Selecting Adjuvant Endocrine Therapy for Breast Cancer

Selecting Adjuvant Endocrine Therapy for Breast Cancer

ABSTRACT: This year alone, more than 215,000 women in the United States will be diagnosed with, and over 40,000 will die from, invasive breast cancer. Recently, mortality from female breast cancer has declined despite an increase in its incidence. This decline corresponds with improved screening for prompt tumor detection, and advances in the treatment of early disease. Of these, endocrine therapy has played a prominent role. For women with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancers, endocrine therapy has proven to be a major component of adjuvant therapy, but it is not effective in women whose breast cancers lack ERs and PRs. The selective estrogen-receptor modulator (SERM) tamoxifen has been well established as safe and effective in the adjuvant care of both pre- and postmenopausal women with hormone-receptor–positive early breast cancer. For premenopausal women, ovarian suppression is an important option to be considered. Additionally, the aromatase inhibitors have recently demonstrated utility in postmenopausal women. The ideal sequencing of treatment with tamoxifen and/or an aromatase inhibitor is the subject of several ongoing studies. Factors involved in selecting an appropriate endocrine regimen have grown considerably over the past decade. It is becoming more important for those caring for women with breast cancer to fully understand the available endocrine treatment options and the prognostic and predictive factors available to help select the most appropriate treatment. The goal of this article is to assist clinicians in making decisions regarding adjuvant hormonal therapy and to provide information regarding available clinical trials. To achieve this, the therapeutic options for hormonal therapy will be reviewed, as will prognostic and predictive factors used in making decisions. Finally, four cases illustrating these difficult decisions will be discussed, with recommendations for treatment.

The incidence of female breast
cancer in the United States has
been rising, with an estimated
215,990 new cases in 2004.[1] Despite
this, there has been a decline in breast
cancer mortality.[2] This decline in
mortality is paralleled by an increasing
use of adjuvant hormonal therapy,
which is associated with an increase
in survival.[3] Selecting an appropriate
endocrine regimen has become
more complex as choices of endocrine
therapy expand. Until that time when
we can identify with certainty the specific
patients who benefit from adjuvant
care, meaningful counseling will
require not only an understanding of
the risks and benefits of the various
treatments, but also an appreciation of
the patient's perspective. Issues regarding
reproduction, body image,
sexuality, and timing of side effects are
part of the quality-of-life decisions
facing women with breast cancer and
those who would advise them.[4]

Since Beatson first reported the
benefit of surgical oophorectomy in
the management of breast cancer over
a century ago,[5] the role of endocrine
therapy has evolved. Synthetic estrogen
use was first reported by Haddow
et al in 1944.[6] Shortly thereafter,
adrenalectomy and hypophysectomy
in women with metastatic breast cancer
were shown to have a benefit in
postmenopausal women.[7,8] Advances
in our understanding of the
endocrine pathways have since revealed the mechanisms by which these
early surgical methods function. There
are now multiple options for blocking
the hormonal stimulation of tumors by
estrogens, the basis of adjuvant hormonal
therapy. These options include
selective estrogen-receptor modulators
(SERMs), aromatase inhibitors, and
medical oophorectomy with luteinizing
hormone-releasing hormone
(LHRH) agonists.

In this article, we will review the
various options available and discuss
their efficacy, side effects, and relevant
ongoing clinical trial options. We will
also review the prognostic and predictive
factors that can be used to make
informed decisions regarding adjuvant
therapy. We will present four cases that
illustrate difficulties in choosing adjuvant
therapy and finally summarize
our recommendations and the major
consensus for adjuvant hormonal
therapy (Table 1).

Treatment Options

Optimum use of adjuvant hormonal
therapy is dependent on menopausal
status. Ovarian ablation-either permanent
(using surgical or radiotherapeutic
ablation) or temporary (using
pharmacologic agents such as LHRH
agonists)-is a potential strategy for
premenopausal women. The aromatase
inhibitors are appropriate only for
postmenopausal women and can be
used in conjunction with LHRH agonists.
SERMs such as tamoxifen are a
viable option regardless of hormonal
status. Table 2 reviews all endocrine
therapies used in the treatment of
breast cancer. This article will focus
only on those treatments indicated for
use in adjuvant therapy.

Selective Estrogen-Receptor

The SERMs have varying estrogenic
or antiestrogenic effects, depending
on type and target tissue. The most
widely studied SERM, tamoxifen, has
become a treatment standard backed
by several well-constructed clinical
trials as well as the overview analysis.[
3] Tamoxifen is the only SERM
currently approved by the US Food
and Drug Administration (FDA) for
use in the adjuvant setting. Women
with estrogen receptor (ER)-positive
breast tumors who have completed
5 years of tamoxifen will derive a 47% reduction in annual rate of relapse
and a 26% reduction in annual
rates of breast cancer-related death,
regardless of menopausal status.[3]
Women with node-positive disease
achieve greater absolute benefit from
tamoxifen at 10 years (15.2% decrease
in recurrence and 10.9% reduction
in mortality) compared to nodenegative
women (14.9% decrease in
recurrence and 5.6% reduction in

The optimal duration of adjuvant
tamoxifen therapy is probably 5 years.
Adjuvant tamoxifen use for 1, 2, and
5 years has been associated with relative
recurrence reductions of 21%,
29%, and 47%, respectively, and relative
mortality reductions of 12%,
17%, and 26%.[3] Current data suggest
no additional benefit from treatment
with more than 5 years of
tamoxifen,[9] and in lymph node-
negative breast cancer patients, there
may be a disadvantage to longer treatment
periods.[10,11] Importantly, no
significant decrease in cancer recurrence
or improvement in survival is
seen when tamoxifen is given to
women with ER-negative tumors.[3]

Adjuvant tamoxifen for 5 years has also been shown to reduce the risk of
contralateral breast cancer by 47%.[3]
While patients treated with tamoxifen
have a higher proportion of ER-negative
second primary breast cancers as
compared with those who did not receive
tamoxifen, the absolute numbers
of ER-negative second primary
tumors are the same and patient survival
does not appear to be significantly

Whether tamoxifen is effective in
reducing the incidence of contralateral
breast cancers in women with ERnegative
primary tumors remains a
matter of debate. The Early Breast
Cancer Trialists' Collaborative group
overviews from 1998 and 2001 demonstrated
a decreased rate of contralateral
breast cancer when all patients,
irrespective of tumor ER status, took
tamoxifen for 5 years.[3,13] Other
studies performed by the National
Surgical Adjuvant Breast and Bowel
Project (NSABP) and the Southwest
Oncology Group (SWOG) showed no
decrease in contralateral breast cancers
with the addition of tamoxifen for
women with high-risk, ER-negative,
node-negative tumors.[14-16]

  • Side Effects-The side-effect profile
    of SERMs is in great measure a
    function of their relative agonist and
    antagonist properties. Agonist effects
    on bone allow tamoxifen to attenuate
    osteoporosis in postmenopausal
    women. Paradoxically, it can increase
    calcium loss in premenopausal
    women.[17] In the liver, the use of
    tamoxifen can improve the lipid profile.
    Tamoxifen is associated with a
    two- to threefold increased risk of
    thrombosis, which is more pronounced
    for older women.[18] Although
    the mechanism is not well
    understood, reduced levels of antithrombin
    III and protein S have been
    seen in women on tamoxifen.[19]

    Effects on the hypothalamicgonadal
    axis contribute to the problematic
    vasomotor symptoms (hot
    flashes). Additionally, there is a 10%
    increased absolute risk of menopause
    over the first year of use for women over
    45 years old.[20] Women younger than
    age 45, however, have no significant
    increased risk of premature menopause
    during this period.[20]

    Tamoxifen's stimulatory effect on
    the endometrium of postmenopausal
    women is associated with an increased
    risk of endometrial cancer and, rarely,
    endometrial sarcoma. For postmenopausal
    women, the relative risk of
    developing endometrial cancer after
    5 years of tamoxifen is approximately
    1%.[21,22] Endometrial hyperplasia,
    polyps, and ovarian cysts are also
    seen. Tamoxifen has also been associated
    with retinopathy, macular
    edema, and subcapsular cataracts.[23]
    Annual eye exams, screening pelvic
    exams, and Pap smears are recommended
    for women while receiving
    tamoxifen therapy and for 1 year upon
    completion of treatment.

Ovarian Ablation/Suppression
Oophorectomy has been shown to
be of benefit in the adjuvant setting
for premenopausal women with hormone-
receptor-positive breast cancer.[
24,25] There are now several
options for ovarian suppression or ablation.
Permanent ablation can be
achieved surgically or with irradiation,
and temporary suppression can be
achieved using one of several LHRH

Surgical oophorectomy is irrevers ible and, when performed laproscopically,
carries minimal risk. It also provides
a 90% decrease in the risk of
ovarian cancer for all women, and for
premenopausal women with germ-line
abnormalities in BRCA1/2, oophorectomy
may confer a 50% reduction in
the risk of breast cancer.[26,27] It is
important to note that oophorectomy,
in this setting, should be discussed
with a gynecologist who is familiar
with the issues of ovarian cancer risk
reduction to consider complete hysterectomy
or just the removal of fallopian
tubes and ovaries. Ovarian irradiation,
on the other hand, may appeal
to many by avoiding surgery. Such
therapy can be accomplished with the
use of either single or multiple fractions;
however, on rare occasions,
menses may return.

The LHRH agonists triptorelin
(Trelstar), goserelin (Zoladex), or
leuprolide may also be utilized to
achieve ovarian suppression. These
agents downregulate LHRH receptors,
causing a decline in leuteinizing hormone
(LH) and follicle-stimulating
hormone (FSH) release from the pituitary,
with a subsequent drop in systemic
estrogen levels. Adverse side effects
are those of menopause and include
headache, vasomotor symptoms,
depression, emotional lability, sexual
dysfunction, and vaginitis. This abrupt
menopause may be poorly tolerated.
Monitoring of bone mineral density for
the treatment of osteoporosis is required
with ovarian ablation. Bone loss occurring
with ovarian suppression is likely
to be reversible[28] or attenuated with
bisphosphonate therapy.

  • Ovarian Suppression vs Chemotherapy-
    Adjuvant ovarian ablation
    in women with hormone-receptor-
    positive breast cancer has been associated
    with a significant reduction in
    the annual risk of relapse (25%) and
    of dying of breast cancer (24%).[24]
    However, no significant difference has
    been observed when ovarian ablation
    is added to chemotherapy.[24,25] It
    may be that much of the observed
    benefit from adjuvant chemotherapy
    is derived from its ability to induce
    menopause in these trials, dampening
    the likelihood of observing a further
    reduction in relapse. The incidence of chemotherapy-induced amenorrhea is
    a function of both patient age and
    chemotherapy regimen, with reported
    rates of 40% to 70%.[29,30]

    Increases in both relapse-free and
    overall survival have been demonstrated
    for women who become amenorrheic
    after chemotherapy over those
    with continued menses.[31,32] Other
    studies have failed to demonstrate
    similar benefits of chemotherapyinduced
    amenorrhea.[33,34] Several
    trials have compared ovarian inhibition
    vs polychemotherapy and demonstrated
    similar efficacy in disease-free
    and overall survival in premenopausal
    woman with hormone-receptor-positive
    tumors.[35-37] However, these
    investigations did not use anthracycline-
    or taxane-based therapy, and
    thus, ovarian suppression has not been
    compared to current optimal chemotherapy.

    Quality of life may be better with
    ovarian suppression as compared to
    chemotherapy.[4] Therefore, it is important
    to compare ovarian suppression
    to current, more effective chemotherapy
    regimens. Given the risk of
    amenorrhea with chemotherapy,
    women hoping to maintain fertility
    may opt for ovarian suppression with
    LHRH agonists. To reduce the risk of
    permanent amenorrhea and provide
    adjuvant ovarian suppression therapy,
    an LHRH agonist could be started
    1 month prior to initiation of chemotherapy.[
    38] Currently, this strategy
    should be used with caution and considered
    experimental. Return of
    menses after an LHRH agonist may
    not be equivalent to fertility, and the
    estrogen withdrawal associated with
    LHRH agonists may theoretically
    slow tumor cell growth, resulting in
    loss of chemosensitivity.

Aromatase Inhibitors
In postmenopausal women and in
women for whom an early menopause
has been induced with ovarian ablation,
aromatase inhibitors may represent
the most effective endocrine option.
Aromatase converts testosterone
to estrogen and androstenedione to
estrone in adipose, muscle, breast, and
breast cancer cells. By blocking this
conversion, estrogen levels are decreased
by more than 90%.

The aromatase inhibitors have been
grouped into three generations. The
first generation includes aminoglutethimide
(Cytadren), originally
used in breast cancer management as
a means of medical adrenalectomy. It
has significant toxicity, causing it to
be mostly of historical significance.
The second-generation agents include
the nonsteroidal rogletimide and
fadrozole (approved for use in Japan)
and the steroidal formestane (administered
intramuscularly). Selective
antiaromatase drugs comprise the third
generation of aromatase inhibitors and
are currently the aromatase inhibitors
of choice. These include the steroidal,
irreversible "suicide" inhibitor exemestane
(Aromasin) and the nonsteroidal
reversibly binding anastrozole
(Arimidex), letrozole (Femara), and
vorozole (R83842).

Despite an increased risk of bone
demineralization and frequent myalgias/
arthralgias, the aromatase inhibitors
are generally well tolerated.[
39,40] Anastrozole is associated
with lower rates of thromboembolic
events than tamoxifen. However,
higher rates of ischemic cardiovascular
events were reported with anastrozole
than with tamoxifen, although
this difference was not statistically different.[
41] Lower rates of endometrial
cancer and vaginal bleeding are seen
with aromatase inhibitors.

  • First-Line/Neoadjuvant Setting-
    As first-line agents in postmenopausal
    women with metastatic hormonereceptor-
    positive breast cancer, the
    aromatase inhibitors have demonstrated
    equal to superior time to progression
    and response rates when
    compared with tamoxifen,[42-44] and
    in the neoadjuvant setting, a decreased
    time to response.[45] In fact, some
    investigators maintain that aromatase
    inhibitors may be superior to chemotherapy
    for the neoadjuvant management
    of hormone-receptor-positive
    tumors by causing uniform, concentric
    tumor shrinkage with less
    multifocal residua and a greater
    likelihood of complete tumor excision
    at surgery.[46] Furthermore, neoadjuvant
    chemotherapy may be less
    effective in ER-positive tumors than
    ER-negative tumors (the inverse of which is true for neoadjuvant hormonal
  • Adjuvant Setting-The benefit of
    the aromatase inhibitors in the firstline
    and neoadjuvant settings has led
    to the question of possible superiority
    to tamoxifen in the adjuvant setting.
    Results reported by the Arimidex,
    Tamoxifen Alone or in Combination
    (ATAC) trialists' group after a median
    follow-up of only 47 months demonstrate
    that anastrozole provides a
    14% reduction in relative risk of recurrence
    and 46% reduction in relative
    risk of a second primary compared
    to tamoxifen.[39,40] Further followup
    of this and other studies of adjuvant
    therapy should help us compare
    the relative risks and benefits of
    tamoxifen vs anastrozole, letrozole,
    and exemestane.

    Additional studies have focused on
    the role of adjuvant aromatase inhibitor
    therapy subsequent to tamoxifen;
    results from four of these trials have
    been released.[48-51] Early closure of
    the letrozole trial led by the National
    Cancer Institute of Canada (NCIC)[49]
    was recommended after a median follow-
    up of 2 years. Interim analysis
    demonstrated a significant increase in
    event-free survival for women randomized
    to letrozole after tamoxifen
    (compared to placebo).

    Two additional trials have recently
    been reported-one using anastrozole[
    50] and another, exemestane[51]
    begun after 2 to 3 years of tamoxifen,
    to complete a 5-year adjuvant treatment
    course, compared to tamoxifen
    alone for 5 years. Both of these studies
    confirmed an increase in diseasefree
    survival with transition to an
    aromatase inhibitor.

    Of note, a trial of sequential
    aminoglutethimide following 2 years
    of tamoxifen vs tamoxifen for 5 years
    (the predecessor to the above anastrozole
    study) demonstrated a mortality
    benefit with sequential therapy.[48]
    However, owing to the poor sideeffect
    profile of aminoglutethimide
    and the advent of the third-generation
    aromatase inhibitors, this trial failed
    to recruit its planned number of patients,
    and its results should be considered
    preliminary. More recently, in
    a presentation updating the above NCIC MA.17 letrozole trial, a significant
    increase in overall survival was
    observed for the node-positive subset
    of patients (personal communication,
    H.B. Muss, 2004).[52]

    The current role of aromatase inhibitors
    in the adjuvant setting is controversial.
    The four trials discussed
    above include over 16,000 women and
    although the follow-up is short, all
    show decreased relapse rates of breast
    cancer for women on aromatase inhibitors
    compared to tamoxifen. Not
    only are these data compelling, but
    they confirm what we already know
    regarding the superiority of aromatase
    inhibitors in the metastatic setting. It
    is, therefore, reasonable to consider
    using aromatase inhibitors for the
    majority of postmenopausal women
    except for those at lowest risk of recurrence,
    in whom survival data associated
    with tamoxifen are an important
    part of the risk/benefit ratio. For
    women currently on tamoxifen, it is
    reasonable to consider changing to an
    aromatase inhibitor, again for those at
    higher risk of recurrence or intolerant
    of tamoxifen. We suggest specific
    aromastase inhibitor selection be
    determined by the currently available
    trial information. That is, anastrozole
    as first-line adjuvant therapy, exemestane
    after 2 to 3 years of tamoxifen,
    and letrozole after 5 years of


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