Endocrine therapy in breast cancer - PowerPoint Presentation

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Endocrine therapy in breast cancer

Dr.Mina Tajvidi Radiation oncologist

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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

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Endocrine therapy for hormone receptor positive early stage breast cancer in premenopausal

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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

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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.

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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.

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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.

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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

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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.

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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

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Endocrine therapy for hormone receptor positive early stage breast cancer in postmenopausal women

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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

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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

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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

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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.

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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,

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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.

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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.

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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

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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

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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

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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.

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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

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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.

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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/PR-positive, HER2-positive MBC is combined

trastuzumab

plus hormone therapy rather than hormone therapy alone

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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

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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.

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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

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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

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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.

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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)

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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

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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

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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.

‘/

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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

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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).

Slide37

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

Slide38

HER2-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.

Slide39

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