DrMina Tajvidi Radiation oncologist Endocrine therapy in breast cancer Endocrine therapy for hormone receptor positive early stage breast cancer in premenopausal women ID: 775320
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Slide1
Endocrine therapy in breast cancer
Dr.Mina Tajvidi Radiation oncologist
Slide2Endocrine 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
Slide3Endocrine therapy for hormone receptor positive early stage breast cancer in premenopausal
Slide4Choice 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
Slide5TAMOXIFEN
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.
Slide6TAMOXIFEN
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.
Slide7TAMOXIFEN
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.
Slide8Summary
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
Slide9OVARIAN 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.
Slide10Summary
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
Slide11Endocrine therapy for hormone receptor positive early stage breast cancer in postmenopausal women
Slide12TAMOXIFEN
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
Slide13AROMATASE 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
Slide15AROMATASE 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.
Slide16Sequential 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,
Slide17Sequential 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.
Slide18Summary 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.
Slide19SUMMARY 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
Slide20Endocrine 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
Slide21Endocrine 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
Slide22Treatment 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.
Slide23Postmenopausal 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
Slide24Premenopausal 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.
Slide25HER2-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/PR-positive, HER2-positive MBC is combined
trastuzumab
plus hormone therapy rather than hormone therapy alone
Slide26Hormone 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
Slide27Tamoxifen
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.
Slide28OTHER 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
Slide29Toremifene
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.
Slide31Ovarian 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)
Slide32AROMATASE 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
Slide33AROMATASE 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
Slide34Summary
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.
‘/
Slide35SEX 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
Slide36RECOMMENDATIONS (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).
Slide37Premenopausal 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
Slide38HER2-overexpressing, ER/PR-positive 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.
Slide39Slide40