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Treatment approach to metastatic hormone receptor-

positive, HER2-negative breast cancer: Endocrine therapy
and targeted agents
Authors: Cynthia X Ma, MD, PhD, Joseph A Sparano, MD
Section Editor: Daniel F Hayes, MD
Deputy Editor: Sadhna R Vora, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 03, 2020.

INTRODUCTION

In general, breast cancer can be broken down into three biologic subgroups, each of which has a
direct bearing on treatment choices: 1) those that express the estrogen receptor (ER), 2) those that
express the human epidermal growth factor receptor 2 (HER2 [with or without ER expression]), and
3) those that do not express either of these, nor the progesterone receptor (triple-negative).

Although metastatic breast cancer is unlikely to be cured, there have been meaningful improvements
in survival due to the availability of more effective systemic therapies, including endocrine therapy
(ET) in the treatment of hormone-sensitive disease.

ET alone or in combination with targeted agents (phosphoinositide 3-kinase [PI3K], mechanistic

target of rapamycin [mTOR], or cyclin-dependent kinase [CDK] 4/6 inhibitors) for metastatic hormone
receptor-positive, HER2-negative breast cancer is presented here. The treatment of HER2-positive
disease is discussed elsewhere, as is chemotherapy (in general) for metastatic breast cancer.
Polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in patients with metastatic breast
cancer and a germline breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutation are also
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discussed separately. Other topics including the approach to breast cancer and the role of adjunctive
therapy, such as pain medications and bone-modifying agents, are also covered separately.

● (See "Systemic treatment for metastatic breast cancer: General principles".)

● (See "Systemic treatment of metastatic breast cancer in women: Chemotherapy" and "Systemic
treatment for HER2-positive metastatic breast cancer".)
● (See "Breast cancer in men".)
● (See "Cancer pain management: Adjuvant analgesics (coanalgesics)" and "Cancer pain
management: Use of acetaminophen and nonsteroidal antiinflammatory drugs" and "Cancer pain
management with opioids: Optimizing analgesia".)
● (See "Use of osteoclast inhibitors in early breast cancer".)
● (See "Prognostic and predictive factors in metastatic breast cancer".)
● (See "Management of brain metastases in breast cancer" and "Radiation therapy for the
management of painful bone metastases".)

GOALS OF THERAPY

Patients with estrogen receptor (ER)-positive metastatic breast cancer often respond to ET alone or
in combination with targeted agents, which can reduce tumor burden and symptoms with generally
fewer side effects and toxicities than chemotherapy. Furthermore, modern ETs appear to prolong
progression and possibly survival compared with older ETs. However, few if any patients with
metastatic breast cancer will be cured, and the goal of therapy is, principally, palliation. We make
efforts to choose the therapy that is most likely to stabilize or reduce the burden of disease with the
fewest side effects and maintain that therapy until either unacceptable toxicities are evident or
disease progression occurs.

GENERAL PRINCIPLES

Types of ET — There are several types of endocrine therapies (ETs). These can be characterized as
strategies to deplete estrogen and strategies to directly target the estrogen receptor (ER).

● Strategies to deplete estrogen – While initial therapies to deplete estrogen were accomplished
in premenopausal women by oophorectomy, estrogen can now be suppressed with the use of
luteinizing hormone-releasing hormone (LHRH) agonists and antagonists. Although ovarian
estrogen production disappears with menopause, postmenopausal women continue to produce
low levels of estrogen. This estrogen is derived from adrenal precursors, testosterone, and

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androstenedione that are converted to estradiol and estrone by aromatase activity in peripheral
cells and even in the cancers themselves.

Specific inhibitors of aromatase are available. Two of these, anastrozole and letrozole, are azole
compounds, while the third, exemestane, is a 17-hydroxy steroid. Prospective randomized clinical
trials in both the adjuvant and metastatic setting have demonstrated that the clinical activity, side
effects, and toxicity of these three aromatase inhibitors (AIs) are almost identical, and the choice of
any one of them is appropriate. (See 'Aromatase inhibitor monotherapy' below.)

● Strategies to directly target the estrogen receptor – There are two strategies to interfere with
ER signaling: the use of selective estrogen receptor modulators (SERMs) or selective estrogen
receptor down-regulators (SERDs).

• Tamoxifen is a SERM with mixed ER antagonistic and agonistic properties. It is principally

antagonistic in breast cancer and breast tissue, as well as brain, whereas it has agonistic
effects in bone, liver, and uterus. (See 'Later-line therapy' below.)

Raloxifene appears to be a weaker SERM. It is not indicated for the adjuvant or metastatic
treatment of breast cancer, and it is only indicated in the prevention setting. (See "Selective
estrogen receptor modulators and aromatase inhibitors for breast cancer prevention",
section on 'Raloxifene'.)

● Fulvestrant is the only available agent that down-regulates ER. Fulvestrant is a highly insoluble
compound with poor oral bioavailability and a short intravenous half-life, and therefore must be
given intramuscularly. Fulvestrant is very dose dependent, with studies showing improved
efficacy at 500 mg rather than 250 mg intramuscularly [1,2]. (See 'Fulvestrant-based
combinations' below.)

While estrogen obviously has agonistic activity for ER, its use is generally restricted to the later-line
setting. Androgens and progestins have been used in the past against ER-positive metastatic breast
cancer; however, the mechanism of action of these agents has never been clear and because of their
toxicities, and relatively lower efficacies compared with more modern ETs, they are rarely if ever used
anymore. (See 'Later-line therapy' below.)

Rationale for inhibition of other targets (eg, CDK 4/6, PI3K, mTOR etc.) — Over the last decade,
several prospective, randomized clinical trials have demonstrated that addition of agents that
mechanistically work in different ways than through ER interference can enhance the benefit seen
with ET alone. In particular, cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with ET are
often used as a first-line therapy. Three separate agents, palbociclib, ribociclib, and abemaciclib,
which inhibit CDK 4/6, substantially improve progression-free survival (PFS) when added to ET as

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first-line or subsequent therapies [3], with ribociclib and abemaciclib also having demonstrated an
overall survival (OS) benefit in combination with ET in some trials. For those with tumor
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations whose
cancers have progressed on or after treatment with an AI, the addition of the alpha isoform-specific
phosphoinositide 3-kinase (PI3K) inhibitor alpelisib to fulvestrant improves PFS. Everolimus, an
inhibitor of the mechanistic target of rapamycin (mTOR), has also demonstrated improved PFS when
added to ET in the endocrine-resistant setting.

At this time, there are no randomized trials addressing the optimal sequencing of various targeted
agents or their combination in patients receiving ET. Because the side-effect profile of the CDK 4/6
inhibitors appears substantially more tolerable than that seen with everolimus or alpelisib, we prefer
using CDK 4/6 inhibitors rather than everolimus or alpelisib as the initial targeted therapy to partner
with ET.

Resistance to treatment — The presence of new metastatic lesions, clinical deterioration, or growth
of lesions suggests a given treatment is not working. Appropriate monitoring, duration of treatment,
and definition of failure is discussed in more detail elsewhere. (See "Systemic treatment for
metastatic breast cancer: General principles", section on 'Monitoring therapy' and "Systemic
treatment for metastatic breast cancer: General principles", section on 'Duration of treatment' and
"Systemic treatment for metastatic breast cancer: General principles", section on 'Definition of
treatment failure'.)

When a patient's cancer fails to respond or stops responding to a given line of ET or a targeted agent,
an important consideration is whether or not to proceed with another line of ET (with or without a
targeted agent) or move to chemotherapy. The relative level of ER in the tissue (1 to 9 versus ≥10
percent), the duration of response to the prior ET or targeted therapy, the patient's tolerance of prior
therapy, and the presence or absence of rapidly progressive visceral disease should all factor into the
decision regarding whether to proceed with another line of ET/targeted therapy or move to
chemotherapy. Testing of PIK3CA mutation status is necessary for treatment with alpelisib plus
fulvestrant. We often offer patients two to three lines of ET (including targeted agents) before moving
to chemotherapy. (See "Systemic treatment of metastatic breast cancer in women: Chemotherapy".)

Many possible reasons exist for resistance to ET. For example:

● Studies have suggested that up to 30 percent of metastatic ER-positive breast cancers may have
activating mutations in the estrogen-binding domain of the gene that encodes for ER (ESR1)
[4,5]. In this case, these cancers may be resistant to estrogen depletion (eg, AIs), but they may
better respond to ER-targeting therapies, perhaps requiring higher doses of SERM or SERD than
needed for wild-type cancers. Clinical trials are being conducted to test this hypothesis, but given

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limited available data and lack of validated assays, we do not routinely test for or use ESR1
mutational status to direct care for those not enrolled in a clinical trial.

● Some data have suggested that altered tamoxifen metabolism may affect its activity by virtue of
inherited deleterious mutations in or pharmacologic inhibition of the cytochrome P450 2D6
(CYP2D6) gene, which both prevent conversion of native tamoxifen to its 4-hydroxy-N-desmethyl
derivative ("endoxifen") [6-13]. Endoxifen has much higher affinity for the ER than native
tamoxifen and is present in approximately 10-fold higher concentrations in patients with wildtype
compared with homozygous mutant CYP2D6. However, the weight of evidence, although not all,
suggests that CYP2D6 abnormalities and/or use of CYP2D6 inhibitors does not substantially
affect outcomes in patients taking tamoxifen [14-21]. We do not test for germline CYP2D6 status
or use it to direct therapy for ER-positive patients in the adjuvant or metastatic disease setting.
(See "Mechanisms of action of selective estrogen receptor modulators and down-regulators",
section on 'Altered tamoxifen metabolism'.)

Resistance mechanisms to targeted therapies against CDK 4/6 or mTOR, or PI3K, are an area of
ongoing research.

DECIDING ON CHEMOTHERAPY VERSUS ENDOCRINE/TARGETED THERAPY

Our approach to deciding whether a patient with metastatic breast cancer is a candidate for ET is as
discussed in the sections below.

Biopsy of a metastatic lesion

● We first biopsy a metastatic lesion in patients with new metastatic disease to confirm estrogen
receptor (ER), progesterone receptor (PR), and HER2 status. This is because up to 15 percent of
metastatic cancers may have discordant ER measurement compared with the primary cancer
[22]. (See "Systemic treatment for metastatic breast cancer: General principles", section on 'Role
of repeat biopsy'.)

• According to American Society of Clinical Oncology/College of American Pathologists

(ASCO/CAP) criteria, immunohistochemical (IHC) staining of 0 to 1 percent should be
considered negative, whereas ≥10 percent should be considered positive, and patients
should not, or should, be candidates for ET, respectively. Tumors with ER 2 to 9 percent IHC
staining are considered positive and ET should be considered, but may be less likely to be
effective. (See "Hormone receptors in breast cancer: Clinical utility and guideline
recommendations to improve test accuracy", section on 'Interpretation of ER and PR tests'.)

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• Approximately 20 percent of hormone receptor-positive breast cancers are also HER2

positive. These patients should receive HER2-directed therapy as part of their treatment
regimen. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on
'Special considerations for hormone receptor-positive disease'.)

● For those in whom hormone receptor positivity is confirmed, we assess tumor

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) status, using the
companion diagnostic test approved by the US Food and Drug Administration to select patients
for possible second-line treatment with alpha isoform-specific phosphoinositide 3-kinase (PI3K)
inhibitor alpelisib [23]. The diagnostic test is approved for use on tumor tissue specimens and
circulating tumor DNA (ctDNA) for the detection of 11 PIK3CA activating mutations. We prefer to
use tissue, if it is available, given available trial data. However, if tumor tissue is not available, we
assess plasma specimens for PIK3CA mutations. If the test is negative for PIK3CA mutations in
plasma, more tissue should be acquired, when possible, for repeat testing for PIK3CA mutations
in tumor tissue [24].

Approach

● Since ET (alone or in combination with targeted agents) is generally less toxic than
chemotherapy, it is preferable for most patients with hormone receptor-positive disease to begin
treatment with ET, reserving chemotherapy for patients whose cancers appear to be either
refractory to ET or have extensive symptomatic visceral involvement. Several studies have
suggested that addition of targeted therapies to ET improves progression-free survival (PFS),
although overall survival (OS) results from several studies are still pending. These agents include
the inhibitor of mechanistic target of rapamycin (mTOR), everolimus, as well as inhibitors of
cyclin-dependent kinase (CDK) 4/6 (palbociclib, ribociclib, and abemaciclib).

• Women who progress ≥12 months from the end of adjuvant ET and patients who present
with de novo metastatic breast cancer are eligible for first-line ET or ET in combination with
a CDK 4/6 inhibitor. (See 'Preferred first-line therapy' below.)

• Those who progress on or within 12 months of completing adjuvant ET are eligible for
subsequent-line ET or ET in combination with a targeted agent. Patients who progress on
first-line ET for metastatic disease are also eligible for second-line treatment. (See
'Subsequent-line' below.)

• For women who progress after two lines of ET (with or without a targeted agent), treatment
should be based on their prior treatment response, tumor burden, and individual
preferences. (See 'Later-line therapy' below.)

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• There are no data that combining ET (with or without targeted agents) with chemotherapy
improves OS, and therefore we do not use this strategy [25].

Data supporting ET plus targeted agents come from a systematic review and network meta-analysis
of 140 randomized trials enrolling over 50,000 patients, in which ET, with or without targeted agents,
was compared against chemotherapy, with or without targeted agents, in the first or second line [26].
Relative to anastrozole alone, PFS was improved with the following combinations, with hazard ratios
of approximately 0.4 in most cases: palbociclib plus letrozole; ribociclib plus letrozole; abemaciclib
plus anastrozole or letrozole; palbociclib plus fulvestrant; ribociclib plus fulvestrant; abemaciclib plus
fulvestrant; everolimus plus exemestane; and, in patients with a PIK3CA mutation, alpelisib plus
fulvestrant; and several chemotherapy-based regimens, including anthracycline- and taxane-
containing regimens. However, no chemotherapy or hormone therapy regimen was better than
palbociclib plus letrozole for PFS. It should be noted that these conclusions are drawn, in most cases,
from cross-trial comparisons.

● For the minority of patients who have extensive visceral metastases with evidence of end-organ
dysfunction, we treat with first-line chemotherapy for several cycles (three to six months) rather
than ET. We take this approach in order to maximize the chances of an early, meaningful, and
more rapid response than one might anticipate from ET alone or in combination with targeted
agents. Other than in this rare circumstance, trials have not shown any benefit for using
chemotherapy prior to ET [27]. (See "Systemic treatment of metastatic breast cancer in women:
Chemotherapy".)

• End-organ dysfunction can include pulmonary symptoms, such as dyspnea; evidence of

pulmonary lymphangitic disease; or elevated liver function tests. Presence of a visceral
metastasis alone, in the absence of these findings, is not an indication to proceed with
chemotherapy in lieu of a trial of ET or ET in combination with targeted agents.

• For patients with confirmed hormone receptor-positive disease who have initiated
chemotherapy, if a satisfactory response is achieved after several cycles (three to six
months) with reduction of the patients' symptoms, it is reasonable to discontinue
chemotherapy and introduce some form of "maintenance" ET. For others, either continuing
chemotherapy (if there is evidence of partial response or stabilization of disease), switching
to another chemotherapy regimen, or shifting to palliative care only are appropriate options.

DEFINITION OF MENOPAUSE

For patients with metastatic hormone receptor-positive breast cancer, menopausal status must first
be ascertained to determine the approach to treatment. (See 'ET for premenopausal women' below
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and 'ET for postmenopausal women' below.)

We define menopause in women <60 years using guidelines from the National Comprehensive
Cancer Network (NCCN) [28]:

● Prior bilateral oophorectomy.

● No menstrual periods in the preceding 12 or more months occurring:

• In the absence of chemotherapy, tamoxifen or toremifene, or ovarian suppression.

• While undergoing treatment with chemotherapy, tamoxifen, or toremifene, provided serum

estradiol levels are in the postmenopausal range. (See "Evaluation and management of
secondary amenorrhea", section on 'Initial laboratory testing'.)

ET FOR POSTMENOPAUSAL WOMEN

Preferred first-line therapy — Women who progress at least 12 months after the end of adjuvant ET
and patients who present with de novo metastatic breast cancer are eligible for first-line endocrine
treatment. Our preferred regimen for most such patients is a cyclin-dependent kinase (CDK) 4/6
inhibitor with an aromatase inhibitor (AI), although fulvestrant and a CDK 4/6 inhibitor is an
appropriate alternative. Single-agent treatment with fulvestrant or an AI alone may also be
appropriate for those with low disease burden or those who are less likely to tolerate combination
treatment. (See 'Alternatives and subsequent-line options' below.)

For most women who progress on adjuvant endocrine therapy or within 12 months of completion, we
move to subsequent-line ET options. However, for the minority of patients with evidence of end-organ
damage from extensive visceral metastases, chemotherapy is appropriate. (See 'Alternatives and
subsequent-line options' below and "Systemic treatment of metastatic breast cancer in women:
Chemotherapy".)

Aromatase inhibitors plus CDK 4/6 inhibitors — The cyclin-dependent kinase (CDK) 4/6
pathway has been found to be overactive in a number of cancers, including breast cancer. CDK 4/6
inhibition leads to activation of the tumor suppressor Rb, causing cell cycle arrest. Among
postmenopausal women with hormone receptor-positive breast cancer, combinations of the AI
letrozole with CDK 4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) have demonstrated improved
progression-free survival (PFS) relative to an AI alone [3], and have been approved by the US Food
and Drug Administration (FDA) in this setting. The CDK 4/6 inhibitors have not been directly
compared in clinical trials.

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● Palbociclib – Palbociclib was approved by the FDA based upon a phase III study that included
666 postmenopausal patients with metastatic, estrogen receptor (ER)-positive, HER2-negative
breast cancer who had not had prior treatment for advanced disease. The combination of
palbociclib and letrozole demonstrated improved PFS (24.8 versus 14.5 months; hazard ratio
[HR] 0.58, 95% CI 0.46-0.72) and objective response rate (ORR; 42 versus 35 percent)
compared with letrozole alone [29].

Neutropenia was higher with the combination (79.5 versus 6.3 percent), though neutropenic fever
was uncommon. Fatigue, nausea, and alopecia are also more common among patients taking the
combination relative to an AI alone. Overall survival (OS) data are not yet available pending longer
follow-up.

● Ribociclib – Ribociclib was FDA approved in combination with letrozole, based upon a phase III
study in which 668 postmenopausal women with hormone receptor-positive, HER2-negative
recurrent or metastatic breast cancer were treated with frontline letrozole, with or without
ribociclib. Those receiving ribociclib experienced an improved PFS (25.3 versus 16.0 months; HR
for progression or death 0.56, 95% CI 0.45-0.70) at a median follow-up of 26 months [30]. The
overall response rates were 43 and 29 percent, respectively.

Grade 3 or 4 adverse events were more common with the combination, notable for neutropenia (62
versus 1.2 percent), leukopenia (21 versus <1 percent), and increased liver function tests (10.2
versus 2.4 percent). Despite this higher frequency of adverse events, only 8.1 percent of patients
required permanent discontinuation of both ribociclib and letrozole. OS data are not yet available
pending longer follow-up. Data and FDA approval for ribociclib in the pre/perimenopausal setting are
discussed below. (See 'Incorporation of targeted agents' below.)

● Abemaciclib – Abemaciclib is FDA approved in combination with an AI for the initial treatment of
postmenopausal women with hormone receptor-positive, HER2-negative breast cancer. In the
MONARCH 3 trial, the combination of abemaciclib with an AI (letrozole or anastrozole) was
compared with AI monotherapy for the frontline treatment of women with advanced hormone
receptor-positive, HER2-negative breast cancer. PFS, the primary endpoint of the trial, was
increased with the combination compared with an AI alone (median not reached versus 14.7
months, respectively; HR 0.54, 95% CI 0.41-0.72) [31]. In addition, the ORR was higher with the
combination (59 versus 44 percent).

The most frequent grade 3 or higher adverse events for abemaciclib versus placebo included
diarrhea (9.5 versus 1.2 percent), neutropenia (21 versus 1.2 percent), and fatigue (2 versus 0
percent), respectively.

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In the network meta-analysis described above, in cross-trial comparisons, no statistically significant

differences in PFS were found among the three CDK 4/6 inhibitors in combination with an AI:
palbociclib plus letrozole versus ribociclib plus letrozole (HR 0·98, 95% CI 0·58-1·66), palbociclib plus
letrozole versus abemaciclib plus anastrozole or letrozole (HR 1.01, 95% CI 0·59-1·70), and
abemaciclib plus anastrozole or letrozole versus ribociclib plus letrozole (HR 0.97, 95% CI 0·53-1·78)
[26]. Further discussion of this analysis is found above. (See 'Approach' above.)

Alternatives and subsequent-line options

Choosing between options — Given the consistent benefits observed with CDK 4/6 inhibitors
and AI, we often prefer those regimens in the front-line setting. However, other frontline alternatives
are also acceptable.

● Front-line alternatives

• CDK 4/6/AI has never been compared directly with fulvestrant alone, fulvestrant in
combination with an AI, or fulvestrant in combination with a CDK 4/6 inhibitor. Given results
of the FALCON trial, we consider fulvestrant to be an acceptable alternative frontline option,
with or without a CDK 4/6 inhibitor. (See 'Fulvestrant-based combinations' below.)

• Fulvestrant plus an AI is an appropriate alternative to a CDK 4/6 inhibitor and an AI for the
unusual case where a patient presents with de novo metastatic breast cancer, given the
accrual and results of SWOG S0226 discussed below. However, we use a modification of
the dose of fulvestrant to 500 mg intramuscularly rather than 250 mg intramuscularly. (See
'Fulvestrant-based combinations' below.)

• Particularly for patients with low burden of disease or those who are unlikely to tolerate
combination treatment, a single-agent option is appropriate, either in the first- or
subsequent-line setting. Although fulvestrant has shown improved PFS compared with AIs in
the front-line setting as a single agent, some patients may prefer the oral administration of
AIs versus intramuscular administration for fulvestrant. (See 'Fulvestrant monotherapy'
below and 'First-line' below.)

● Subsequent-line options – There is no optimal sequence for ET upon progression. Options

available in the second-line setting include fulvestrant, with or without a CDK 4/6 inhibitor
(palbociclib, abemaciclib, ribociclib), or for those with tumor phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, fulvestrant with the alpha
isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor alpelisib; everolimus, with either an AI,
tamoxifen, or fulvestrant; or, for those who have progressed on both ET and chemotherapy,
abemaciclib. (See 'Later-line therapy' below.)

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A choice between treatments depends on the patient's previous treatment history and tolerance of
treatment. For example, for a patient who progressed on an AI and a CDK 4/6 inhibitor, we might opt
for fulvestrant alone, as it represents a different mechanism of action and is well tolerated. For such a
patient who prefers to avoid intramuscular injection, everolimus plus ET would be an acceptable
alternative. (See 'Fulvestrant-based combinations' below and 'Everolimus plus ET' below.)

The option of CDK inhibition with an AI is also appropriate as a subsequent-line treatment for those
who have not received prior treatment with a CDK 4/6 inhibitor. However, it should be noted that for
patients with progression on or within 12 months of AI treatment, the efficacy of the combination of a
CDK 4/6 inhibitor and an AI has not been assessed. (See 'Aromatase inhibitors plus CDK 4/6
inhibitors' above.)

Single-agent AIs have been evaluated in the second-line setting but are associated with lower
response rates than combination strategies. (See 'Everolimus plus ET' below and 'Fulvestrant-based
combinations' below and 'Aromatase inhibitor monotherapy' below.)

Fulvestrant monotherapy — Fulvestrant is an estrogen receptor (ER) antagonist that blocks ER

dimerization and DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor [32-
34]. Because it blocks ER function before estrogen can bind the receptor, fulvestrant can theoretically
overcome resistance that is driven by the agonist properties of tamoxifen [35]. Although originally
approved as a monthly intramuscular injection (250 mg per month), use of the higher dose was
proven to be more effective in subsequent trials and is now the preferred schedule [36-39].
Fulvestrant is administered as an intramuscular injection (500 mg loading dose on days 1, 14, and 29
of the first month, then maintenance dosing monthly at day 28, ±3 days). Although given the dose
dependence it might theoretically be preferable to attempt even higher doses, this would be difficult
due to the large volume required for intramuscular injection. Oral ER down-regulators (SERDs) are
under investigation. (See 'Investigational agents' below.)

Fulvestrant monotherapy has never been compared with the combination of an AI and a CDK 4/6
inhibitor. However, the benefit of fulvestrant over AI monotherapy in the front-line setting was shown
in the phase III FALCON trial. In this study of 462 women with metastatic ER-positive breast cancer,
all of whom were ET naive, those randomly assigned to fulvestrant 500 mg experienced improved
PFS over anastrozole at a median follow-up of 25.0 months (16.6 versus 13.8 months; HR for
progression or death 0.80, 95% CI 0.637-0.999) [1]. Subgroup analysis showed an even greater PFS
benefit for patients whose disease had not spread to the liver or lungs at baseline in the fulvestrant
arm (22.3 versus 13.8 months). While there was no difference in OS, only 31 percent of events had
been collected. Quality of life outcomes were similar between the two groups, with the most common
adverse effects being arthralgia (17 versus 10 percent) and hot flashes (11 versus 10 percent) for
fulvestrant and anastrozole, respectively. Previous studies using lower doses of fulvestrant (250 mg)

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showed equivalent PFS between fulvestrant and AIs [38,40-42], and therefore we use the higher
dose.

In the ET-refractory setting, fulvestrant monotherapy has shown equivalent activity as exemestane in
postmenopausal women with hormone receptor-positive disease who had progressed on a
nonsteroidal AI [41]. However, the lower maintenance dose of fulvestrant was used in this trial (250
mg), and it is expected that the higher dose (500 mg) would lead to improved outcomes, based on a
separate trial comparing the doses [39].

Fulvestrant-based combinations

Fulvestrant plus CDK 4/6 inhibitors — Both palbociclib and abemaciclib are approved for use
in combination with fulvestrant in the subsequent-line setting. Ribociclib is approved for use with
fulvestrant either in the first-line or subsequent-line setting. Dosing and administration of fulvestrant
are discussed above. (See 'Fulvestrant monotherapy' above.)

● Fulvestrant plus palbociclib – The combination of palbociclib plus fulvestrant is a reasonable

option for women who progress after front-line ET for metastatic disease or on or within 12
months of adjuvant ET.

This was supported by the PALOMA3 trial, which randomly assigned 521 women with advanced
hormone receptor-positive and HER2-negative breast cancer to receive palbociclib and
fulvestrant or placebo and fulvestrant [43,44]. Eligibility included relapse during or within 12
months after completion of adjuvant ET or progression on prior ET in the metastatic setting (with
progression from prior AI therapy required for postmenopausal women). Of note, premenopausal
or perimenopausal women (21 percent of the trial population) were also eligible and received
goserelin [43]. At a median follow-up of 8.9 months, compared with fulvestrant plus placebo,
fulvestrant plus palbociclib resulted in [44]:

• An improvement in PFS (median 9.5 versus 4.6 months with fulvestrant plus placebo; HR
0.46, 95% CI 0.36-0.59). The study was stopped early because of the positive efficacy data
observed at interim analysis. A subsequent updated analysis continues to show an
improvement in PFS (median, 11.2 versus 4.6 months with fulvestrant plus placebo; HR 0.5,
95% CI 0.40-0.62; absolute difference, 6.6 months) [45].

• Higher rates of neutropenia (65 versus 1 percent, respectively) and fatigue (39 versus 28
percent). However, discontinuation rates were low on both study arms (4 percent in the
fulvestrant and palbociclib arm versus 2 percent for those receiving fulvestrant only), and the
rate of febrile neutropenia was low (1 percent in each arm). Dose modifications for grade 3
to 4 neutropenia did not affect PFS outcomes [46]. Patient-reported quality of life outcomes

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were higher among those receiving fulvestrant and palbociclib compared with fulvestrant
alone [47].

• A delay to receive chemotherapy (median, 17.6 versus 8.8 months; HR 0.58, 95% CI 0.47-
0.73) [48].

• A nonsignificant trend towards improvement in OS (median, 34.9 versus 28.0 months; HR

0.81, 95% CI 0.64-1.03) [48], at a median follow-up of 45 months and 60 percent data
maturity.

The planned OS analysis was performed at 60 percent maturity (310 of 521 patients enrolled had
died at the time of data cutoff). The sample size had only approximately 46 percent power to detect
an HR of 0.8 in OS improvement. Additionally, 16 percent of patients assigned to fulvestrant plus
placebo received a cyclin-dependent kinase (CDK) 4/6 inhibitor after progression. These issues limit
the ability of the analysis to detect a statistically significant OS difference between the groups.
Overall, the data from PALOMA3 support the combination of palbociclib plus fulvestrant for women
with metastatic hormone receptor-positive breast cancer.

● Fulvestrant plus abemaciclib – Abemaciclib is approved by the FDA in combination with

fulvestrant for women with progressive disease after prior ET [49]. Use of abemaciclib as
monotherapy in patients with progressive disease after ET and chemotherapy is discussed
below. (See 'Later-line therapy' below.)

Abemaciclib has been shown to combine effectively with fulvestrant. In the MONARCH 2 phase
III trial, 669 patients who had progressed while receiving ET were randomly assigned to
fulvestrant with or without the CDK 4/6 inhibitor abemaciclib [50]. Those receiving abemaciclib-
fulvestrant experienced an improved PFS relative to those receiving fulvestrant alone (16.4
versus 9.3 months; HR 0.55, 95% CI 0.45-0.68). The ORR was higher in those receiving
abemaciclib-fulvestrant (48 versus 21 percent). In MONARCH 2, abemaciclib-fulvestrant also
improved OS (47 versus 37 months; HR 0.68, 95% CI 0.56-0.82) [51]. Patients taking
abemaciclib were able to defer chemotherapy for 50 versus 22 months for those on fulvestrant
alone. Patients receiving abemaciclib had higher rates of diarrhea, neutropenia, nausea, and
fatigue.

● Fulvestrant plus ribociclib – Results of MONALEESA-3 suggest efficacy of ribociclib in

combination with fulvestrant [52], and this combination is FDA approved for initial- or
subsequent-line ET for postmenopausal women with metastatic hormone receptor-positive,
HER2-negative breast cancer [53]. In this phase III trial of 726 patients with advanced hormone
receptor-positive breast cancer and zero or one prior endocrine treatments, PFS was improved
with the addition of ribociclib to fulvestrant versus fulvestrant alone (21 versus 13 months,

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respectively; HR 0.59, 95% CI 0.48-0.73). Benefits were consistent across patients with and
without prior endocrine treatment. In subsequent reporting, patients assigned to the ribociclib-
fulvestrant arm had not reached a median survival after a median of 42 months of treatment [54].
Women assigned to placebo-fulvestrant had a median OS of 40 months (HR 0.72, 95% CI 0.57-
0.92). The addition of ribociclib to fulvestrant improved the survival rate at 42 months relative to
placebo-fulvestrant (58 versus 46 percent).

In the network meta-analysis described above, no statistically significant differences in PFS were
found among the three CDK 4/6 inhibitors in combination with fulvestrant: palbociclib plus fulvestrant
versus abemaciclib plus fulvestrant (HR 0.83, 95% CI 0·47-1·46), palbociclib plus fulvestrant versus
ribociclib plus fulvestrant (HR 0.77, 95% CI 0·44-1·35), and abemaciclib plus fulvestrant versus
ribociclib plus fulvestrant (HR 0.93, 95% CI 0·54-1·61) [26]. However, this conclusion is based on
cross-trial comparisons. Further discussion of this analysis is found above. (See 'Approach' above.)

Preliminary results from one trial of everolimus and fulvestrant are discussed below, as are data in
premenopausal women. (See 'Everolimus plus ET' below and 'Incorporation of targeted agents'
below.)

Fulvestrant plus alpelisib for PIK3CA-mutant tumors — The phosphoinositide 3-

kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a
critical role in mediating cell growth, survival, and angiogenesis. Mutations in components of the PI3K
pathway are frequently observed in ER-positive breast cancer. Specifically, mutations in
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the
alpha isoform of the catalytic subunit of PI3K, are detected in over 40 percent of ER-positive breast
cancers [55]. Alpha isoform-selective PI3K inhibitors have demonstrated promising activities in
endocrine-resistant, PIK3CA-mutant, advanced, hormone receptor-positive breast cancer, and the
alpha isoform-specific PI3K inhibitor alpelisib is approved by the FDA for such cancers, in
combination with fulvestrant. Determination of PIK3CA status is discussed above. (See 'Biopsy of a
metastatic lesion' above.)

In a phase III trial of 572 patients with advanced hormone receptor-positive breast cancer, all of whom
had received a prior aromatase inhibitor either for local or advanced disease, alpelisib plus fulvestrant
improved PFS relative to fulvestrant alone among those with tumor PIK3CA mutations (11.0 versus
5.7 months; hazard ratio [HR] 0.65, 95% CI 0.50-0.85) [56]. In the cohort without tumor PIK3CA
mutations, the median PFS was 7.4 months in the alpelisib-fulvestrant group and 5.6 months in the
fulvestrant-only group (HR 0.85, 95% CI 0.58-1.25). In the overall population, the most frequent
adverse grade 3 or 4 events in the alpelisib-fulvestrant versus fulvestrant-only group, respectively,
included hyperglycemia (37 and 0.7 percent), rash (10 and 0.3 percent), and diarrhea (7 and 0.3
percent).

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However, this trial included a limited number of patients with prior therapy of CDK 4/6 inhibitors.
Clinical trials are ongoing to evaluate the activity of PI3K inhibitors in delaying or overcoming
resistance to CDK 4/6 inhibitors.

Earlier trials evaluating combinations of fulvestrant with either pan-isoform PI3K inhibitors (eg,
buparlisib and pictilisib) or the beta isoform-sparing agent taselisib suggested limited improvements in
PFS in patients with endocrine-resistant disease, but a narrow therapeutic window due to toxicities
(eg, gastrointestinal side effects, transaminitis, and hyperglycemia [57-61]). Buparlisib was also
associated with anxiety and depression [57-59].

Fulvestrant plus anastrozole — The combination of fulvestrant plus anastrozole is an

acceptable alternative to the AI/CDK 4/6 inhibitor combination for the patient who presents with de
novo metastatic breast cancer (and is therefore ET naïve).

In addition to single-agent therapy, several trials investigating the combination of fulvestrant plus
anastrozole have been published, but with discrepant results [62-64]. Of note, in these trials,
fulvestrant was administered at a dose of 250 mg monthly, which is lower than the currently approved
prescribed dose. Examples of these trials are discussed below:

● In the SWOG S0226 trial, 707 women (60 percent endocrine naïve) with metastatic hormone-
positive breast cancer were randomly assigned to treatment with anastrozole plus fulvestrant or
to single-agent anastrozole [62,65]. Most of the patients assigned to fulvestrant received 250
mg/month, although a fraction of patients were permitted to receive 500 mg/month after release
of the data from the trial that demonstrated the superiority of the higher dose. At a median follow-
up of seven years, compared with anastrozole alone, combined treatment resulted in an
improvement in PFS (15 versus 14 months; HR 0.81, 95% CI 0.69-0.94) and OS (50 versus 42
months; HR 0.82, 95% CI 0.69-0.98) [65]. These improvements were despite the fact that
approximately 45 percent of the patients in the anastrozole-alone group crossed over to receive
fulvestrant. On subgroup analysis, the benefit of combination therapy appeared to be restricted to
previously untreated patients.

Accrual to this trial was unique. Designed as a first-line ET trial in the metastatic setting, any
patient who had prior AI was ineligible. Roughly halfway through accrual, the Arimidex,
Tamoxifen, Alone or in Combination (ATAC) study demonstrated the superiority of adjuvant
anastrozole over tamoxifen, leading to far more patients receiving adjuvant AIs and making it
difficult to accrue patients without prior AIs. Therefore, although unusual, presentation of
simultaneous new primary with metastases became a common scenario for accrual to this trial,
ultimately accounting for nearly one-half of the patients enrolled.

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● In the FACT trial, survival outcomes were similar between the combination of fulvestrant and
anastrozole and anastrozole alone [63]. Among 514 women with relapsed hormone receptor-
positive disease (one-third of whom were ET naïve), those randomly assigned to anastrozole
plus fulvestrant (500 mg loading dose, 250 mg on days 14 and 28, then 250 mg every 28 days)
experienced equivalent median time to progression (11 versus 10 months; HR 0.99, 95% CI
0.81-1.20) and OS (38 months in both arms; HR 1.0, 95% CI 0.76-1.32) as those receiving
anastrozole alone.

There were significantly more cases of endocrine-naïve patients in the SWOG S0226 trial than the
FACT trial, whereas there were many patients with non-metastatic locally advanced cancers in the
FACT trial (all patients in S0226 must have had distant metastases). These two factors, or other
unknown ones, might explain the difference in trial outcomes. Further studies are needed to confirm
the findings from the SWOG S0226 trial and to determine whether this combination is superior to
anastrozole or fulvestrant alone.

Aromatase inhibitor monotherapy — Although fulvestrant as a single agent has shown better
activity than aromatase inhibition, some patients may prefer oral therapy to intramuscular injection.
For such patients, AIs may be appropriate.

First-line — The efficacy of AIs as a first-line treatment for advanced or metastatic breast
cancer and their OS superiority to tamoxifen in postmenopausal women were shown in a 2006 meta-
analysis of 23 randomized trials (n = 8504 patients) [66]. Treatment with an AI resulted in an
improvement in OS compared with tamoxifen (HR 0.89, 95% CI 0.80-0.99) and with other ETs (HR
0.87, 95% CI 0.82-0.93).

Head-to-head comparative prospective randomized trials demonstrate that no one AI is better than
the others. In one trial of 128 women with advanced breast cancer, exemestane and anastrozole
resulted in a similar ORR (15 percent in both groups) and OS (31 and 33 months, respectively) [67].
Although pharmacokinetic data suggest that letrozole is a more effective AI, other data suggest that
once a certain threshold of aromatase inhibition is reached, differences in estrogen suppression
between the AIs are not associated with clinically significant differences in efficacy [68,69].

Subsequent-line — Although less preferable to the options discussed above, single-agent AIs
are available as subsequent-line therapy to those who seek a single-agent oral treatment, particularly
if they have not received AIs in the frontline.

There have been no differences in efficacy between the AIs in the second-line setting [67,70,71]. For
example, in a phase III trial, 713 women with disease progression on a prior tamoxifen were randomly
assigned to treatment with either letrozole or anastrozole [71]. Although the ORR was significantly

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higher with letrozole (19 versus 12 percent), there was no significant difference in time to progression
or OS.

The strategy of switching from one AI to another upon progression has shown mixed results, and we
typically opt for another class of agent or a combination with a targeted agent instead. For example,
the administration of exemestane in the second-line setting after progression on a nonsteroidal AI
(anastrozole or letrozole) was evaluated in a 2011 systematic review of nine studies [72]. The ORR
ranged from 2 to 26 percent with a clinical benefit rate that ranged from 12 to 55 percent. However, in
the largest prospective trial comparing exemestane alone with exemestane plus everolimus after a
previous nonsteroidal AI, the response rate and PFS suggest that those in the exemestane-alone arm
received little or no benefit from it [73].

Everolimus plus ET — The PI3K/AKT/mTOR signaling pathway plays a critical role in mediating
cell growth, survival, and angiogenesis, and activating mutations in this pathway are frequent in
breast cancer [55]. Studies show that the mTOR inhibitor everolimus, in combination with either an AI,
tamoxifen, or fulvestrant is an option for postmenopausal women for the treatment of AI-resistant,
advanced, ER-positive breast cancer. The data on these options are discussed below.

The benefit of everolimus plus exemestane over exemestane alone was shown in the BOLERO-2
trial, which enrolled 724 women who had progressed on anastrozole. Patients randomly assigned to
exemestane (25 mg daily) and everolimus (10 mg daily) experienced an improvement in PFS (7
versus 3 months; HR for mortality 0.45, 95% CI 0.35-0.54) and ORR (9.5 versus 0.4 percent) relative
to those receiving exemestane alone, although there was no difference in OS (31 versus 26.6
months; HR 0.89, 95% CI 0.73-1.10) [73,74]. Everolimus was associated with serious side effects
(grade 3/4), including stomatitis (8 percent), dyspnea (4 percent), noninfectious pneumonitis (3
percent), and elevated liver enzymes (3 percent) [73,74]. For patients who develop shortness of
breath or increase in cough, everolimus should be held and patients assessed for pneumonitis. A
brief course of steroids may be necessary. Additional information on the toxicity of everolimus is
discussed separately. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly
targeted agents", section on 'Rapamycin and analogs' and "Oral toxicity associated with
chemotherapy", section on 'Dexamethasone mouthwash for patients receiving mTOR inhibitors'.)

The combination of everolimus plus tamoxifen is another option for patients previously treated with an
AI, and may be preferable for those who were previously poorly tolerant of AI treatment. In a study
conducted by the Groupe d’Investigateurs Nationaux pour l’Étude des Cancers Ovariens et du sein
(GINECO), 111 postmenopausal women who had progressed on an AI were randomly assigned
treatment with tamoxifen with or without everolimus [75]. Compared with tamoxifen alone,
combination treatment with everolimus resulted in an improvement in time to progression (8.6 versus
4.5 months; HR 0.54, 95% CI 0.36-0.81) and risk of death (HR 0.45, 95% CI 0.24-0.81). Incidence of

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serious pain or fatigue was also reduced. There was no difference in ORR (14 versus 13 percent).
Combination treatment resulted in higher incidence of grade 3 or 4 stomatitis (11 versus 0 percent)
and any-grade pneumonitis (17 versus 4 percent), though grade 3/4 toxicity was rare in either group.

Results from the randomized phase II PrE0102 trial suggest the combination of everolimus and
fulvestrant may also be an effective strategy for patients resistant to AIs, with a doubling in PFS
compared with fulvestrant alone (10.3 versus 5.1 months; HR 0.61, 95% CI 0.4-0.92) [76]. Adverse
events of all grades occurred more often in the everolimus arm, including oral mucositis (53 versus 12
percent), fatigue (42 versus 22 percent), rash (38 versus 5 percent), anemia (31 versus 6 percent),
and diarrhea (23 versus 8 percent), although grade 3 to 4 events were uncommon. Similar results
were found in the MANTA trial, a randomized phase II trial in 324 patients with AI-resistant MBC
comparing fulvestrant alone or in combination with either everolimus or with one of two different
schedules of the dual TORC1-2 inhibitor vistusertib [77]. The addition of everolimus improved median
PFS (4.6 versus 12.2 months; HR 0.64, 95% CI 0.43-0.94), whereas no improvement was observed
with addition of vistusertib. The adverse event profile was consistent with the known profile of
everolimus.

Later-line therapy — For women who progress after two lines of ET, treatment must be
individualized based on their prior treatment response, tumor burden, and preferences for treatment.
In general, patients who have progressed after multiple lines of ET should receive chemotherapy.
(See "Systemic treatment of metastatic breast cancer in women: Chemotherapy".)

However, for patients who are asymptomatic with slowly progressive disease, continuation of ET is
reasonable, with one of the options below.

● Tamoxifen – Although we prefer other options over tamoxifen for initial lines of ET, it may be an
option in the later-line setting, recognizing that response rates are low. In a combined analysis of
two randomized trials evaluating a sequence strategy (ie, tamoxifen followed by anastrozole or
vice versa), 137 women crossed over to tamoxifen [78]. Second-line treatment with tamoxifen
resulted in a 10 percent ORR and a clinical benefit rate (ORR plus stable disease for ≥6 months)
of 49 percent.

● Abemaciclib – While CDK 4/6 inhibitors have been shown to combine effectively with ET, they
also possess single-agent activity. The CDK 4/6 inhibitor abemaciclib is FDA approved for use as
monotherapy for women with progressive disease after ET and chemotherapy [49].

In preliminary results from the phase II MONARCH 1 study, which enrolled 132 patients with a median
of three prior lines of treatment (including one or two prior chemotherapy regimens in the metastatic
setting), single-agent treatment with the novel CDK 4/6 inhibitor abemaciclib induced tumor response

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in 20 percent of patients, with a clinical benefit rate (stable or responding disease) of 42 percent, and
median PFS of 6.0 months [79].

● Hormones – We choose other options before hormones for treatment of metastatic breast
cancer, though they do show some activity and were used more frequently in the past. Both
progestins and estrogens are associated with an increased risk of thromboembolic events, and
their use should be avoided in patients with thromboembolic disorders or other risk factors for
thromboembolic disease. (See "Overview of the causes of venous thrombosis".)

• Progestins – Megestrol acetate and medroxyprogesterone acetate are progestational

agents with activity in metastatic breast cancer, with an approximate response rate of 25
percent and median duration of response of 15 months [80,81]. Activity appears to be
maintained in patients who experience disease progression on tamoxifen. However, the
activity of progestins following progression on an AI has not been studied. Megestrol acetate
is typically dosed at 160 mg daily (40 mg four times daily), as higher doses are no more
effective but are associated with more weight gain, fluid retention, vaginal bleeding, and a
lower quality of life [80,82]. The mechanism of action of progestins in the treatment of
advanced breast cancer is unclear. They may inhibit aromatase activity or increase estrogen
turnover, since estrogen levels fall during therapy [83]. They may also act through the
glucocorticoid receptor, androgen receptor, or progesterone receptor.

• Estrogens – Estrogenic compounds can be used as a treatment for metastatic breast

cancer, though there are no data on the impact on outcomes of treatment compared with
placebo. If used, estradiol is the preferred estrogen of choice. Although high-dose estrogen
(estradiol 30 mg daily in divided doses) has typically been used, lower doses (estradiol 6 mg
daily in divided doses) may be just as effective with less toxicity [84].

The efficacy of estrogens was shown in a trial involving 143 women who were randomly
assigned to diethylstilbestrol (DES) or tamoxifen [85]. Compared with tamoxifen, DES resulted in
a similar response rate (41 versus 37 percent) and median PFS (five versus six months).
However, DES was shown to be significantly more toxic; 12 percent of patients on DES
discontinued treatment due to congestive heart failure, gastrointestinal intolerance,
thrombophlebitis, and the onset of lower extremity edema. None of the patients on tamoxifen
discontinued treatment.

For patients who experience vaginal bleeding on estrogens, progestin therapy is effective
treatment [84]. In addition, patients with bone metastasis should be treated with
bisphosphonates before giving estradiol to avoid hypercalcemia.

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• Androgens – Androgens, including testosterone, fluoxymesterone, and danazol, are inferior

to high-dose estrogens and are rarely used to treat metastatic breast cancer [86]. Although
they have response rates of 10 to 20 percent in pretreated patients, side effects include
virilization, edema, and jaundice [87-89]. We seldom administer androgen therapy for
metastatic breast cancer. However, if it is prescribed, the preferred formulation is
fluoxymesterone (10 mg by mouth twice daily).

Special considerations for BRCA mutation carriers — For patients with metastatic HER2-negative
breast cancer who have a germline breast cancer susceptibility gene (BRCA) mutation, the use of
poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors is discussed elsewhere. (See
"Systemic treatment for metastatic breast cancer: General principles", section on 'PARP inhibition for
BRCA carriers'.)

ET FOR PREMENOPAUSAL WOMEN

For premenopausal women, options for ET include, in order of preference:

● Ovarian suppression or ablation in combination with ET, with addition of a targeted agent
(following the approach for endocrine treatment used for a postmenopausal woman). (See 'ET for
postmenopausal women' above.)

● Ovarian suppression or ablation in combination with ET, without addition of a targeted agent.

● Tamoxifen alone.

Ovarian suppression/ablation plus ET — Although old studies suggest that adjuvant ovarian
suppression/ablation is effective in reducing recurrence and mortality, it is rarely used alone in
modern treatment. Rather, it is either used to permit premenopausal women to receive an aromatase
inhibitor (AI), which is contraindicated in women with functioning ovaries, or to complement tamoxifen
or fulvestrant. In this case, targeted agents such as cyclin-dependent kinase (CDK) 4/6 inhibitors or
mechanistic target of rapamycin (mTOR) inhibitors are added, using a similar approach as is used in
naturally postmenopausal women. (See 'ET for postmenopausal women' above.)

As in the adjuvant setting, AIs should not be used as monotherapy in premenopausal women. (See
"Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast
cancer", section on 'Transitioning from tamoxifen to an AI after menopause'.)

In a randomized trial, the combination of tamoxifen and ovarian suppression with buserelin improved
overall survival (OS) compared with treatment with either agent alone [90]. Furthermore, small studies

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have suggested that the addition of a gonadotropin-releasing hormone agonist (GnRHa) to an AI is as

effective in premenopausal women as an AI alone is in postmenopausal women [91,92].

Ovarian suppression and ablation have shown equivalent outcomes in clinical trials [93]. However, for
women with disease progression on a regimen including ovarian suppression, serum estradiol levels
should be checked to ensure menopausal status was achieved. If high estradiol levels are noted
despite ovarian suppression, ovarian ablation should be performed. If estradiol is within the
postmenopausal range, next-line therapy should be pursued.

Incorporation of targeted agents — Ovarian suppression allows premenopausal women to take

advantage of the addition of targeted agents that have been evaluated in the postmenopausal setting,
such as CDK 4/6 inhibitors or everolimus. Once ovarian suppression or ablation is achieved, we
follow a treatment approach as per postmenopausal women; for example, a regimen we commonly
use for premenopausal women is a GnRHa plus the combination of an AI and CDK 4/6 inhibitor. Data
for CDK 4/6 inhibitors in premenopausal women are discussed here, while data in postmenopausal
women are presented above. (See 'Preferred first-line therapy' above.)

While the majority of the trials that combined targeted agents (mTOR inhibitor or CDK 4/6 inhibitor)
have been limited to postmenopausal women or included premenopausal women on ovarian
suppression as a small subset, MONALEESA-7 focused specifically for pre- or perimenopausal
women with advanced, hormone receptor-positive, and HER2-negative breast cancer, and
demonstrated that a CDK 4/6 inhibitor may be effectively combined with ovarian suppression/ablation
and tamoxifen or an AI. In MONALEESA-7, 672 pre- or perimenopausal women with hormone
receptor-positive, HER2-negative, advanced breast cancer were randomly assigned to front-line
ribociclib or placebo to be taken concurrently with goserelin, and either tamoxifen or a nonsteroidal
AI. PFS was improved with ribociclib (median PFS, 24 versus 13 months; HR 0.55, 95% CI 0.4-0.69)
[94], as was the OS rate at 3.5 years, in subsequent reporting (70 versus 46 percent; HR 0.71, 95%
CI 0.54-0.95) [95]. The benefit of adding ribociclib was consistent across patient subgroups and
regardless of the ET partner. Although this was the first trial to demonstrate an OS benefit with the
addition of a CDK 4/6 inhibitor to ET, the observed benefits may be a class effect, as trials of other
CDK 4/6 inhibitors have subsequently reported OS benefits, when combined with ET in
postmenopausal women. (See 'Fulvestrant plus CDK 4/6 inhibitors' above.)

The most frequent all-grade adverse events were neutropenia (76 versus 8 percent), hot flashes (34
percent in each arm), nausea (32 versus 20 percent), leukopenia (31 versus 6 percent), and
arthralgia (30 versus 27 percent). This trial was the basis of the US Food and Drug Administration
approval of ribociclib with endocrine therapy for pre/perimenopausal women with hormone receptor-
positive, HER2-negative advanced breast cancer.

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Similarly, a CDK 4/6 inhibitor may effectively combine with fulvestrant and ovarian suppression.
Among the 108 premenopausal women with advanced endocrine-resistant disease in the PALOMA 3
trial, the addition of palbociclib to the combination of fulvestrant and goserelin improved the median
PFS (9.5 versus 5.6 months; HR 0.50, 95% CI 0.29-0.87) and objective response rate (ORR; 25
versus 11.1 percent) [96]. Furthermore, in preliminary analysis of the pre/perimenopausal subset of
MONARCH 2, the addition of abemaciclib to fulvestrant and a GnRHa in a pretreated population of
women with hormone receptor-positive, HER2-negative advanced breast cancer improved both PFS
(not reached versus 10.5 months, respectively; HR 0.45, 95% CI 0.26-0.75) and ORR (61 versus 29
percent) relative to those receiving fulvestrant and a GnRHa [97].

Versus chemotherapy — For most premenopausal women with hormone receptor (HR)-
positive, HER2-negative advanced breast cancer, ET, with or without a targeted agent, is preferred
over chemotherapy. This is the same approach as for postmenopausal women. (See "Systemic
treatment for metastatic breast cancer: General principles", section on 'Hormone receptor-positive,
HER2-negative patients'.)

In results of a randomized phase II study, among 184 premenopausal women with advanced HR-
positive, HER2-negative breast cancer, those assigned to exemestane, palbociclib, and a GnRHa
experienced a better progression-free survival (PFS) than those assigned to capecitabine (20 versus
14 months; hazard ratio [HR] 0.66, 95% CI 0.44-0.99) [98]. Nonhematologic toxicities were less
common with ET/palbociclib compared with capecitabine (eg, diarrhea, 13 versus 39 percent; hand-
foot syndromes, 1 versus 100 percent, respectively), but hematologic toxicity was more common
(grade ≥3 neutropenia, 64 versus 16 percent, respectively).

Tamoxifen — While our preference is for ovarian suppression or ablation plus ET, with or without a
targeted agent, single-agent treatment with a selective estrogen receptor modulator (SERM) alone is
an alternative for those who wish to avoid combined-modality treatment. In a 1991 review of phase II
trials of tamoxifen in premenopausal women, the ORR was 45 percent among the 31 patients with
confirmed estrogen receptor-positive disease [99].

INVESTIGATIONAL AGENTS

The combination of ET plus a molecular-targeted agent continues to be explored in clinical trials with
the aim to overcome endocrine resistance in hormone receptor-positive breast cancer.

Examples include:

● Novel SERDS – Novel selective estrogen receptor down-regulators (SERDs) are appealing
because they may be effective in targeting estrogen receptor 1 (ESR1) mutations and because

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the existent SERD, fulvestrant, is limited by its intramuscular administration in regards to how
much can be delivered. Novel SERDs with the ability to degrade mutant estrogen receptors
(ERs) are being investigated. An example is GDC-0810, which is in phase I/II evaluation in
postmenopausal women with locally advanced or metastatic ER-positive breast cancer with or
without ESR1 mutation (NCT01823835). Further discussion of ESR1 mutations is found
elsewhere. (See "Mechanisms of action of selective estrogen receptor modulators and down-
regulators", section on 'ESR1 gene mutations' and "Mechanisms of action of selective estrogen
receptor modulators and down-regulators", section on 'Fulvestrant, oral SERDs, and
SERM/SERD hybrids'.)

● ET plus androgen receptor blockade – Androgen receptor (AR) expression is observed in

majority of ER-positive breast cancers. Preclinical evidence indicated synergism between ER
and AR targeting [57]. This strategy is being examined in a randomized phase II trial
(NCT02007512).

The addition of bevacizumab to letrozole in hormone receptor-positive metastatic disease has been
shown to improve progression-free survival (PFS) in one trial (but not another), but with increased
toxicity and no demonstrated improvement in overall survival in either trial [58,59]. We therefore do
not endorse the use of bevacizumab in patients with ER-positive breast cancer.

Trials of other promising agents are ongoing. For example, entinostat, an investigational histone
deacetylase inhibitor, is being evaluated in combination with exemestane in postmenopausal women
with metastatic hormone receptor-positive disease (NCT02115282).

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

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● Beyond the Basics topics (see "Patient education: Treatment of metastatic breast cancer
(Beyond the Basics)")

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

● Although metastatic breast cancer is unlikely to be cured, there have been meaningful
improvements in survival due to the availability of more effective systemic therapies, including
endocrine therapy (ET) in the treatment of hormone-sensitive disease. (See 'Introduction' above.)

● Given that up to 15 percent of metastatic cancers may have discordant estrogen receptor (ER)
measurement compared with the primary cancer, we biopsy a metastatic lesion in patients with
new metastatic disease to confirm ER, progesterone receptor (PR), and human epidermal growth
factor receptor 2 (HER2) status. (See 'General principles' above.)

● Since ET (alone or in combination with targeted agents) is generally less toxic than
chemotherapy, it is preferable for most patients with hormone receptor-positive disease to begin
treatment with ET, with or without a targeted agent.

However, for patients with rapidly progressive or extensive visceral metastasis with end-organ
dysfunction, we suggest chemotherapy rather than ET as their first-line treatment (Grade 2C).
Patients who demonstrate a good clinical response to chemotherapy may become candidates for
discontinuation of chemotherapy and initiation of ET. (See "Systemic treatment for metastatic
breast cancer: General principles".)

● Patients without rapidly progressive or extensive visceral metastases are appropriate

candidates for ET. Our approach to first-line therapy in such patients is as follows:

• For such patients who are postmenopausal, we suggest a cyclin-dependent kinase (CDK)
4/6 inhibitor in combination with an aromatase inhibitor (AI) rather than an AI alone (Grade
2B). However, other acceptable options include single-agent fulvestrant, or fulvestrant in
combination with either an AI or a CDK 4/6 inhibitor. Single-agent AI is an option if patients
prefer or could not tolerate the above approaches, or have a low burden of disease. (See
'Preferred first-line therapy' above and 'Alternatives and subsequent-line options' above.)

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• For such patients who are premenopausal, we recommend adding a CDK 4/6 inhibitor to
ovarian suppression or ablation (OS/OA) plus ET (Grade 1B). This recommendation is
based on an overall survival benefit observed in premenopausal women with the addition of
ribociclib to OS plus ET. OS/OA with ET, or tamoxifen alone, is acceptable in patients who
cannot tolerate CDK 4/6 inhibitors. (See 'Incorporation of targeted agents' above.)

- If a patient progresses on a regimen including ovarian suppression, serum estradiol

levels should be checked to ensure menopausal status was achieved, and if not,
ablation should be pursued. Once menopause is achieved (by ablation or by
suppression, with confirmation by laboratory testing), the treatment approach for
postmenopausal women is used. (See 'ET for postmenopausal women' above.)

● While there is no optimal sequence for sequencing ET at progression, a choice between options
depends on the patient's previous treatment history and tolerance of treatment, and tumor
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) status.
Fulvestrant with or without a CDK 4/6 inhibitor may be offered to patients who did not receive
these agents in the first-line setting. Everolimus plus either an AI or tamoxifen are reserved for
patients who have progressed on at least one line of ET. For those with PIK3CA-mutant cancers
progressive on ET, fulvestrant with the alpha isoform-specific phosphoinositide 3-kinase (PI3K)
inhibitor alpelisib may be used. (See 'Subsequent-line' above.)

● For patients who have progressed on two or more lines of ET, a switch to chemotherapy may be
appropriate. However, for patients who are asymptomatic with slowly progressive disease,
continuation of ET is reasonable, and tamoxifen may be an appropriate later-line option. (See
'Later-line therapy' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Matthew Ellis, MD, PhD, FRCP; Michael J
Naughton, MD; and Maura Dickler, MD, who contributed to an earlier version of this topic review.

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Topic 778 Version 79.0

Contributor Disclosures
Cynthia X Ma, MD, PhD Grant/Research/Clinical Trial Support: Pfizer [Breast cancer treatment (Palbociclib)];
Puma Biotechnology [Breast cancer treatment (Neratinib)]. Consultant/Advisory Boards: Pfizer [Breast cancer
https://www.uptodate.com/contents/treatment-approach-to-metastatic-hormone-receptor-positive-her2-negative-breast-cancer-endocrine-therapy-an… 34/35
3/24/2020 Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents - Up…

treatment (Palbociclib)]; Novartis [Breast cancer treatment (Ribociclib, alpelisib)]; Lilly [Breast cancer treatment
(Abemaciclib)]; Tempus [Breast cancer treatment (Mutation analysis of tumor)]; Myriad Genetics [Breast cancer
prognostic marker (Endopredict)], Agendia [Breast cancer prognostic marker (Mammaprint)], Seattle Genetics
[Breast cancer treatment (Investigational antibody drug conjugate)], AstraZeneca [Breast cancer treatment (DS-
8201a)]. Joseph A Sparano, MD Grant/Research/Clinical Trial Support: Prescient Therapeutics, Deciphera,
Genentech/Roche, Merck, Novartis, Radius Health [Breast cancer (Ribociclib)]. Consultant/Advisory Boards:
Genentech/Roche, Novartis, Celgene, Celldex, Pfizer, CStone Pharmaceuticals, Cardinal Health [Breast cancer
(Palbociclib)]. Other Financial Interest: Metastat [Breast cancer]. Daniel F Hayes, MD Grant/Research/Clinical
Trial Support: Menarini Silicon Biosystems, LLC [Breast cancer]; Pfizer [Breast cancer]; AstraZeneca [Breast
cancer]; Merrimack Pharmaceuticals, Inc. [Breast cancer]. Consultant/Advisory Boards: Cepheid [Breast cancer];
Freenome, Inc. [Breast cancer]; Artiman Ventures [Breast cancer]; CVS Caremark [Breast cancer expert panel];
Agendia, Inc. [Breast cancer]. Patent Holder: Immunicon Corporation [Inventor]; University of Michigan [Inventor];
University of Michigan [Inventor]. Equity Ownership/Stock Options: Oncimmune LLC [Stock]; Inbiomotion [Stock].
Other Financial Interest: Royalties from licensing of patent above to Menarini Silicon Biosystems [Breast cancer];
University of Michigan [Inventor]. Sadhna R Vora, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

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