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Endocrine therapy in breast
cancer
Dr.Mina Tajvidi
Radiation oncologist
Endocrine therapy in breast
cancer
 Endocrine therapy for hormone receptor positive
early stage breast cancer in premenopausal women
 Endocrine therapy for hormone receptor positive
early stage breast cancer in postmenopausal women
Endocrine therapy in metastatic breast cancer
Endocrine therapy for hormone
receptor positive early stage breast
cancer in premenopausal
Choice of agent/method
Over time, surgical and radiotherapeutic methods of endocrine therapy
have been gradually replaced with pharmacologic methods, including
blockade of the ER (eg, tamoxifen), suppression of estrogen synthesis by
luteinizing hormone-releasing hormone (LHRH) agonists (eg, goserelin)
Aromatase inhibitors are generally not used in premenopausal women.
The reduced feedback of estrogen to the hypothalamus and pituitary
increases gonadotropin secretion, which stimulates the ovary, leading to an
increase in androgen substrate and aromatase
Sequential administration of AIs may be considered for younger women
who become menopausal following adjuvant chemotherapy and tamoxifen
chemotherapy-induced amenorrhea may not be permanent in these
women. Furthermore, concerns have been raised that the use of AIs in this
setting may promote recovery of ovarian function
if this approach is used, careful monitoring of ovarian function and
frequent assay of serum estradiol levels is needed
TAMOXIFEN
Tamoxifen, a selective estrogen receptor modulator (SERM), inhibits the
growth of breast cancer cells by competitive antagonism of estrogen at the
ER
Some of the most important information regarding the benefits of
adjuvant tamoxifen have come from the Early Breast Cancer Trialists
Collaborative Group (EBCTCG).
Very young women(ie, those under the age of 35) :The EBCTCG analysis
included women under the age of 50 and did not stratify results according
to age group.,
On the other hand, the benefit of adjuvant tamoxifen is uncertain in this
group.
TAMOXIFEN
 Tamoxifen also decreases the risk of developing a contralateral breast
cancer.
Duration : Five years of treatment is considered standard regardless of
menopausal status.
Three published trials directly compared five years of tamoxifen versus a
longer treatment duration (10 years or indefinite) . Two of these, a
National Surgical Adjuvant Breast and Bowel Project (NSABP) trial and a
Scottish trial, raise the possibility that longer treatment might be
associated with worse outcomes(node-negative )
Eastern Cooperative Oncology Group (ECOG) trial,: The initial report of
this trial suggested that outcomes with tamoxifen treatment beyond five
years were not worse, and in fact, for women with ER+ disease, longer
treatment was associated with a significantly better relapse-free survival
(RFS) and a trend toward longer overall survival (node-positive )
Longer follow-up of the ECOG trial and two other large randomized trials
with relatively short follow-up that have reported only in abstract form (the
aTTom, and ATLAS trials ), will hopefully clarify these issues.
TAMOXIFEN
Timing of tamoxifen and chemotherapy : sequential rather than
concurrent therapy has been adopted as standard of care when
both chemotherapy and tamoxifen are administered
Timing of tamoxifen and RT : some clinical studies suggest the
possibility of increased breast and pulmonary fibrosis with
concurrent treatment
Two cohorts within the treated group were identified
retrospectively because RT was allowed either before adjuvant
therapy: these data support the view that sequencing of tamoxifen
and RT does not substantially affect outcomes.
However, the only way this question can truly be answered is
with a randomized controlled trial.
Summary
Tamoxifen (20 mg daily) is a standard adjuvant treatment
option for premenopausal women with ER+ early breast
cancer. Until more data become available, the
recommended duration of therapy is five years. If combined
chemotherapy and tamoxifen are given, sequential rather
than concurrent administration is recommended
OVARIAN FUNCTION
SUPPRESSION (OFS)
Methods : Surgical oophorectomy , Radiation-induced
ovarian ablation (4.5 Gy in one fraction, to 10 to 20 Gy in
five to six fractions), pharmacologic methods
Benefits of OFS in meta-analyses: The addition of an LHRH
analog to tamoxifen, chemotherapy, or both led to smaller
but more clearly proven reductions in the risk of recurrence
(13 percent, p = 0.02) and death (15 percent, p = 0.04)
compared to the same therapy without the LHRH analog.
Summary
these results support the view that endocrine therapy that includes OFS
is a reasonable alternative to adjuvant CMF , and possibly AC, FEC, and FAC
chemotherapy for premenopausal women with ER+ breast cancer
At least in North America, premenopausal women (especially those with
node-positive disease) are more likely to be offered chemotherapy plus
endocrine therapy (tamoxifen or OFS) rather than OFS with or without
tamoxifen.
whether combined endocrine therapy that includes OFS provides
superior outcomes over tamoxifen alone, particularly in women who
remain premenopausal after adjuvant chemotherapy .
This question is currently being addressed in the ongoing SOFT trial
Endocrine therapy for hormone
receptor positive early stage breast
cancer in postmenopausal women
TAMOXIFEN
five years of tamoxifen was associated with a 41 percent relative
reduction in the annual risk of relapse and a 34 percent relative reduction
in the annual risk of death among all women with ER+ breast cancer
Treatment duration :
Timing of tamoxifen:
The impact of concurrent aromatase inhibitors and RT is unknown
Tamoxifen 20 mg daily is a standard adjuvant treatment option for both
premenopausal and postmenopausal women with ER+ early breast cancer.
Until more data become available, the recommended duration of therapy
is five years
AROMATASE INHIBITORS
AIs , markedly suppress plasma estrogen levels in
postmenopausal women by inhibiting or inactivating
aromatase, the enzyme responsible for synthesizing
estrogens from androgenic substrates
In contrast to tamoxifen, these compounds lack partial
agonist activity.
AIs are generally avoided in premenopausal women. The
reduced feedback of estrogen to the hypothalamus and
pituitary increases gonadotropin secretion, which
stimulates the ovary, leading to an increase in androgen
substrate and aromatase
Efficacy
 at least five randomized trials have explored AIs in the adjuvant setting,
either as initial therapy, or sequentially after two to three or five years of
tamoxifen
In the landmark ATAC trial(Anastrozole, Tamoxifen Alone or in
Combination) , anastrozole (1 mg daily) was compared to tamoxifen (20 mg
daily) alone or the combination for five years in 9366 postmenopausal
women with ER+ (or unknown) breast cancer . At a median follow-up of
100 months, compared to tamoxifen alone, anastrozole was associated
with the following benefits
 Since tamoxifen reduces the risk of contralateral tumors by about 50
percent, this finding suggests that anastrozole might prevent 70 to 80
percent of ER+ contralateral tumors
No difference in overall survival has emerged, and there is no advantage
for combination therapy over tamoxifen alone
Similar benefit for letrozole over tamoxifen was noted in the multicenter
BIG 1-98 trial
AROMATASE INHIBITORS
Similar benefit for letrozole over tamoxifen was noted in
the multicenter BIG 1-98 trial, in which 8010
postmenopausal women were randomly assigned to
tamoxifen or letrozole for five years, or tamoxifen or
letrozole for two years, followed by the alternative agent for
three years
initial letrozole rather than tamoxifen was associated with
significantly better event-free survival (EFS, HR 0.82), but
not overall survival . The five-year DFS estimates were 84
versus 81 percent, respectively
Both anastrozole and letrozole are approved in the United
States for initial adjuvant therapy of postmenopausal
women with ER+ breast cancer.
Sequential tamoxifen and AIs
At least seven trials have compared tamoxifen alone to
sequential tamoxifen followed by an AI
After five years of tamoxifen :The most important trial
examining an SAI after five years of tamoxifen is the NCIC
MA 17 trial
The optimal duration of SAI therapy after five years of
tamoxifen is unknown
Women who chose letrozole (approximately two-thirds of
the cohort) had a significantly better DFS and distant DFS
compared to those who did not,
Sequential tamoxifen and AIs
The benefit of extending adjuvant endocrine therapy beyond five years
with an AI was also addressed in the Austrian Breast and Colorectal Cancer
Study Group (ABCSG)
At a median follow-up of 62 months, the sequential use of anastrozole
was associated with a significant 38 percent reduction in the risk of a new
or recurrent breast cancer but no overall survival benefit.
the optimal duration of AI therapy after five years of tamoxifen remains
uncertain
After two or three years of tamoxifen :
At least four other trials have studied switching to an AI after two to
three years of tamoxifen versus continued tamoxifen, all of which show a
significant DFS benefit from switching to an AI
the latest reports from two of the trials also suggest an overall survival
advantage for this approach
Letrozole and exemestane are both approved in the United States for this
indication.
Summary and ASCO
recommendation
the available data support the benefit of including an AI as a component
of adjuvant endocrine therapy in postmenopausal women with ER+ breast
cancer.
 AI is a reasonable alternative to tamoxifen for initial treatment of
postmenopausal women with ER+ disease. It is the treatment of choice in a
woman with a contraindication to tamoxifen or a desire to avoid the other
side effects associated with tamoxifen
Postmenopausal women who complete five years of tamoxifen should
consider taking an AI for up to five years. Ongoing analyses from the MA17
trial suggest additional benefit gained with each year of letrozole in
comparison to placebo
Alternatively, postmenopausal women completing two to three years of
tamoxifen could consider crossover to an AI, for a total of five years of
therapy, It is not known if a longer duration of AI therapy provides further
benefit.
SUMMARY AND
RECOMMENDATIONS
 five years of anastrozole (1 mg daily) or letrozole (2.5 mg daily)
rather than tamoxifen for initial treatment in postmenopausal
women with ER+ breast cancer . The role of additional tamoxifen
in women who have received an AI for five years is unknown, and
we suggest not doing this
Endocrine therapy in metastatic
breast cancer
endocrine therapies are classified:
1-Selective estrogen receptor modulators (ie, tamoxifen
and the related agent toremifene) ,
2- Steroidal antiestrogens (eg, fulvestrant) ,
3- Estrogen-deprivation therapies ,
4- Sex steroid therapies, including high-dose estrogen,
androgens,
5- and progestins (megestrol, medroxyprogesterone),
6-Sex steroid receptor-independent therapies
Endocrine therapy in metastatic
breast cancer
Over the last 35 years, the selective estrogen receptor modulator (SERM)
tamoxifen became the standard of care in much of the Western world for
hormone-responsive MBC in both premenopausal and postmenopausal
women due to its more favorable safety profile.
More recent studies suggest estrogen depletion may be a slightly more
effective strategy than tamoxifen, at least for postmenopausal women
Selective aromatase inhibitors (SAIs, anastrozole, letrozole, and
exemestane, ) are more effective and safer than aminoglutethimide
Moreover, randomized trials and a meta-analysis , suggest that SAIs are
more effective than tamoxifen for first-line therapy in postmenopausal
women whose tumors have not become previously resistant to these drugs
Treatment algorithms
a trial of endocrine therapy is warranted in a patient with
slowly progressive disease, no visceral involvement, and
minimal symptoms, even if the breast cancer has low or
absent ER expression.
Many patients with hormone-responsive MBC undergo
sequential endocrine maneuvers for second-line, third-line,
and even fourth-line therapy, reserving chemotherapy until
all endocrine options have been exhausted
Since palliation is the principal goal of therapy for MBC,
one can be relatively pragmatic about selection of
endocrine agents for individual patients, following certain
basic guidelines.
Postmenopausal women
most clinicians now favor SAIs over tamoxifen as the first choice for advanced
disease if a woman has relapsed while receiving adjuvant tamoxifen, if she has not
received any adjuvant endocrine treatment, or if she has relapsed more that one year
after discontinuing adjuvant tamoxifen or an SAI
If she has relapsed during or within 12 months of receiving an SAI in the adjuvant
setting, a SERM such as tamoxifen or toremifene, or fulvestrant represent appropriate
first-line treatment options
The treatment of patients whose tumors are resistant to SAIs has not been
adequately studied, and choices are largely based on toxicity, rather than efficacy
considerations. Tamoxifen is the most commonly used agent
The related agent toremifene appears to have similar efficacy and tolerability as
tamoxifen, but it is not effective for tamoxifen-refractory disease
For patients with disease progression following an SAI and tamoxifen or toremifene,
appropriate agents for third-line endocrine therapy or beyond include fulvestrant,
exemestane , megestrol acetate, or estrogen therapy (in carefully selected patients
with no history of thrombosis, uncontrolled hypercalcemia or cardiovascular risk
factors) Oophorectomy and GnRH agonists are ineffective treatments for
postmenopausal women and should not be offered
Premenopausal women
For premenopausal women, appropriate initial options include tamoxifen
(or toremifene) or ovarian function suppression (oophorectomy or a GnRH
agonist), or combined ovarian suppression plus tamoxifen.
Combined hormone therapy is favored over tamoxifen alone by many
clinicians, because it results in higher response rates and a longer time to
tumor progression (TTP), and it possibly has a small beneficial impact on
overall survival as well
For premenopausal women who progress after initial tamoxifen
monotherapy, ovarian function suppression is an alternative to
chemotherapy
An SAI is often introduced immediately following oophorectomy or in
conjunction with a GnRH agonist. However, there are no randomized trial
data of a GnRH agonist versus a GnRH agonist plus an SAI to support this
practice.
HER2-positive MBC
High expression levels identify patients who might respond to
therapies targeting HER2, such as trastuzumab and lapatinib
Another option for initial treatment of women with ER/PRpositive, HER2-positive MBC is combined trastuzumab plus
hormone therapy rather than hormone therapy alone
Hormone withdrawal response
Prior to the introduction of tamoxifen, it was observed that 25 to 35 percent
of patients treated with high-dose estrogens had a secondary response after the
estrogen was stopped at disease progression . This same phenomenon has been
observed (although less frequently) upon withdrawal of tamoxifen, progestins,
and exemestane
Convincing withdrawal responses generally occur in patients who have
experienced an initial response to hormone therapy. Although usually short
lived, some patients may experience disease stability for more than six months
Tamoxifen
Tamoxifen is an appropriate first-line agent in premenopausal women
who have never received tamoxifen or who relapse at least 12 months
after completion of adjuvant tamoxifen. It is also appropriate for
postmenopausal women who have a disease relapse during or within 12
months of receiving adjuvant therapy with an SAI.
expression of HER2 should not be used to select patients who might be
resistant to the beneficial effects of tamoxifen or any other endocrine
therapy
Tamoxifen withdrawal is an appropriate therapeutic maneuver for
patients who progress after achieving an objective response to tamoxifen
and whose symptoms are minimal at the time of disease progression.
OTHER ANTIESTROGENS
Several newer SERMs (raloxifene, toremifene, idoxifene) have
been evaluated for endocrine therapy of MBC, both in patients
who are resistant to tamoxifen and also as primary therapy.
only toremifene is commercially available in the United States
and approved for treatment of advanced breast cancer
Toremifene
Toremifene is a SERM that is 40-fold less estrogenic than tamoxifen, an effect that might
be expected to improve its side effect profile
Several trials and a meta-analysis directly comparing toremifene versus tamoxifen in
patients with untreated MBC have concluded that both agents have comparable activity and
a similar toxicity profile
toremifene is a reasonable alternative to tamoxifen for endocrine treatment of MBC,
although it provides no specific advantage over tamoxifen
Like raloxifene and idoxifene, toremifene is cross-resistant with tamoxifen and is
ineffective as second-line therapy in patients refractory to tamoxifen
Pure antiestrogens
Fulvestrant (Faslodex®), a "pure" antiestrogen, has a steroid structure
that allows it to compete with estrogen for the ER
Fulvestrant is also active in women who are refractory to an SAI
With respect to first-line endocrine therapy, one trial directly compared
fulvestrant versus tamoxifen in 587 women with previously untreated MBC
. No significant advantage was shown for fulvestrant in terms of response
rates, TTP, or treatment tolerability.
 No trials have directly compared fulvestrant versus an SAI for first-line
therapy.
The use of fulvestrant is limited to postmenopausal women
A second orally active pure antiestrogen, EM-800, is also active in
patients with tamoxifen-resistant breast cancer [62]. EM-800 is not
commercially available in the United States.
Ovarian ablation/suppression
plus tamoxifen
Combined therapy with tamoxifen and ovarian ablation/suppression is
favored over either approach alone for premenopausal women by many
clinicians, because it results in higher response rates, a longer TTP, and
possibly has a small beneficial impact on overall survival as well
Combined therapy is not necessarily associated with worse side effects
a combination of oophorectomy or a GnRH agonist plus tamoxifen as
first-line endocrine therapy could be recommended to premenopausal
women with MBC who have either never received adjuvant tamoxifen or
relapsed more than 12 months after completion of such therapy.
since the overall survival gains from combination therapy are small, it is
also reasonable to offer patients sequential treatment with tamoxifen
initially, followed by either a GnRH agonist or oophorectomy at the time of
disease progression.
Third-line treatments for premenopausal women with MBC resistant to
tamoxifen and oophorectomy or a GnRH agonist include an SAI or
fulvestrant (for women who have become menopausal)
AROMATASE INHIBITORS IN
POSTMENOPAUSAL WOMEN
Aminoglutethimide; The benefit of aromatase inhibition for
advanced breast cancer was first recognized in patients who
received high doses of aminoglutethimide
Anastrozole: Anastrozole was the first SAI to be approved in both
North America and Europe.
Letrozole:Letrozole is a more potent suppressor of aromatase
activity than is anastrozole
Whether letrozole is superior to anastrozole is unclear. Although
from a pharmacokinetic standpoint, letrozole is a more effective
aromatase inhibitor
AROMATASE INHIBITORS IN
POSTMENOPAUSAL WOMEN
Vorozole:Vorozole is another third-generation nonsteroidal AI that is not
commercially available in the United States
There are no trials of vorozole in the setting of first-line therapy.
Exemestane and formestane :Steroidal aromatase inhibitors such as
exemestane (Aromasin®) and formestane (Lentaron®, available outside of
the United States) are androgenic steroids that are resistant to the action
of aromatase
A response to exemestane can be observed in patients who never
responded to tamoxifen (primary tamoxifen resistance) as well as in those
who have failed other nonsteroidal aromatase inhibitors such as
anastrozole and letrozole
Fadrozole”: Like formestane, fadrozole is a second generation , It is
effective in patients with tamoxifen-refractory advanced breast cancer, and
at least two trials suggest similar efficacy as tamoxifen for first line therapy
Summary
Several trials and a meta-analysis demonstrate that the SAIs are
slightly more effective than other endocrine agents, including
tamoxifen, for treatment of hormone sensitive MBC in terms of
response rate, delay of disease progression, and even prolongation
of survival
unless a patient is refractory to SAIs (ie, relapses while receiving
an SAI in the adjuvant setting), an SAI (anastrozole, letrozole, or
exemestane) should be considered as superior to tamoxifen for
first line treatment of postmenopausal women with hormone
receptor-positive MBC.
‘/
SEX STEROID HORMONES
Patients who have low volume disease that is restricted to bone or soft
tissue, few disease-related symptoms, and a history of a response to either
tamoxifen or an SAI (or both) may be considered candidates for third or
fourth-line endocrine therapy using progestins, androgens, or estrogens
Progestins:Megestrol acetate and medroxyprogesterone acetate are
progestational agents with significant activity in advanced breast cancer
Androgens :Androgens, including testosterone, fluoxymesterone, and the
less virilizing agent testolactone, are rarely used to treat MBC
Estrogens:Before the advent of contemporary endocrine therapy options,
advanced breast cancer in postmenopausal women was commonly treated
with high dose estrogen, this approach is ineffective before the menopause
Patients with prior heavy exposure to endocrine therapy (tamoxifen,
megestrol acetate, SAI) may still respond to high dose estrogens
RECOMMENDATIONS
(Postmenopausal women with ER
and/or PR-positive MBC)
For postmenopausal women who have not received adjuvant therapy
with a SAI or whose disease relapses longer than 12 months after finishing
adjuvant SAI, we recommend a SAI rather than tamoxifen as the first choice
for advanced disease
If disease relapse has occurred within 12 months of receiving an adjuvant
SAI, we suggest initiating therapy with tamoxifen rather than an SAI , An
acceptable alternative to tamoxifen in this setting is fulvestrant
For patients with disease progression following tamoxifen and an SAI,
appropriate agents for third-line hormone therapy include fulvestrant or an
alternative class of SAIs (eg, if a triazole such as letrozole or anastrozole
was used initially, one might try a steroidal agent such as exemestane and
vice versa).
Options for fourth line therapy and beyond include megestrol acetate or
estrogen therapy in carefully selected patients (no history of thrombosis,
uncontrolled hypercalcemia or cardiovascular risk factors).
Premenopausal women with ER
and/or PR-positive MBC
For premenopausal women who have never received adjuvant
tamoxifen or who relapsed more than 12 months after completion
of such therapy, we suggest a combination of a GnRH agonist and
tamoxifen as first-line therapy
an acceptable alternative approach, particularly for
asymptomatic women with slowly progressive disease, is
sequential treatment (tamoxifen followed by either a GnRH analog
or oophorectomy at the time of progression
For women who relapse within 12 months of adjuvant
tamoxifen, we recommend ovarian ablation or suppression as
initial endocrine treatment
For premenopausal women who progress after ovarian
ablation/suppression and tamoxifen, options for sequential
endocrine treatment include an SAI or fulvestrant (if the woman
has become menopausal) or megestrol acetate
HER2-overexpressing, ER/PRpositive MBC
For women whose breast cancers coexpress HER2 and hormone
receptors we suggest trastuzumab plus hormone therapy rather
than hormone therapy alone
Initiation of trastuzumab may be delayed if the patient does not
wish to undergo IV therapy, particularly if the pace of disease
growth is slow and there are no rapidly progressing liver or lung
metastases.