancers, working by reducing estrogen levels or blocking estrogen receptors. 2. The document discusses various hormone therapy options for early and locally advanced breast cancer including surgical ovarian suppression, radiation ovarian suppression, medications like aromatase inhibitors, LHRH analogues, SERMs, and more. 3. Evidence shows that hormone therapy reduces the risk of recurrence and death from breast cancer in both premenopausal and postmenopausal women with hormone receptor positive early breast cancer.

1. HORMONE THERAPY IN
EARLY AND LOCALLY
ADVANCED BREAST
CANCER
DR. ASHUTOSH MUKHERJI
ASSISTANT PROFESSOR, RADIOTHERAPY
REGIONAL CANCER CENTRE, JIPMER

2. INTRODUCTION

3. • Endocrine manipulation in breast cancer 1st
introduced by BEATSON in
1896 → Demonstrated objective regression of breast cancer after
oophorectomy.
[Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma:
Suggestions for a new method of treatment with illustrative cases. Lancet 2:104-107,
1896.]
• Hormone therapies now used :
 For palliative treatment of metastatic or very elderly hormone sensitive
breast cancer patients.
 Adjuvant therapy in hormone sensitive early breast cancer cases.
• Goal of hormone therapy is either to reduce synthesis of estrogen or
blocking estrogen receptors in hormone dependent tumours.

4. RATIONALE FOR ENDOCRINE
THERAPY

5.  All estrogens produced by action of AROMATASE enzyme.
 Aromatase present in high concentration in granulosa cells of ovaries
of pre-menopausal women; and produces 90% of plasma estrogens.
 In post-menopausal women who are devoid of ovarian aromatase
production, (only 10% of pre-menopausal levels), stromal and
epithelial cells of breast cancers contain measurable amount of
aromatase.
 Virtually all breast cancers that respond to hormonal therapy express
significant levels of ESTROGEN RECEPTOR ALPHA (ER) which
increases with age (upto 80% ER positive above 65 yrs age).

7.  Unconjugated estrogen crosses the cell membrane and binds to the
ER, leading to various changes like dissociation from heat shock
protein, homodimerization, phosphorylation and conformational
change in activating factor (AF-2) domain.
 This leads to production of mRNA and DNA sequences to with
subsequent trancriptional and translational changes.
 This leads to formation of specific protein sequences which bring
about various actions.

8. ACTIVATION OF HORMONE RECEPTOR

9. MECHANISM OF HORMONE ACTION

10.  Thus in breast cancers in post menopausal women, the small
amount of estrogen produced by the breast tissue is still sufficient to
promote tumour growth.
 Hormonal therapy thus aims either in preventing the formation of
hormones by blocking of the action of aromatase or to prevent
upregulation of receptors by blocking the formation/release of
regulatory hormones.
 According to EBCTCG-1996; adjuvant ovarian ablation resulted in
18% reduction in risk of death in women less than 50 years age with
early breast cancer.

11. SITE OF ACTION OF HORMONAL DRUGS

12. TYPES OF HORMONAL
INTERVENTIONS

13. HORMONAL THERAPY
SURGICAL
RADIOTHERAPY
MEDICAL
SELECTIVE
AROMATASE
INHIBITORS
NON SELECTIVE
AROMATASE
INHIBITORS
LHRH ANALOGUES
SERMs/SERDs

14. SURGICAL OVARIAN FUNCTION SUPPRESSION
 First report of surgical oophorectomy for the treatment of advanced breast
cancer published by Dr. George Beatson in 1896 who saw a young
lactating woman with advanced breast cancer and had tumor regression
after removing both her ovaries.
 Oophorectomy reliably and promptly reduces circulating estrogens to
postmenopausal levels in nearly 100% of women, and has the advantage
of simultaneously reducing ovarian cancer risk. It is also the most cost-
effective method of ovarian ablation.
 But oophorectomy may require hospitalization and carries potential
operative and anesthesia-related morbidity and mortality. It also
irreversibly induces premature menopause with sequelae including
osteoporosis, an increased risk of coronary artery disease and permanent
loss of fertility.

15. OVARIAN FUNCTION SUPPRESSION BY RADIATION
 Ovarian ablation by radiation therapy has been used for over 50
years. The obvious advantage over oophorectomy is to avoid
invasive surgery; however, radiation therapy may be less
efficacious than surgery in permanently ablating ovarian function.
 Ultrasound guidance to ascertain correct ovarian position for
simulation has been utilized to improve the results of radiation
ablation.
 Doses range from a single 450 cGy fraction up to 1,000-2,000
cGy divided in five or six fractions.

16. TYPES OF DRUGS FOR
MEDICAL OVARIAN
SUPPRESSION
LHRH ANALOGUES
NON SELECTIVE
AROMATASE
INHIBITORS
ESTROGEN
RECEPTOR
DOWNREGULATORS
SELECTIVE
AROMATASE
INHIBITORS
Example:
Gosserelin,
Example:
Anastrozole,
Letrozole,
Exemustane,
Fadrozole
Example:
Aminoglutethimide,
Formestane
Example:
Tamoxifen, Toremifen
Fulvestrant,
Arzoxifene HCl

17. HORMONE RECEPTOR STATUS AND
PROBABILITY OF RESPONSE TO THERAPY
Estrogen Receptor
Status
Progesterone Receptor
Status
Response Probability
Positive Positive High (50-70%)
Positive Negative Intermediate (33%)
Negative Positive Intermediate (33%)
Negative Negative Low (Less than 10%)

18. ANTIESTROGENS
TAMOXIFEN
 Has been the standard of care in endocrine therapy for the last 35-40
years.
 Is recommended as 1st
line therapy for metastatic breast cancer in pre-
and post-menopausal women and as adjuvant therapy in patients with
node – positive or node – negative hormone receptor positive
disease irrespective of menopausal status.
 Also approved for chemoprevention of women at increased risk who
have DCIS.
 This drug is metabolized by demethylation and hydroxylation; and is a
strong anti-estrogen and weak estrogen receptor agonist. In tumours
that express Her-2, tamoxifen acts as weak agonist leading to poor
response to treatment.
 Response rates in pre-menopausal women with hormone responsive
disease vary from 15-53%.
 The benefits of adjuvant hormonal treatment with tamoxifen were first
demonstrated in theNational SurgicalAdjuvant Breast and Bowel
Project (NSABP) B-14 trial.

19. ANTIESTROGENS (contd)
TOREMIFENE
 Is a triphenylethylene analogue of tamoxifen.
 Is approved as 1st
line therapy for metastatic breast cancer in ER
positive or unknown ER status tumours.
 Action and sequelae profile is similar to tamoxifen.
FULVESTRANT
 Is an ER downregulator and pure ER antagonist with affinity 50 times
that of tamoxifen.
 Administered as a monthly 250 mg IM injection.
 In randomized phase III trials it has been found to have similar efficacy
to Anastrozole (Howell et al 2005), and to Tamoxifen (Howell et al
2004).
 Is presently FDA approved for post-menopausal hormone receptor
positive breast cancer progressing on other anti-estrogen therapy.
 Safety profile similar to tamoxifen.

20. AROMATASE INHIBITORS
 Two types of Aromatase inhibitors (AIs): Suicidal (type 1) or
irreversible inhibitors and Competitive inhibitors (type 2).
 Type 1 or suicidal inhibitors are steroidal drugs (Aminoglutethimide
or testolactone) which bind to catalytic site of aromatase enzyme
and cause permanent blockage. They also block other enzymes in
CyP-450 family and alter other steroid hormone levels thereby
causing side effects. They had been used in metastatic breast
cancer, but are now replaced by competitive blockers.
 Type 2 or competitive inhibitors bind to the active enzyme site
reversibly and their continued activity depends on their serum levels.
These drugs alter only estrogen levels.
 These drugs can used only in women with no ovarian function; either
in post-menopausal women or pre-menopausal women having had
ovarian ablation.

21. FORMESTANE
 Was the 1st
selective AI. Also has weak androgenic properties.
 Found to be superior to aminoglutethimide.
 Given as IM injection.
ANASTROZOLE
 This drug has rapid oral absorption with peak plasma levels within 2
hrs.
 Was found to be superior to tamoxifen in reducing recurrences at 5
yrs (ATAC). A higher fraction of women with ER positive tumours
show benefit with anastrozole.
 Is FDA approved for 1st
or 2nd
line therapy for post-menopausal
women with hormone sensitive tumours.
 Side effects includes arthralgias, increased risk of fractures, risk of
ischaemic events; but decreased risk of vaginal bleeding/ hot
flashes/ mood changes/ DVTs compared to tamoxifen.
 Recommended dose is 1 mg/day for 3-5 years.

22. LETROZOLE
 Another selective AI which has been approved as 1st
or 2nd
line
therapy in post-menopausal women with hormone receptor positive
disease.
 It markedly suppresses estradiol, estrone levels within 2 weeks of
start of therapy.
 Is associated with lower risk of thromboembolic events, vaginal
bleeding or endometrial cancer risk compared to tamoxifen; but has
higher incidence of cardiac risk and hyperlipidemia.
 Recommended dose is 2.5 mg / day for 3-5 years.
EXEMUSTANE
 Is a steroidal androgen derivative and a selective AI.
 It suppresses estradiol and estrone levels similar to those of
anastrozole and letrozole. Is presently FDA approved for 2nd
line
therapy of hormone sensitive metastatic breast cancer.
 If given ih high doses (upto 200mg/day), may cause androgenic side
effects like alopecia, hoarseness.

23. FADROZOLE
 Is a competitive inhibitor more selective than aminoglutethimide but
less than letrozole. No significant difference in response compared
to megestrol acetate, but lesser incidence of weight gain and
thrombo-embolic events.

24. LHRH AGONISTS
 Used increasingly for ovarian ablation. Also called GnRH agonists.
 They reduce the release of estrogen by providing a constant high
level of pituitary-releasing hormones leading to stopping of
gonadotropin release.
 Chronic use results in estrogen levels similar to post oophorectomy
patients.
 Gosserelin approved for use in pre-menopausal women.
 Administration initially results in “Flare” symptoms due to initial rise
in gonadotropin levels.

25. EVIDENCES ON ADJUVANT
HORMONE THERAPY IN BREAST
CANCER

26. IN PRE-MENOPAUSAL WOMEN
 Data from EBCTCG (2005) indicate that patients whose tumours are
potentially responsive to endocrine therapy achieve a reduction in
risk of relapse and death from breast cancer from treatment
strategies that reduce the levels, or block the action, of circulating
oestrogens.
 In premenopausal women with oestrogen receptor alpha (ER)
positive tumours, ovarian ablation or suppression is associated with
a reduction in risk of relapse and death from breast cancer.
 Whether younger women, not rendered menopausal as a
consequence of adjuvant chemotherapy gain additional benefit from
ovarian suppression remains a subject of continuing research.
 Menopausal symptoms following ovarian ablation/suppression are
worse than after chemotherapy.

27.  In 2000, the National Institutes of Health (NIH) recommended that
adjuvant chemotherapy should be offered to the majority of
premenopausal women with early breast cancer, and that tamoxifen
should be given to ER-positive patients for 5 years. The panel did
not recommend the use of ovarian suppression in patients who were
receiving both chemotherapy and tamoxifen for 5 years, but its use
could be considered instead of tamoxifen in selected patients.
 In contrast, the St. Gallen panel in 2003 highlighted the primacy of
endocrine therapy in the management of premenopausal women
and recommended the combination of tamoxifen for 5 years as an
acceptable alternative to chemotherapy in ERpositive women

28.  Ovarian ablation or suppression versus none: in premenopausal
women with breast cancer that is ER-positive or with unknown ER
status, ovarian ablation or suppression is beneficial compared to no
ovarian treatment in terms of recurrence (respective rates 47% and
52%, p<0.0001) and breast cancer mortality (respective rates 40%
and 44%, p<0.004), both assessed at 15 years follow-up (Early
Breast Cancer Trialists' Collaborative Group, 2005).
 Ovarian ablation and the role of chemotherapy: the most recent
evidence from a meta-analysis of individual patient data suggests
that ovarian ablation has benefit in terms of recurrence and survival
over no ablation in premenopausal women, with or without
chemotherapy (EBCTCG, 2005).
 LHRHa versus no systemic therapy: Premenopausal women with
operable breast cancer showed a 5 and 10 year disease-free survival
and overall survival rates were significantly improved following
adjuvant oophorectomy and tamoxifen (Love et al., 2008).

29.  The ZEBRA trial showed that 2 years of Gosserelin treatment was
equivalent to 6 cycles CMF chemotherapy for ER positive tumours
at 6 years follow up.
 ABCSG 05 trial showed that gosserelin plus tamoxifen was
superior to CMF chemotherapy in increasing relapse free period.
 Role of aromatase inhibitors is not indicated till complete ovarian
ablation is achieved with use of LHRH agonists. In this subset of
patients, AIs do not show benefit over tamoxifen.
 Low levels of either ER or PR correlated with a shorter time to
recurrence but hormone status did not predict the superiority of
anastrazole over tamoxifen that had been found in a large multi-
centre RCT (Dowsett et al., 2008).
 Positive hormone receptor status (either estrogen or progesterone)
was associated with significantly longer relapse-free survival
compared with negative receptor expression whilst those with ER-
ve status had a poorer relapse-free survival (Dowsett et al., 2006).

30. SIDE-EFFECTS
 Ovarian ablation, ovarian suppression and chemotherapy each
have adverse side effects and each can induce menopausal
symptoms, including amenorrhoea (Brunt et al., 2004a; Groenvold
et al., 2006; Schmid et al., 2007; Love et al., 1999; Sharma et al.,
2007 and Celio et al., 2002).
 A Cochrane Review cited trials which found that side effects are
more severe following LHRHa plus tamoxifen compared to
tamoxifen alone (Sharma et al., 2007).
 Health-related quality of life tends to favour ovarian ablation or
suppression over chemotherapy, wherein acute adverse effects
appear to be worse following chemotherapy. In contrast,
menopausal symptoms (for example hot flushes) appear to be
worse following ablation or suppression, than after chemotherapy,
and with earlier onset.
 Amenorhoea can be longer lasting following chemotherapy
compared with LHRHa (Brunt et al., 2004a; Groenvold et al., 2006;
Sharma et al. 2007 and Schmid et al. 2007).

31. POST-MENOPAUSAL PATIENTS
 The aromatase inhibitors (anastrozole, exemestane and letrozole),
are alternative options to tamoxifen for ER-positive invasive breast
cancer in postmenopausal women. (ATAC, BIG-98, ITA, ARNO-95
trials)
 The risk of disease recurrence is significantly reduced with
anastrozole and is reported to be independent of nodal status,
tumour size or prior chemotherapy. All ER-positive patients showed
a benefit but there was no statistical difference between the
progesterone receptor (PR)-positive or PR-negative subgroup
( Buzdar et al., 2006; Dowsett et al., 2005; and Kaufmann et al.,
2007b).
 When patients who were disease-free at the end of receiving 5
years of adjuvant tamoxifen were randomly assigned to receive
either 3 years of anastrozole or no further treatment; the disease-
free survival was statistically improved with significantly fewer
recurrences.

32.  The risk of contralateral breast cancer is significantly reduced only if
anastrozole is given as first line adjuvant treatment; it is not
significantly different if given after tamoxifen.
 In the BIG-98 trial letrozole when compared to tamoxifen showed
improved DFS than with tamoxifen alone.
 In the IES trial, exemustane after 2-3 years of tamoxifen showed
improved DFS with lower incidence of side effects.
 In the ARNO trial anastrozole after 2-3 years of tamoxifen improved
relapse free intervals.
 Hence the recommendations were to shift to aromatase inhibitors
after 2-3 years of tamoxifen.

34. EXTENDED ADJUVANT HORMONAL
THERAPY
 MA.17 was a phase III,
randomized, double-blind, placebo
controlled trial of letrozole as
extended adjuvant therapy in
postmenopausal women with
primary breast cancer who had
completed approximately 5 years
of adjuvant tamoxifen therapy
 Letrozole significantly improved
DFS in all patients, irrespective of
nodal status.

36.  Letrozole significantly improved OS in patients with node-positive
tumors (hazard ratio = 0.61; 95% CI 0.38, 0.98; P = 0.04)
 The risk of disease recurrence increased over time in the placebo
group, whereas in patients receiving letrozole, risk appeared to peak
at around 2 years of treatment and decrease thereafter.
 On the basis of this trial, letrozole was approved as extended
adjuvant therapy, and it is currently the only AI approved for this
indication
 MA.17 demonstrated that extended adjuvant therapy with letrozole
provides women further protection against relapse after the
completion of tamoxifen. Also women in all risk categories benefited
in terms of reduced risk for recurrence of their cancer.
 This could mean that distant micrometastases that have survived 5
years of tamoxifen therapy remain highly estrogen-sensitive and
responsive to extended adjuvant letrozole treatment.
 Extended therapy with adjuvant letrozole should therefore be
considered for all women completing tamoxifen.

37. NEOADJUVANT HORMONE THERAPY
 Two trials (IMPACT and PROACT) evaluated Anastrozole and
tamoxifen in post-menopausal women with locally advanced
inoperable tumours. A comparative analysis (Smith et al 2004)
showed better response with anastrozole but no statistically
significant difference.
 P024 trial (Eiermann 2001) evaluated Letrozole and found that
Letrozole made breast conserving surgery more possible than
tamoxifen.
 Exemustane also been evaluated and results are promising.
 Optimal neoadjuvant hormone therapy recommendations are
awaited.

38. RECOMMENDATIONS
• Hormone therapy results in disease palliation in 50-60% of hormone
sensitive tumors.
• Alone or with chemotherapy, it significantly reduces disease
recurrence.
• Tamoxifen is standard adjuvant endocrine therapy in pre-
menopausal women.
• Aromatase inhibitors now recommended in adjuvant treatment of
post-menopausal hormone sensitive breast cancers.

39.  Do not offer adjuvant ovarian ablation/suppression to
premenopausal women with ER-positive early invasive breast
cancer who are being treated with tamoxifen and, if indicated,
chemotherapy.
 Offer adjuvant ovarian ablation/suppression in addition to tamoxifen
to premenopausal women with ER-positive early invasive breast
cancer who have been offered chemotherapy but have chosen not to
have it.
 Postmenopausal women with ER-positive early invasive breast
cancer who are not considered to be at low risk should be offered an
aromatase inhibitor, either anastrozole or letrozole, as their initial
adjuvant therapy. Offer tamoxifen if an aromatase inhibitor is not
tolerated or contraindicated.

40.  Offer an aromatase inhibitor, either exemestane or anastrozole
instead of tamoxifen to postmenopausal women with ER-positive
early invasive breast cancer who are not low-risk and who have
been treated with tamoxifen for 2–3 years.
 Offer additional treatment with the aromatase inhibitor letrozole
for 2–3 years to postmenopausal women with lymph node-
positive ER-positive early invasive breast cancer who have been
treated with tamoxifen for 5 years.
 Following drugs were recommended:
a) Anastrozole for primary adjuvant therapy
b) Exemestane for adjuvant therapy following 2–3 years of adjuvant
tamoxifen therapy
c) Letrozole for primary adjuvant therapy and extended adjuvant
therapy following standard tamoxifen therapy.