Hormonal treatment

of Breast Cancer

Moderator: Dr. S C Sharma

HOD, Department of
Radiotherapy, PGIMER
Background
 Henri François 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.
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
Time Line
1990’s
Demonstration
1940’s of the
Full range of 1970’s therapeutic
ablative hormonal efficacy of
Development of
therapy developed Tamoxifen
Tamoxifen

1870 1950’s 1980’s

1st description of Era of Additive ER/PR
surgical hormonal therapy detection and
oophorectomy resurgence in
interest in
endocrine Rx
Endocrine pathways in cancer
Estrogen and Progesterone receptors
 Several authors
demonstrated the
relationship of the cytosolic
form ER to the efficacy of
endocrine therapy.
 The nuclear translocation
and subsequent
transcription are
dependent on several co-
repressors and activators.
 The SRC co activator
action is particularly
important in this regard.
 Recently ER-β has been
identified.
Rationale for receptor based Rx
 Response rates to endocrine 0% 20% 40% 60% 80% 100%
manipulation in ER +ve
patients was as high as 53% (
only 6% in ER –ve) – Whitliff
et al. ER+/PR+ 78%
 Receptors correlate with other
prognostic markers:
 Cellular turnover rates,
 Nuclear grade, and ER-/PR+ 45%
 Degree of histologic
differentiation
 Receptor positivity also
correlates with:
 Disease-free interval ER+/PR- 34%
 Decreasing tumor size
 Prolongation of DFS is
independent of menopausal
status, tumor size, and nodal ER-/PR- 10%
status.
Endocrine therapies
 Selective Estrogen  Aromatase inhibitors:
Receptor  Letrozole
 Anastrazole
Modulators:
 Exemestane
 Tamoxifen
 Steroidal Antiestrogens:
 Torimefene
 Fulvestrant
 Androgens  LHRH agonists
 Fluoxymesterone  Leuprolide
 Progestins  Goserelin

 Megestrol acetate  Gland ablation

 Medroxyprogesterone  Ovary
 Pituitary
acetate
 Adrenals
 High dose Estrogens
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.
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
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.
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.
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
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 cross-
resistance with tamoxifen and
should not be used in tamoxifen-
resistant disease
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
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 Anastrazole
more potent than
aminoglutethemide.
 Dose:
 Letrozole (Femara) – 2.5 mg OD
 Anastrazole (Arimidex) – 1 mg OD
 Exemestane (Aromasin) – 25 mg OD Letrozole
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
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.
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
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.
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.
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.
Endocrine therapy in
the adjuvant setting
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
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.
 Ca Breast for adjuvant therapy

Low risk*, node -ve High risk, node -ve Node +ve

Receptor - ve Receptor + ve Receptor + ve Receptor - ve

No Rx Chemotherapy

Tamoxifen only
Premenopausal Postmenopausal

CCT + Tamoxifen# CCT + Tamoxifen

* Low risk defined as -ve axillary lymph nodes and tumor size ±1 cm, nuclear grade 1, special
histologic type or 1-2 cm tumor with positive steroid receptor and special histologic type.
#
Ovarian suppression may be considered in those who remain premenopausal after
chemotherapy.
Adjuvant Tamoxifen alone
 Several trials have demonstrated that tamoxifen
adds significantly to the DFS in the adjuvant
setting.
 Two major trials have also demonstrated a OS
benefit

Trial Dose Duration DFS OS

NATO 20 2 P < 0.05 P < 0.05
Christie 20 1 P < 0.05 NS
Stockholm 30 2 P < 0.05 NS
CRC 20 2 P < 0.01 NS
Scottish 20 5 P < 0.05 P < 0.05
Overall benefits of tamoxifen Rx
 While the patients are
on tamoxifen:
 1 of every 2
Reduction in Annual Odds ± SE
recurrences and
Years Recurrence Death  1 of every 3 deaths are
avoided by the
0–1 53 ± 5 22 ± 10 tamoxifen therapy.
 Tamoxifen continues to
2–4 42 ± 5 29 ± 6 demonstrate further
reductions in the odds
5–9 31 ± 6 29 ± 5 of recurrence and
death in years 5
through 9.
 This is called the
“carryover effect”
Optimal Duration of Tamoxifen Rx
Reduction in recurrences Reduction in deaths
Tamoxifen ~ 1 yr 18% ± 3 11% ± 3
Tamoxifen ~ 2 yr 24% ± 2 14% ± 2
Tamoxifen ~ 5 yr 43% ± 3 23% ± 4

 In the EBCTSG meta-analysis 5 yr tamoxifen

reduced the risk of recurrence and death twice
as much as 2 yr tamoxifen therapy.
 In two large European trials from Britain and
Sweden, women treated with tamoxifen for 5
years, had fewer recurrences and deaths than
those treated for only 2 years.
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
counterbalanced 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?)
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.
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
Tamoxifen & ER status
Reduction (SE) in Annual Odds
ER Level Recurrence Cancer Death Any Death
Poor (<10 fmol/mg) <4 (7%) <4 (8%) <3 (7%)
Positive (≥10, <100
36 (4%) 27 (5%) 22 (5%)
fmol/mg)
Positive (≥100 fmol/mg) 49 (5%) 45 (6%) 33 (5%)

Unknown 31 (7%) 20 (9%) 14 (8%)

Results of tamoxifen therapy for 5 years in patients with ER +ve or –ve tumors.
Adapted from Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast
Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67
Tamoxifen & ER status
 Most of the trials and meta-analyses have
demonstrated no benefit of adjuvant tamoxifen in
ER poor / -ve tumors.
 Three trials however showed some benefit:
 NATO study:
 When 5 fmol/mg was taken as a cut off point beneficial
effect of tamoxifen was equal in both ER +ve and –ve
tumors.
 Scottish trial: Showed that even in ER –ve tumors
there was a increase in DFS over control group.
 NSABP B-09 trial: some women aged 60 to 70 years
received benefit from tamoxifen even if their tumor
had an ER content of 0 to 9 fmol per mg protein
 However in two recent prospective trials which
compared tamoxifen alone in ER-ve, node
negative patients no survival benefit could be
demonstrated for 5 yrs tamoxifen therapy.
Tamoxifen & PR status
 Effect of PR status:
 It is believed that in ER –ve patients PR +ve patients
may be more responsive to tamoxifen therapy.
 Results are interpolated from results in metastatic
disease.
 In a recent retrospective analysis patients who were
both ER and PR +ve, fared better than patients who
were ER +ve and PR –ve
 53% reduction* in risk of recurrence for patients who
were ER & PR +ve.
 In patients who were ER +ve only the risk was reduced*
by 23% only.
 The lesser benefit of Tamoxifen in patients with ER +ve
but PR –ve tumors has also been confirmed in the
ATAC trial recently.
Tamoxifen & Receptor status
 Unresolved questions:
 Does addition of tamoxifen to ER –ve older
woman improve their outcome ?
 Impact of PR in patients who are ER –ve
tumors ?
 Is the reduction in contralateral breast cancer
in patients with ER –ve tumor worthwhile ?
 Impact of newer immunohistochemical
analytic techniques in the measurement of
receptor levels – specially impact of false
negative results.
Tamoxifen & Menopausal status
 Initially believed to Reduction of
odds of
Absolute
reduction
have lesser efficacy in recurrence at 10 yrs
premenopausal women. Age 0-4 yrs 5-9 yrs
 Many trials gave <50 42% 22% 10.7%
tamoxifen for 2 years.
50+ 49% 33% 14.6%
 Greater proportion of
premenopausal women
have ER –ve tumors. Reduction of Absolute
odds of deaths reduction
 Recent trials have at 10 yrs
Age 0-4 yrs 5-9 yrs
revealed a substantial
<50 31% 28% 6.8%
benefit in terms of:
50+ 32% 36% 8.2%
 Long term survival
 Recurrence rates
Tamoxifen in Elderly patients
 All meta-analyses have demonstrated a
stastically significant benefit for addition of
Tamoxifen in patients aged > 70 yrs.
 ECOG evaluated the role of 2yr tamoxifen therapy
vs placebo in 180 women aged > 65yrs
 Drug was well tolerated
 Significant reduction in recurrences
 Borderline significant reduction in risk of death
 Tamoxifen also reduced the incidence of contralateral
breast cancers
 Problems with adjuvant tamoxifen in elderly
population:
 High risk of death for unrelated cancer (22% in ECOG
trial)
 Poor adherence to prescribed treatment
 Risk of thromboembolism increases with age.
Tamoxifen & nodal status
 The NSABP – B14 protocol
outlined the following
benefits of adjuvant
tamoxifen in node –ve
patients:
 Fewer ipsilateral breast,
local-regional, and
distant recurrences.
 Substantial reduction (~
50%) in contralateral
breast cancer.
 These benefits persisted
beyond 14 years of
follow-up

Data from Early Breast Cancer Trialists’

Collaborative Group
Tamoxifen & nodal status
Reduction in Annual Odds*
Recurrence Cancer Deaths Any Deaths
Node negative
0 – 4 yrs 48% 33% 25%
5 + yrs 35% 30% 21%
Node Positive
0 – 4 yrs 41% 40% 29%
5 + yrs 20% 38% 36%

 At 10 yrs:
 The recurrence rates were reduced by 14% and 11%
in node –ve and +ve patients respectively.
 Similarly, mortality reduced by 14.8% and 12%
respectively.
Tamoxifen alone vs XRT + Tmx
 Fisher et al (NSABP B21)
evaluated whether tamoxifen
alone is as good as XRT
followed by tamoxifen in node-
negative women with invasive
breast cancers of < 1 cm.
 Overall 49% reduction in the
hazard ratio for ipsilateral
recurrence was seen when XRT
was added w.r.t. tamoxifen
alone.
 Fyles et al also demonstrated
that addition of XRT after
lumpectomy significantly
reduces the breast and axillary
recurrences in women > 60yrs NSABP B 21 data ( N = 1009)
with early T1 / T2 leisons.
Tamoxifen and chemotherapy
 Advantages of combining  Disadvantages of
CCT with Tmx include:
 Elimination of both
chemoresistant and
tamoxifen resistant cell
populations.
 Tamoxifen and
progestins inhibit p-
glycoprotein, an effect
that could enhance
sensitivity to drugs such
as doxorubicin.
 The apoptosis inhibitor
Bcl-2 is down-regulated
by tamoxifen, possibly
enhancing sensitivity to
drugs using this cell
death pathway.
combined approach:
 Cytostatic nature of
tamoxifen may interfere
with chemotherapy by
locking cells in
chemoresistant phases of
cell cycle.
 It also antagonizes
calmodulin and is an
effective Ca2+ channel
antagonist—effects that
could alter drug uptake.
Chemoendocrine Rx - Premenopausal
 Tmx has been evaluated against Tmx + CCT in a
NSABP trial in ER +ve, node negative tumor
 Women < 50 yrs who received concurrent CCT and
tamoxifen compared with tamoxifen alone had a 35%
reduction in annual odds of recurrence.
 Initial trials had failed to show a benefit for
addition of tamoxifen to chemotherapy in
premenopausal women.
 Addition of different CCT may explain the variable
results as it is now known Tmx may inhibit the
action of some CCT agents e.g. Melphalan (Used
in NSABP B09 where premenopausal women had
a poorer DFS and OS)
Chemoendocrine Rx - Premenopausal
 The 1995 Oxford meta-analysis showed a
significant reduction in recurrence rates and
deaths.
 Similar findings were seen in the 2000 overview
also in premenopausal patients with ER +ve
tumors.

Reduction in Annual Odds in % (SE)

Recurrence Cancer Mortality Any Death
CCT+tamoxifen 35 (± 7) 34 (± 9) 31 (± 9)
CCT alone 38 (± 4) 29 (± 5) 27 (± 4)
Chemoendocrine Rx - Postmenopausal
 Benefits are less certain in this group.
 Apparently greatest benefit in:
 Postmenopausal node positive disease patients who
receive an anthracycline based CCT
 Women in the age group of 50 - 60 yrs benefit
greatest.
 3 main trials have evaluated the impact of
addition of CCT to tamoxifen in postmenopausal
age group:
 NSABP B20: Benefit greatest in women below 60 yrs
age and DFS prolonged longest in women aged < 50 yr
 SWOG 8814: 9% improvement in DFS after 5 yrs of
Tmx after anthracycline (FAC) based CCT ( ER +ve ,
postmenopausal females)
 IBCSG Trial IX: Improvement in outcome of
postmenopausal females with ER –ve disease only (?
Suboptimal CCT regimen – CMF x 3)
Chemoendocrine Rx - Postmenopausal
 The findings of meta analysis are less clear as far
as post menopausal females are concerned as:
 Less number of females in the trials.
 Patients likely to receive less toxic combinations in less
dose intense fashion.
 Likely to experience more toxicity.
 Likely to die of unrelated causes in F/U period.

Reduction in Annual Odds in % (SE)

Recurrence Cancer Mortality Any Death
CCT+tamoxifen 16 ± 3 10 ± 3 10 ± 3
CCT alone 22 ± 4 13 ± 4 11 ± 4
Sequence of Tmx and CCT
 Concurrent administration considered by some
western observers as harmful due to cytostatic
action of tamoxifen
 Sequential vs Concurrent administration has been
evaluated in a single trial till date.
 Intergroup trail 0100: 8 yr DFS was 67% in
patients receiving sequential vs 62% in patients
receiving concurrent Tmx.
 In the 2000 Oxford overview patients who had
received sequential Tmx vs concurrent had a 7%
reduction in the annual odds of recurrence.
 AI in adjuvant setting
 7 trials have been reported all of which involve post
menopausal females with HR +ve disease.
 A theoretical priming benefit initial tamoxifen made many
trials use tamoxifen in initial 2-3 yrs prior to witching over
to tamoxifen.

Trial Yrs Tmx N FU (mo)  DFS  OS

MA 17 (Let)* 5 5157 30 2.4% NA
ATAC (Ana) 0 6186 68 2.4% 0.3%
BIG 01-98 (Let) 0 8010 26 1.9% 0.7%
ABCSG/ARNO (Ana) 2 3224 28 2.4% NA
ITA (Ana) 2 426 24 7.1% NA
IES (Exe) 2-3 4742 31 3.5% 0.6%
* Placebo
controlled
AI in adjuvant setting
 Data about the use of AI as 1st line adjuvant therapy is not
mature enough to support routine use of AI.
 Results have shown that:
 No advantage in use of AI over tamoxifen in first 2-3 yrs
 No survival benefit over Tmx in first 5 yrs
 Clinical impact of long term AI toxicity not known
 Tamoxifen “priming” may be important for control of disease
as well as prevention of bone damage due to Tmx
 However timing and duration of switch remain to be
established.
 Use in premenopausal women not recommended
(hypophyseal feedback is presumably strong enough to
overcome AI induced ovarian estrogen blockade).
 Data for specific subgroups not available.
 Use of Tmx with AI may impair the efficacy of AI as seen in
the ATAC trial.
Adjuvant Ovarian ablation
 60% of premenopausal women are receptor +ve at
diagnosis.
 Poorer prognosis of premenopausal women < 35 yrs age:
 More poorly diff. & higher grade
 Greater vascular invasion
 ~ 10% reduction in 10 yr DFS & OS (Aebi et al)
 Paradoxically poorer survival in ER +ve patients compared to
ER –ve patients who received CCT only.
 Greater proportional benefits of CCT in the
premenopausal (vis a vis postmenopausal) may be
secondary to the endocrine effects of CCT in this
population.
 Despite drug induced amenorrhea in 30% women CCT
induced hormonal effects not sufficient to prolong DFS/OS
in hormone sensitive patients.
Results : 2004 EBCTSG review
Reduction (SE) in annual odds
Age group Recurrence % Cancer death % Any death %
Ovarian ablation vs nil
<40 30 ± 17 29 ± 16 22 ± 16
40–49 33 ± 8 32 ± 9 30 ± 8
LHRH agonist vs nil
<40 33 ± 12 45 ± 17 35 ± 17
40–49 16 ± 9 15 ± 13 13 ± 13
Ablation or LHRH agonist vs nil
<40 42 ± 10 32 ± 12 28 ± 12
40–49 25 ± 6 26 ± 7 25 ± 7
Ovarian ablation + CCT vs CCT alone
<40 7 ± 10 <1 ± 11 <1 ± 11
40–49 7±7 <2 ± 8 <3 ± 8
Ovarian ablation vs CCT
 Two trials have evaluated ovarian suppression vs
ablation:
 Scottish trial:
 Ovarian ablation was equally effective as adjuvant CCT
with CMF
 In ER +ve women a trend towards better survival was
found with ovarian ablation
 ZEBRA trial:
 Goserelin ( x 2yrs) was as effective as CMF ( x 6
cycles) in ER +ve, stage II & node +ve patients.
 In the ER –ve subgroup CMF had better OS and DFS.
 Thus at best, ovarian ablation is as good as CMF
based CCT ( but not better) in the ER +ve
premenopausal females with early stage disease.
Tamoxifen with ovarian ablation
Author Design Comments
ABCSG CMF x 6 CMF < G +Tam for DFS
Jakesz G x 3 years + Tam x 5 years [HR = 1.40; P = .017]
ZIPP G x 2 yrs G > no G ( HR 0.9;
Rutqvist Tam x 2 yrs p= 0.001)
G + Tam x 2yrs
INT - 0101 FAC FAC + G = FAC alone (HR =
Davidson FAC + G x 5 yrs 0.93 , p = 0.25)
FAC + G + Tam x 5 yrs FAC + G + Tam > FAC + G
(HR = 0.73 , p = 0.01)

 A recent SOFT trial is evaluating the question whether the

addition of ovarian ablation to tamoxifen is better than
tamoxifen in premenopausal females after CCT who are
hormone receptor +ve.
Conclusions
 Ovarian ablation or suppression by LHRH agonists are
equally good at preventing cancer related deaths.
 In the premenopausal age group a significant reduction in
the mortality and recurrence seen with either modality
compared to no adjuvant therapy.
 Ovarian irradiation or surgery are equally effective as
ablative modalities.
 Addition of tamoxifen provides an additional benefit in
terms of DFS.
 Caveat:
 The duration of treatment with LHRH agonists is not well
defined (most trial use 2 -3 yrs treatment).
 The impact of resumption of ovarian function after stoppage
of these agents on risk of recurrence remains to be seen.
 The exact benefit of addition of ovarian ablation in receptor
+ve females already receiving tamoxifen after CCT remains
to be ascertained.
Ancillary benefits of Tamoxifen
 Cardiovascular:
 Fewer non cancer related deaths due to
cardiovascular events.
 Fewer hospitalizations for cardiac events
 Serum LDL / cholesterol reduced.
 Actual magnitude of benefit still unclear.
 Skeletal:
 Significant reduction in incidence of fractures
of weight bearing bones.
 Estrogen agonist action on BMD
 Prevention of contralateral breast cancer
Toxicity
 Menopausal symptoms:
 50% - 60% ( N.B. 40% -
50% in placebo)
 MC in premenopausal
 Vaginal dryness and
discharge may occur in
excess.
 Depression:
 Maybe seen in as high as
10% of patients.
 But no randomized
comparisons available.
 Ocular toxicity:
 Keratopathy, maculopathy &
cataract
 Reported with high doses
 However NSABP studies
have found no increase in
vision threatening ocular
toxicity.
 Thromboembolism:
 Severe thromboembolism
seen in ~ 1% patients in the
preventive setting.
 Risk up to 10 times that
experienced by healthy
women
 Complication more common
in elderly patients with
metastatic breast cancer
and who are receiving CCT
 Carcinogenesis:
 Increased risk of
endometrial cancers (hazard
rate of 1.7 per 1000 –
NSABP B 14 data)
 Mostly low grade & stage I
tumors.
 Other tumors:
 Hepatomas
 Clear cell sarcomas of ovary
Tamoxifen toxicity
 The excess incidence of serious adverse
events for patients receiving tamoxifen
therapy was approximately 5 per 1000
woman years in NSABP P1 trial.
 Serious side effects occur in approximately
1 in 200 patients annually
 In large randomized trial ~ 5% patients
withdrew from therapy due to toxicity.
 Relative to the toxicities of chemotherapy,
these side effects are tolerable.
Contraindications to Tmx Rx
 Absolute:
 Retinal macular edema or degeneration
 History of benign or malignant liver tumor secondary
to oral contraceptives
 Pregnancy
 Other hormonal therapy (estrogens, oral
contraceptives)
 Relative:
 History of thrombophlebitis, particularly hormone
related
 History of depression, particularly hormone related
 Cataract
 Drugs: Chlorpromazine, chloroquine, thioridazine,
amiodarone, other
 Severe vasomotor symptoms
 Polycystic ovaries
Toxicity of AIs vs Tamoxifen
MA -17 ATAC BIG IES

Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tmx

Endometrial Cancer NA - 0.6% - 0.4% NA poorer
Thromboembolic events NA - 1.7% - 1.2% - .9%
Cardiac complications 0.5% 0% 0.4% NA AI
Arthalgia /Myalgia 23% 7% NA 6% poorer
Osteoporotic fractures 2.3% 2.2% 1.7& 2%
Hot flushes 6% 5% 4% 2%

Since the absolute benefit of using a AI in adjuvant setting over tamoxifen is ~

2% reduction in recurrence rates and 1.5% reduction in mortality this excess
toxicity needs to be balanced against the bone damage produced by AIs in this
setting.
Toxicity management
 Hot Flushes:
 Usually self limiting and respond well to placebos.
 HRT/ SSRIs are not recommended
 Best managed by life style changes.
 Vaginal Bleeding:
 Routine work up indicated.
 Watch out for an endometrial CA in post menopausal
females.
 Myalgia / Arthalgia:
 More common with AI
 Switching to Tmx may be required.
 Osteoporosis:
 Calcium supplements, Vitamin D and bisphosphonates
 HRT / Raloxifen not recommended (Raloxifen with AI –
may limit efficacy)
Endocrine therapy in
the neoadjuvant
setup
Background
 Limited experience
 Data derived from trials comparing endocrine therapy vs
surgery in older women ( >70 yrs) stage I/ II disease with
ER +ve status
 A multicenter Italian trial (GRETA) compared surgery
followed by tamoxifen with tamoxifen alone in 473 patients
 No difference was seen in disease-free or overall survival
 Local control was inferior in the tamoxifen arm, with a 25%
chance of local recurrence (vs. 6% in Sx arm)
 Response rates (CR & PR) = 43% to 78% in patients not
selected for hormone receptor status.
 Now a days in absence of serious comorbidities &/or limited
life expectancy endocrine therapy should not be used solely
in the treatment of such patients.
Use of hormone therapy
 Best suited for a hormone receptor positive,
postmenopausal woman
 Presence of +ve HR strongly influences response
to preoperative endocrine therapy
 Complete and partial response rates of the order
of 40 - 70%
 Majority of patients will have evidence of tumor
shrinkage by 3 months.
 Progression of disease is uncommon in hormone-
sensitive patients receiving preoperative therapy
(<5%)
Studies
 Eirmann et al conducted a RCT comparing 4 months of
Tmx vs Letrozole:
 337 postmenopausal woman with ER/PR +ve, T2 to T4a-c
breast cancer
 Overall clinical response rates are 36% for tamoxifen and
55% for letrozole (p < .001)
 Conservative surgery was possible in 45% of patients treated
with letrozole versus 35% with tamoxifen (P=0.022)
 Both treatments well tolerated
 PROACT trial:
 Preoperative Tmx vs. Anastrazole vs. the combination in ER
+ve, postmenopausal patients with tumors >2 cm
 No difference in clinical response between the treatment
arms (36%-T, 37%-A, 39%-C)
 Women who were initially thought to require a mastectomy
were more likely to undergo breast-conserving surgery if
they were randomized to the Anastrazole alone arm (46%-A
vs. 22%-C, p = .03)
Summary
 The strategy of preoperative endocrine therapy
will require more studies.
 Exciting area for further translational research:
 The therapeutic target is known and can, therefore, be
measured
 The biologic pathways arising from the therapeutic
target have been extensively studied
 Slower response to therapy gives a greater window of
opportunity for assessing changes in tumor tissue.
Caution: 2nd generation taxane based CCT
regimes have clinical response rates ranging from
80 -90%.
Endocrine therapy in
Metastatic Breast
Cancer
Guidelines
 Endocrine therapy should be started in all hormone
receptor positive females with metastatic breast cancer.
 Hormone therapy may be suitable as a sole therapy in
patients with severe comorbid conditions or very old age.
 AI are standard 2nd line agents after tamoxifen therapy.
 Recently evidence has emerged which highlights the
superiority of AI in the 1st line setting too.
 In premenopausal females ovarian ablation may be another
alternative. It also allows use of AI in this population.
 Selection of the appropriate initial management depends
on:
 Tempo of the disease (Slower progress, fewer symptoms)
 Vital organ involvement ( Bone & Soft tissue)
 General condition of the patient (Older age, poorer GC)
 Socio economic conditions.
Selection of patient & Rx
Premenopausal
Site % OR
Local recurrence 12%
Ovarian Ablation
Opposite breast 10%
Opposite axilla 10% Postmenopausal
Bone (osteolytic) 40%
Bone (osteoblastic) 30% Tamoxifen AIs
Lung 15% Resistance

Liver 11%
Brain 2% Fulvestrant / Progestins
Soft tissue 15% ??
Neck nodes 13% High dose Estrogen
Overall effect of endocrine Rx
 Bone Mets:
 Significant and quick relief of pain
 Increased bone calcification and sclerosis
 Reduced hypercalcemia and calcium loss.
 Better benefit in osteolytic (osteoclastic) leisons.
 Skin / soft tissue mets:
 Nodular leisons respond better than lymphangitic leisons.
 Edema is rarely reduced.
 Choroidal metastasis:
 Regression and vision recovery may be seen in 10 - 20%
 Pleuropulmonary leisons:
 Significant number of patients have reduction in size of leisons and
effusions.
 Systemic effects:
 Increased feeling of well being
 Reduced incapacitation due to pain
 Metastatic leisons that don’t respond:
 Hepatic
 Cerebral
Endocrine Rx in Metastatic CA
 Tamoxifen remains the gold standard.
 Been in use since 1970s
 Began to be used instead of high dose estrogens
which were due to highly favourable side effect
profile.
 Response rates range from 16% to 56% (Median
30%) – same as ovarian ablative techniques.
 Overall mean TTP for patients with metastatic
disease treated with tamoxifen is about 6 months
 Duration of response is between 12 and 18
months
Tamoxifen resistance
 Mechanism:
 Tamoxifen agonism: AI still produce effects
on breast cancer through estrogen
deprivation.
 ER β phenotype and ER βα hetrodimer
formation
 ER mutations.
 HER -2 receptor mediated ER downregualtion
(through MAP kinase pathway)
Tumor Flare
 Tumor Flare:
 Incidence:
 4% to 7% with high-dose estrogen
 3% to 13% with tamoxifen
 Dramatic  in bone pain, an  in size & number of
metastatic skin nodules, and erythema.
 Within days to several weeks after starting treatment
 Hypercalcemia in 5%
 Tumor regression may occur as the flare reaction
subsides
 Look for objective evidence of disease progression if
the patient's symptoms have not resolved by 4 to 6
weeks as flare is transient
Withdrawal response
 Secondary response after discontinuation of
treatment resulting from disease progression
 25% to 35% of patients on high-dose estrogen
therapy
 Seen in patients who experience an initial
response, followed by subsequent recurrence of
tumor
 Patients may experience disease stability for
more than 6 months
 Withdrawal therapy trial is therefore appropriate
for patients who responded well to prior
tamoxifen therapy and whose symptoms are
minimal at the time of disease progression
AI : 2nd Line therapy
 Initially used instead of high dose steroid in
tamoxifen resistant patients.
 Showed a small but significant benefit in 5 RCTs
in terms of survival and better side effect profile
 However overall the response rates were in the
10% to 20% range
 Significant clinical benefit from Aromatase
inhibitors often occurs in the absence of
dramatic disease regression.
 Therefore now the standard 2nd line endocrine
therapy in tamoxifen resistant metastatic breast
cancer.
Results: AIs as 2nd line Rx
Trial Drug N RR TTP (mo) OS (mo)
Anastrazole vs Ana (10 mg) 764 8.9 < 21 25.5
Megestrol Ana (1 mg) 10.3 26.7 *
acetate
Meg (40 mg) 7.9 22.5
Letrozole vs Let (2.5 mg) 551 24 5.6* 25.3*
Megestrol Let (0.5 mg) 13 5.1 21.5
acetate
Meg (40 mg) 16 5.5 21.5
Letrozole vs Let (2.5 mg) 602 16 3 29
Megestrol Let (0.5 mg) 21 6* 33*
acetate
Meg (40 mg) 15 3 26
AI : 1st line therapy
 3 major pahse III trials have directly compared tamoxifen
against AI.
 All have shown an improvement in time to progression
(TTP)
 The study by the International Letrozole Breast Cancer
Group is the largest in the series.

Trial Drug N RR TTP (mo) Comment

Nabholtz et Ana 353 21% 11.1* Retrospective
al1 analysis revealed
Tmx 17.7% 5.6 longer TTP with
TARGET trail2 Ana 668 32.9% 8.2 Anastrazole after
combining these
Tmx 32.6% 8.3 two trials3,4
Mouridsen et Let 907 30% 9.4
al5 Tmx 20% 6.0
AI : 1st line therapy
 Several trials have shown that the TTP is
significantly improved in metastatic breast cancer
when AI are used as 1st line therapy instead of
tamoxifen.
 The impact on OS not clear however.
 In the trail comparing Letrozole to Tamoxifen it
was shown that OS improved in the first 2 yrs.
 However no benefit exists at 5yrs.
 However due to crossing over a significant impact
on OS may have been lost.
 Crossing over to Tamoxifen after initial AI therapy
may be theoretically unwise as:
 Estrogen deprived cancer cells may be become
paradoxically sensitive to tamoxifen.
AI : 1st line therapy
 Toxicity:
 Patients on AI therapy have experienced significantly
lesser thromboembolic phenomenon.
 However the incidence of hot flashes is increased.
 There have been no trials which showed a benefit
of one AI over another.
 One trial comparing Letrozole vs Anastrozole
failed to show a difference in TTP or other
parameters.
 Because intratumoral Aromatase inhibition is
most important so it s unlikely any particular AI
will be more beneficial over the other.
Treatment after progression on AI
 Progression after 1st line AI therapy is difficult to
tackle.
 A retrospective analysis has shown that objective
response after tamoxifen therapy is of the order
of 10% after AI failure.
 Another phase II trial has shown that
Exemestane may be associated with a response
rate of 6.6% after Letrozole / Anastrazole
therapy.
 No endocrine therapy is thus available that can
give promising results after AI failure.
Fulvestrant
 A potent inhibitor of estrogen-dependent transcription.
 In preclinical models, Fulvestrant was found to be effective
against tamoxifen-resistant MCF7 cell xenografts.
 In a trial comparing 1st line tamoxifen vs fulvestrant, no
advantage was obtained in TTP or overall response over
tamoxifen.
 Given easier use of AI / Tamoxifen place in therapy remains
questionable.

Stable Time to
Response
Trial N Disease ≥ 24 Progression
Rates (%)
wk (%) (mo)
Osborne An 17.5 18.6 3.4
400
et al Ful 17.5 24.8 5.4
Howell Ana 15.7 45 5.1
451
et al Ful 20.7 44.6 5.4
Ovarian Ablation
 In a 2001 meta analysis by Klijn
et al comparing adjuvant
Tamoxifen + LHRH agonist vs TMX
LHRH agonist alone in advanced alone
breast cancer: LHRH
 22% reduction in the hazard of +
death for the combined Tmx
treatment group
 30% reduction in the hazard of LHRH
progression/death for the alone
combined treatment group.
 Median duration of response in
patients receiving combined
treatment was 602 days,
compared with a median of 350
days in those receiving LHRH
agonist alone Klijn, J. G. M. et al. J Natl Cancer Inst
2000;92:903-911
High Dose Estrogens
 Considered only in postmenopausal women as ineffective
before the menopause
 Activation of the FAS cell death receptor  therapeutic
response
 Estrogen deprivation  upregulation of FAS receptor
 Estrogen  FAS ligand expression
 Reduction in serum IGF -1 and 2 levels.
 Reasonable alternative to chemotherapy in setting of failure
to initial hormonal therapy (old age / poor GC)
 Doses:
 DES – 5 mg TDS
 Ethinyl Estradiaol: 30 mg in 3 – 4 divided doses
 Contraindication:
 DVT
 Cardiac problems
 Can produce objective responses in ~ 30 – 40% patients
who have received endocrine therapy.
Progestins
 Useful in some selected patients who have
developed resistance to SERM and AIs
 Megestrol acetate is used (160 mg /d)
 C/I include:
 Thromboembolic events
 Diabetes
 Needs evaluation in phase II trials for usefulness
as 3rd line agent.
 MOA:
 ? Aromatase inhibition
 ? Estrogen turnover increased (Estrogen deprivation)
 ? Separate action through PRs.
Other ablative procedures
 Adrenalectomy:
 Adrenals are source of estrogen in PM female.
 In large series ( 1950s – 60s) objective response rates
varied from 28% - 59% (Mean 42%)
 Duration of benefit varied from 12 – 36 months.
 Necessity for life long hormone replacement and high
operative mortality  obsolescence.
 Hypophysectomy:
 Another ablative procedure associated with response
rates ranging from 40% - 50%
 Response duration ~ 18 months
 Better tolerance than adrenalectomy made this
procedure a better choice.
Radiation Hypophysectomy
 Modalities:
 Interstitial Brachytherapy
 Proton Rx
 Need to deliver doses in range of 100 Gy – 200
Gy to bring pituitary ablation.
 Investigators in the Berkley university have used
proton beam therapy ( 50 Gy x 6 # = 300 Gy)
 This dose ablated 90% of the pituitary glands
with minimal morbidity.
 Growth Hormone  Thyroid hormones 
Gonadotropin  Estrogen and Progesterone 
Corticosteroid.
Interstitial Brachytherapy
 Yttrium 90 most commonly used.
 Pure β emitter with one of the highest energies
( 0.9 MeV)
 A circumscribed ring of necrosis is produced – 4.0
mm in diameters.
 Short t1/2 61 hrs. (Using Sr90 can overcome the
problems of handling due to this short t1/2)
 Easily packed in small spherules.
 Objective:
 Deliver 1000 Gy to pituitary
 Deliver 50 Gy or less to neighboring nervous tissue.
Technique and results

Circumscribed necrosis
Methods to overcome Tmx resistance
 HER 2 targeted therapy (Trastuzumab)
 Franesyl Transferase inhibitors
 Rapamycin analogues
 COX 2 inhibitors.
Endocrine therapy in
Preventive & other
settings
Rationale: Preventive setting
 Prevention : Reduction in cancer mortality via
reduction in incidence.
 There is a discreet, multistep progression of
leisons that lead to cancer over a long period of
time.
 Premalignant change progresses via this route:

Ductal Hyperplasia  Atypical ductal hyperplasia 

Ductal carcinoma in situ  Invasive cancer
 Chemoprevention based strategies are now being
tried to interrupt this process.
Hypothesis generation
 Women with early disease benefit more from adjuvant
therapy
 Benefit in DFS and OS in most trials with adjuvant
tamoxifen
 Several trials have demonstrated a reduction in the
incidence of contralateral breast cancer in women receiving
tamoxifen.
 Preclinical studies have demonstrated a preventive effect in
animal populations.

Trial Tamoxifen Placebo Comment

ECOG (1993) 1 (90) 3(91) Post meno

Stockholm (1989) 18 (711) 32 (696) Post meno

Scottish (1987) 8 (661) 14 (651 ) Pre / post meno

NSABP (1989) 13 (1318) 29 (1326) Pre / post meno

Results
 The BCPT trial (NSABP P1) was designed to
evaluate the efficacy of tamoxifen given for 5yrs
in high risk population
 49% reduction in invasive breast cancer
 50% reduction in non invasive cancers
 ER +ve tumors were much less frequent in women
receiving tamoxifen
 Incidence of ER –ve tumors remained same
 Reduction in rates of occurrence of tumors of all sizes
 The FDA has now approved the use of tamoxifen
in high risk women to reduce breast cancer
incidence.
 Ongoing STAR trial evaluating role of Raloxifen in
prevention.
Criticisms
 Validated approach for only selected high risk females:
 Women more than 35 yrs, who have completed family with high risk
as defined by the Gail model (5 yr risk > 1.66%)
 Age > 60 yrs ( intrinsic risk > 1.66%)
 Presence of LCIS
 Application in face of other high risk factors not validated
 Duration of follow up is too limited (5 yrs)
 Duration of tamoxifen therapy not known
 Duration of beneficial effect not known
 Optimal time at which to start tamoxifen in high risk patients is
not known
 Questions remain on the long term effect on cancer related
mortality.
 The benefits have not been reciprocated in two European trials.
 Finally who all should be screened for high risk factors not known
 Without proper public health backup chemoprevention not suited
in the Indian setup.
Hereditary Breast Cancer Prevention
 Kauff et al showed a statistically significant
reduction in 5 yr breast cancer free rates in
patients who are BRCA 1 or 2 +ve ( ~ 24%
improvement) after prophylactic oophorectomy.
 Further reduction in risk of ovarian cancers and
diagnosis of some ovarian cancers during surgery
itself.
 Rebbeck et al found in a series of 241 women, a
53% breast cancer risk reduction.
 Most benefit in breast cancer risk reduction was
observed in women who had prophylactic
oophorectomy by age 50 years.
Other uses of Endocrine Rx
 Risk reduction in LCIS:
 NSABP P1 trial: Risk reduction for invasive breast
cancer was 56% in those receiving tamoxifen.
 Use in DCIS:
 NSABP B24 and UK DCIS trial ( n = 3374)
 Significant reduction in Local recurrence and incidence
of contralateral breast cancers.
 Systemic Rx may be a safe, well tolerated option in
these females.
 Male Breast Cancer:
 Prognosis poorer
 Treatment same as that for females – tamoxifen is
DOC for endocrine therapy.
Conclusions
 Endocrine therapy is a safe and well tolerated
targeted treatment modality in majority of
patients with breast cancer.
 In the adjuvant setting primary treatment with
Tamoxifen should be considered in all receptor
positive females.
 Ovarian ablation may have additive benefits with
tamoxifen in premenopausal females.
 While AIs are a better option in metastatic breast
cancer in postmenopausal females, use in
adjuvant setting should be tempered with caution
as long term F/U data is lacking.
Thank You