Treatment for hormone receptor-positive, HER2-

negative advanced breast cancer

Authors: Cynthia X Ma, MD, PhD, Joseph A Sparano, MD
Section Editor: Harold J Burstein, MD, PhD
Deputy Editor: Sadhna R Vora, MD

Contributor Disclosures

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

Literature review current through: Feb 2024. | This topic last updated: Dec 13, 2023.

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 (PR; triple-negative).

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

ET alone or in combination with targeted for metastatic hormone receptor-positive,

HER2-negative breast cancer is presented here. The treatment of HER2-positive
disease is discussed elsewhere, as is chemotherapy for endocrine therapy resistant,
metastatic hormone receptor-positive breast cancer. Other topics including the
approach to breast cancer and the role of adjunctive therapy, such as bone-modifying
agents, are also covered separately.
● (See "Overview of the approach to metastatic breast cancer".)
● (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative
advanced breast cancer" and "Systemic treatment for HER2-positive metastatic
breast cancer".)
 ● (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and
"Cancer pain management: Use of acetaminophen and nonsteroidal anti-
inflammatory 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 "Brain metastases in breast cancer" and "Radiation therapy for the
management of painful bone metastases".)

GOALS OF THERAPY

Patients with estrogen receptor-positive metastatic breast cancer often respond to

endocrine therapy (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 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 and targeted agents — There are several types of endocrine therapies
(ETs), as discussed:
● Strategies to deplete estrogen – In premenopausal patients, these strategies
include oophorectomy or use of luteinizing hormone releasing hormone agonists
and antagonists. In postmenopausal patients, estrogen is derived from adrenal
precursors, testosterone, and androstenedione that are converted to estradiol
and estrone by aromatase activity in peripheral cells. There are three aromatase
inhibitors (anastrozole and letrozole are azole compounds, while exemestane, is a
 17-hydroxy steroid). 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 are virtually identical, and the choice
of any one of them is appropriate. (See 'Alternative front-line options' below.)
● Strategies to directly target the ER – There are two strategies to interfere with
estrogen receptor (ER) signaling: the use of selective ER modulators such as
tamoxifen or raloxifene, or selective ER down-regulators. Fulvestrant and
elacestrant down-regulate ER. (See 'No alternations in PIK3CA, AKT1, or PTEN'
below.)
● Addition of targeted agents – Addition of agents that mechanistically work in
different ways than through ER interference can enhance the benefit seen with ET
alone. These include cyclin-dependent kinase (CDK) 4/6 inhibitors; everolimus (an
inhibitor of the mechanistic target of rapamycin); and, for those with tumor
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)
mutations, alpelisib (an alpha isoform specific inhibitor of phosphatidylinositol-
4,5-bisphosphate 3-kinase) [1]. (See 'AIs plus CDK 4/6 inhibitors' below and
'Alterations in PIK3CA, AKT1, or PTEN' below.)

Biopsy of a metastatic lesion — For patients who develop metastatic disease, we

biopsy a metastatic lesion.
● On the biopsy, we confirm ER, progesterone receptor (PR), and HER2 status,
irrespective of whether the patient previously had early breast cancer. This is
because up to 15 percent of metastatic cancers may have discordant ER
measurement compared with the primary cancer [2]. (See "Hormone receptors in
breast cancer: Clinical utility and guideline recommendations to improve test
accuracy", section on 'Interpretation of ER and PR tests'.)

• 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
tissue and/or blood for PIK3CA and ESR1 status, which is particularly important
when making treatment decisions after disease progression on first-line CDK 4/6
inhibitor and ET. We recommend the use of multigene panel–based assays [3].
Mutations in PIK3CA or ESR1 detected in either tumor tissue (preferably biopsy of
a metastatic lesion) or blood are acceptable. Testing both tumor tissue and blood
may increase the chance of detection [4]. Since ESR1 mutations are often
acquired after an ET-based approach and tumor evolves under treatment
pressure, we recommend repeated or longitudinal genomic testing at disease
progression [4,5].

CHOOSING BETWEEN ENDOCRINE THERAPY AND CHEMOTHERAPY

Our approach to endocrine versus chemotherapy in hormone receptor-positive, HER2-

negative metastatic cancers is as follows:
● Since endocrine therapy (ET; alone or in combination with targeted agents) is
generally less toxic than chemotherapy, with comparable outcomes [6,7], it is
preferable for most patients with hormone receptor-positive disease to begin
treatment with ET.
● For the minority of patients who have extensive visceral metastases,
chemotherapy may be considered an appropriate alternative to ET plus targeted
agents; however, there are no data suggesting a survival benefit to this approach.

• In one randomized phase II trial (RIGHT Choice study), in 222 pre- or

perimenopausal patients with aggressive, hormone receptor-positive, HER2-
negative breast cancer (half of whom had visceral crisis), initial ET plus
ribociclib improved progression-free survival relative to combination
chemotherapy (24.0 versus 12.3 months, hazard ratio [HR] 0.54, 95% CI 0.36-
0.79), with similar response rates (65 versus 60 percent) and fewer grade 3 to 4
adverse events (0.9 versus 7.0 percent) [8]. Time to tumor response was 4.9
months in the ET/ribociclib arm versus 3.2 months with chemotherapy, but this
difference was not statistically significant. Overall survival results are pending.
Although these results support frontline ET plus a CDK 4/6 inhibitor for
 patients with aggressive hormone receptor-positive, HER2-negative disease,
we note that the majority of patients in this trial had de novo metastatic
disease. Many patients treated in the United States have received prior
treatments in the neoadjuvant/adjuvant setting. (See "Endocrine therapy
resistant, hormone receptor-positive, HER2-negative advanced breast cancer",
section on 'Special considerations for those with rapidly progressive disease'.)
● There are no data that combining ET (with or without targeted agents) with
chemotherapy improves overall survival, and therefore we do not use this
strategy [9].

CONSIDERATIONS FOR THOSE WHO RECEIVED ADJUVANT ET

● Women who progress ≥12 months from the end of adjuvant endocrine therapy
(ET) and patients who present with de novo metastatic breast cancer are offered
first-line ET or ET in combination with a cyclin-dependent kinase (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 in combination with a CDK 4/6 inhibitor. (See
'Subsequent-line options' below.)

PREFERRED FIRST-LINE THERAPY

AIs plus CDK 4/6 inhibitors — Our preferred initial regimen is a cyclin-dependent
kinase (CDK) 4/6 inhibitor with an aromatase inhibitor (AI). Premenopausal women
must have ovarian suppression/ablation when on AIs. (See 'Ovarian
suppression/ablation, in combination with ET' below.)

Rationale for use of a CDK 4/6 inhibitor — 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 [10], and have been approved by
the US Food and Drug Administration (FDA) in this setting. The addition of ribociclib to
an AI has also shown overall survival (OS) benefits. Furthermore, in a meta-analysis of
nine randomized trials with over 5000 postmenopausal patients, the addition of CDK
4/6 inhibitors to ET improved OS (hazard ratio [HR] 1.33, 95% CI 1.19-1.48), but
increased risks of neutropenia, leukopenia, and diarrhea [11]. The CDK 4/6 inhibitors
have not been directly compared in clinical trials. Available trials are summarized in
the table ( table 1).

Although we typically incorporate CDK 4/6 inhibitors in first-line treatment paradigms,

there are data to support deferring to the second-line setting. Although this is not our
preferred treatment strategy, it is a reasonable option to consider for those with
endocrine sensitive disease (ie, metastatic recurrence occurred >12 months from
adjuvant endocrine therapy) who prefer to avoid initial treatment with a CDK 4/6
inhibitor (eg, due to concerns regarding toxicity, financial considerations, or need for
radiation to symptomatic sites of disease).

The SONIA trial was developed by the Danish government as a cost containment
strategy and randomly assigned 1050 women to either first-line treatment with a
nonsteroidal aromatase inhibitor (NSAI) plus a CDK 4/6 inhibitor, followed by single-
agent fulvestrant upon disease progression; or to first-line treatment with an NSAI
followed thereafter by fulvestrant plus a CDK 4/6 inhibitor upon progression [12]. At a
median follow up of 37 months, median overall survival was 46 months in the first-line
CDK 4/6 inhibitor group and 54 months in the second line CDK 4/6 inhibitor group (HR
0.98, 95% CI 0.80-1.20). The first-line group remained on CDK 4/6 inhibitor for 25
months, versus 8.1 months for the second-line group, which was associated with an
increase in drug expenditure of 200,000 dollars per patient. Given the longer time on
CDK 4/6 inhibition, there were 42 percent more grade ≥3 toxicities with first-line CDK
4/6 inhibition (2782 versus 1620 events).

A caveat to interpretation of this study is that the first-line CDK 4/6 inhibitor group
received single-agent fulvestrant in the second-line, which is no longer what most
patients receive given the emergence of other targeted agents (eg, alpelisib,
elacestrant). Nevertheless, deferring the CDK 4/6 inhibitor to the second-line setting is
an appropriate strategy in select patients. Data regarding initial treatment with single-
agent aromatase inhibitors are found below. (See 'Alternative front-line options'
below.)
Choosing between agents
● Choosing between CDK 4/6 inhibitors – There is controversy regarding the
choice of CDK 4/6 inhibitors. We consider any of the three CDK 4/6 inhibitors to be
acceptable options, with a choice between them driven by efficacy and toxicity
profile of the agents. Palbociclib and ribociclib are associated with higher rates of
neutropenia than abemaciclib, whereas abemaciclib more frequently causes
diarrhea ( table 1). Ribociclib has a higher incidence of liver function test
abnormalities than the other agents and can cause QTc prolongation, and
therefore may be less preferred for some patients (eg, those on QTc-prolonging
agents).

Of the three agents, abemaciclib has been evaluated in patients with brain
metastases and may be preferred in this setting. However, this is a very rare
occurrence in first- or second-line treatment of hormone receptor-positive breast
cancer. Data are discussed elsewhere. (See "Brain metastases in breast cancer",
section on 'Other options in specific subsets'.)

Overall survival data have emerged from the randomized trials of CDK 4/6
inhibitors in combination with an AI:

• Ribociclib has demonstrated OS benefit when added to an AI or AI plus ovarian

function suppression in the MONALEESA-2 (64 months versus 51 months, HR
0.76, 95% CI 0.63-0.93) [13] and MONALEESA-7 trials (58 months versus 48
months, HR 0.76, 95% CI 0.61-0.96) [14].

• Although palbociclib did not demonstrate OS benefit in the PALOMA-2 trial (54
months versus 51 months, HR 0.96, 95% CI 0.78-1.2) [15], there were significant
missing follow-up data that were imbalanced between the arms. Combined
analysis of PALOMA-1 and PALOMA-2 did show OS benefit in the group that
had disease-free interval over 12 months [16].

• In MONARCH 3, there was a trend toward longer OS with the addition of

abemaciclib to an AI (median 67 versus 54 months; HR 0.80, 95% CI 0.64-1.02),
which did not reach statistical significance [17].

In preclinical studies, ribociclib and abemaciclib are four- and five-times more
selective toward CDK 4 over CDK 6 and abemaciclib has a broader CDK target
 including cyclin B–CDK1, cyclin A/E–CDK2, and cyclin T–CDK9 [18], suggesting
potential differences among the three different CDK 4/6 inhibitors. Nevertheless,
we consider each agent to be an acceptable option.

Novel CDK 4/6 inhibitors (eg, dalpiciclib) are under investigation [19], with
promising results.
● Choosing between AIs – Although the AIs have not been compared when
combined with a common CDK 4/6 inhibitor, randomized trials of single-agent AIs
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
objective response rate (15 percent in both groups) and OS (31 and 33 months,
respectively) [20]. 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 [21,22].

Alternative front-line options — Acceptable alternatives to AIs plus CDK 4/6

inhibitors are discussed below. Ovarian suppression or ablation is added for
premenopausal women. (See 'Ovarian suppression/ablation, in combination with ET'
below.)
● Fulvestrant monotherapy – Fulvestrant is an alternative option, but is less
preferable than front-line AI and CDK 4/6 inhibition.

Fulvestrant is an ER antagonist that blocks ER dimerization and DNA binding,

increases ER turnover, and inhibits nuclear uptake of the receptor [23-25].
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).

Fulvestrant monotherapy has never been compared with the combination of an

AI and a CDK 4/6 inhibitor. However, in the phase III FALCON trial, fulvestrant 500
mg improved PFS over anastrozole at a median follow-up of 25 months (16.6
versus 13.8 months; HR for progression or death 0.80, 95% CI 0.637-0.999) [26].
There was no benefit in OS. 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) showed
equivalent PFS between fulvestrant and AIs [27-30], and therefore the higher
dose is preferred.
● Fulvestrant plus a CDK 4/6 inhibitor – Fulvestrant plus a CDK 4/6 inhibitor may
be an option for those who do not tolerate AI-based therapy.

Fulvestrant plus palbociclib was compared with letrozole plus palbociclib in a

randomized trial in 486 patients with previously treatment-naive, hormone
receptor-positive, HER2-negative advanced breast cancer [31]. Median PFS was
27.9 months for fulvestrant-palbociclib versus 32.8 months for letrozole-
palbociclib, a difference that was not statistically significant.

A trial evaluating fulvestrant plus the CDK 4/6 inhibitor ribociclib included
treatment-naïve patients, as well as those with prior lines of ET, and is discussed
below. (See 'For those on an AI alone, or relapse on or soon after adjuvant AI'
below.)
● In an FDA pooled analysis, in two trials evaluating the combination of CDK 4/6
inhibitors or placebo in combination with fulvestrant (396 patients), the estimated
HR for overall survival was 0.74 (95% CI 0.52-1.07) favoring addition of CDK 4/6
inhibitors [32].
● 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).

Several trials investigating the combination of fulvestrant plus anastrozole versus

anastrozole alone have been published, but with discrepant results [33-36]. PFS
and OS benefits, when present, appeared to be greatest in those with de novo
metastatic disease [36]. 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:
● AI monotherapy – For patients who have not received an aromatase inhibitor (AI)
in the adjuvant setting and are unlikely to tolerate a CDK 4/6 inhibitor, AI
 monotherapy is an appropriate alternative. Although fulvestrant as a single-agent
has shown better activity than aromatase inhibition, some patients may prefer
oral therapy to intramuscular injection.

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) [37].
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).

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
"Overview of the approach to metastatic breast cancer", section on 'Monitoring
therapy' and "Overview of the approach to metastatic breast cancer", section on
'Duration of treatment' and "Overview of the approach to metastatic breast cancer",
section on 'Definition of treatment failure'.)

When a patient's cancer fails to respond or stops responding to a given line of

endocrine therapy (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 estrogen receptor (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. We often
offer patients two to three lines of ET (including targeted agents) before moving to
chemotherapy. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-
negative advanced breast cancer".)

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)
[38,39]. In this case, these cancers may be resistant to estrogen depletion (eg,
aromatase inhibitors), but they may better respond to ER-targeting therapies such as
fulvestrant or elacestrant. Elacestrant is superior to fulvestrant for the treatment of
ESR1 mutated breast cancer. (See 'ESR1 mutation-positive' below.)

SUBSEQUENT-LINE OPTIONS

The optimal sequence upon progression on ET is not well defined, and multiple
strategies are possible. Our approach is outlined in the sections below, and takes into
account the patient's previous treatment history and the side effect profiles of
treatment.

After an AI plus CDK 4/6 inhibitor

No alternations in PIK3CA, AKT1, or PTEN

ESR1 wild-type — For patients with PIK3CA and ESR1 wild-type tumors who have
experienced progression on an aromatase inhibitor (AI) plus cyclin-dependent kinase
(CDK) 4/6 inhibitor, we suggest the selective estrogen receptor degrader (SERD)
fulvestrant, with or without the mechanistic target of rapamycin (mTOR) inhibitor
everolimus.

In rare instances, breast cancers have HER2 mutations (not gene amplifications) on
genomic sequencing. For ER positive tumors with HER2 mutations, fulvestrant in
combination with anti-HER2 therapy with trastuzumab and neratinib is another
treatment option. For patients who received a nonsteroidal AI (anastrozole, letrozole),
another alternative is exemestane plus everolimus. A choice between these options is
driven by patient preferences, considering the side-effect profile of everolimus, which
includes mucositis, rash, fatigue, diarrhea, and pneumonitis. 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
systemic anticancer therapy", section on 'Dexamethasone mouthwash'.)
● Fulvestrant – In the endocrine therapy (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 [29]. 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 [40].
● Fulvestrant plus everolimus – This combination has been studied in patients
with progression after an AI, but not after an AI/CDK 4/6 inhibitor combination.

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 progression-free survival (PFS) compared with
fulvestrant alone (10.3 versus 5.1 months; hazard ratio [HR] 0.61, 95% CI 0.4-0.92)
[41]. 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 (median PFS 12.2 versus 4.6 months, with and without
everolimus) [42].
● Fulvestrant plus neratinib and trastuzumab, for cancers with HER2-
activating mutations – For patients with hormone receptor positive, HER2-
negative metastatic breast cancer with activating HER2 mutation(s) and prior CDK
4/6 inhibitor therapy, fulvestrant plus trastuzumab and neratinib is an acceptable
option, and has been associated with an objective response rate of 39 percent
and median PFS of 8.3 months in this population [43].
● Alternatives to fulvestrant-based therapy – For patients who prefer to avoid
the intramuscular injections of fulvestrant, alternatives exist. Studies show that
everolimus pairs effectively with an AI or tamoxifen, for the treatment of AI-
resistant, advanced, estrogen receptor (ER)-positive breast cancer. Activating
mutations in the alpha isoform of the catalytic subunit of PIK3CA and
PIK3CA/AKT/mTOR pathway activation status are not predictive of benefit from
everolimus.
 • Everolimus plus AI – 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 objective response rate (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) [44,45]. 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) [44,45].

• Everolimus plus tamoxifen – 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 GINECO, 111 postmenopausal women who had progressed
on an AI were randomly assigned treatment with tamoxifen with or without
everolimus [46]. 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 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.

Data are insufficient to support a CDK 4/6 inhibitor plus fulvestrant after progression
on an AI and CDK 4/6 inhibitor. Trials have not found benefit with continuation of a
CDK 4/6 inhibitor with second-line endocrine therapy compared with second-line
endocrine therapy alone, among patients with prior progression on first-line
endocrine therapy with a CDK 4/6 inhibitor [47,48].

ESR1 mutation-positive — Elacestrant (aka RAD1901) is a SERD that has

regulatory approval in the United States for use in postmenopausal women and in
men with ESR1-mutated advanced hormone receptor-positive, HER2-negative breast
cancer that has progressed on at least one line of prior ET [49]. Given PFS benefits
over fulvestrant, as well as the ease of oral administration, we suggest its use in this
setting, particularly in patients who experienced prolonged PFS on the prior lines of
ET and CDK 4/6 inhibitors.
● Elacestrant – In the EMERALD trial, elacestrant was compared against standard
of care (SOC) ET (investigator's choice of fulvestrant or an AI) among 477 patients
who had received one or two prior lines of ET and up to one line of chemotherapy
in the metastatic setting, and who had progressed on prior treatment with a CDK
4/6 inhibitor [50]. The majority of patients in the SOC group received fulvestrant.
At 12 months, the elacestrant group had a better PFS rate than the SOC group
and those specifically receiving fulvestrant (22 versus 9 and 10 percent,
respectively). Greater PFS improvements were observed in the subgroup with
ESR1 mutations with elacestrant versus SOC and fulvestrant (12-month PFS rates
of 27 versus 8.2 and 8.4 percent, respectively). Benefit of elacestrant is more
marked in patients who experienced longer PFS on the prior ET plus CDK 4/6
inhibitor (likely more endocrine sensitive disease) [51]. Among patients who were
on prior a CDK 4/6 inhibitor for at least 12 months, the median PFS was 8.6
months on elacestrant versus 1.9 months on SOC ET (HR 0.41). Overall survival
results were immature, but there was a trend favoring elacestrant.

The most frequent toxicity with elacestrant was nausea, occurring in 35 percent.
Grade ≥3 adverse events were observed among 7 percent of patients in the
elacestrant arm and 3 percent in the SOC arm.
● Investigational strategies – The PADA1 trial found that, among patients who
develop a blood ESR1 mutation on an AI plus a CDK 4/6 inhibitor, a switch from
the AI to fulvestrant (with the same CDK 4/6 inhibitor) before clinical progression
improved PFS over continuation of the AI/CDK 4/6 inhibitor [52]; but effect on OS
was uncertain. We await further prospective data prior to using this strategy in
routine clinical practice.

Lasofoxifene is an orally administered selective ER modulator under investigation

in ESR1 mutated cancers and has shown promise [53,54].
Alterations in PIK3CA, AKT1, or PTEN — 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 PIK3CA, which encodes the alpha isoform of the catalytic
subunit of PI3K, are detected in over 40 percent of ER-positive breast cancers [55].

Preferred: Fulvestrant plus capivasertib — For patients with hormone

receptor-positive, HER2-negative advanced breast cancer with one or more alterations
in PIK3CA/AKT1/PTEN who have experienced progression on at least one endocrine-
based regimen in the metastatic setting, or recurrence on or within 12 months of
completing adjuvant therapy, the AKT inhibitor capivasertib has regulatory approval
by the US Food and Drug Administration (FDA) in combination with fulvestrant [56]. As
such, patients with tumors harboring activating PIK3CA mutations are eligible for
fulvestrant with either capivasertib or alpelisib. There have been no head-to-head
trials of these strategies. As such, either alpelisib or capivasertib are acceptable
options, but we have a preference for capivasertib, based on seemingly better
tolerability, including lower rates of hyperglycemia.

A randomized phase III trial (CAPItello-291) has shown PFS benefits with the addition
of capivasertib to fulvestrant therapy among patients with progression on a previous
AI, with or without a CDK 4/6 inhibitor [57]. Among 708 patients, the median PFS was
7.2 months in the capivasertib–fulvestrant group versus 3.6 months in the placebo–
fulvestrant group (HR 0.60, 95% CI 0.51-0.71). Among patients with PI3K pathway–
altered (PIK3CA, AKT1, or PTEN) tumors, benefits were comparable (PFS 7.3 versus 3.1
months; HR 0.50, 95% CI 0.38-0.65). The estimated OS at 18 months was 74 percent
with capivasertib–fulvestrant and 65 percent with placebo–fulvestrant in the overall
population (HR 0.74, 95% CI 0.56-0.98); and 73 versus 63 percent, respectively, in the
AKT pathway–altered population (HR 0.69, 95% CI 0.45-1.05). While the outcomes in
patients previously treated with a CDK 4/6 inhibitor also favored capivasertib, the
absolute gains in PFS were smaller than in the overall group.

Although benefits were observed in the overall population, the previous randomized
phase II FAKTION study demonstrated that benefit was limited to tumors with
AKT1/PTEN/PIK3CA mutations. In this study, among the 76 patients with pathway-
altered tumors, the addition of capivasertib to fulvestrant improved median PFS (12.8
months compared with 4.6 months with placebo; HR 0.44, 95% CI 0.26-0.72) [58]. OS
was 39 versus 20 months, respectively (adjusted HR 0.46, 95% CI 0.27-0.79). PFS and
OS benefits were not observed among the 64 patients lacking pathway alterations.
Regulatory approval has only been granted in the United States to patients whose
tumors harbor alterations in PIK3CA, AKT1, or PTEN.

The most frequent grade ≥3 adverse events in the capivasertib–fulvestrant group

were rash (12 percent) and diarrhea (9.3 percent). Grade ≥3 hyperglycemia occurred in
2.3 percent. Adverse events leading to discontinuation were reported in 13 percent of
the patients receiving capivasertib and in 2.3 percent of those receiving placebo.

The improvement in overall survival is encouraging; other targeted agents of the AKT
pathway including alpelisib and everolimus have not yet shown such benefits. Longer
term data are needed to confirm a survival benefit.

Alternative in PIK3CA mutant tumors: Fulvestrant plus alpelisib — For those

with tumor PIK3CA mutations whose cancers have progressed on or after treatment
with an AI, the combination of the alpha isoform-specific PI3K inhibitor alpelisib and
fulvestrant is an appropriate alternative to fulvestrant/capivasertib. (See 'Preferred:
Fulvestrant plus capivasertib' above.)

In a phase III trial of 572 men and postmenopausal patients with advanced hormone
receptor-positive breast cancer, all of whom had received a prior AI 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; HR 0.65, 95% CI
0.50-0.85) [59]. Median OS was 39 months for alpelisib-fulvestrant and 31 months for
placebo-fulvestrant (HR 0.86, 95% CI 0.64-1.15) [60]. 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).
Permanent discontinuation of alpelisib or placebo due to adverse events occurred in
71 patients (25 percent) receiving alpelisib-fulvestrant and in 12 (4.2 percent) receiving
placebo-fulvestrant.

However, this trial included a limited number of patients with prior therapy with CDK
4/6 inhibitors. Results from a single-arm phase II study in 127 patients with tumor
PIK3CA mutations and prior AI/CDK 4/6 inhibitor treatment suggest activity of
fulvestrant and alpelisib in this population, with approximately 50 percent of patients
not progressing after six months on treatment [61].

Alpelisib is associated with several important side effects that led to a 25 percent rate
of permanent treatment discontinuation in the SOLAR1 trial, including stomatitis,
diarrhea, rash, and hyperglycemia. Strategies for prevention and management of
adverse events is described in the tables ( table 2 and table 3 and table 4 and
table 5 and table 6). Our approach is to treat hyperglycemia with metformin as it
arises on alpelisib; however, an acceptable alternative is to administer prophylactic
metformin, particularly for those at high risk of hyperglycemia [62]. In one non-
randomized phase II trial in 68 patients with normal baseline fasting glucose or pre-
diabetic HbA1c level, prophylactic metformin beginning with initiation of alpelisib was
associate with a low rate of grade 3 to 4 hyperglycemia by cycle 2 of
alpelisib/fulvestrant therapy (5.9 percent), which compares favorably with that
observed in the SOLAR1 trial (37 percent) [63].

A separate investigational strategy using the novel alpha isoform-specific PI3K

inhibitor and degrader inavolisib with palbociclib and fulvestrant has shown promise
in endocrine therapy resistant PIK3CA-mutated, hormone receptor positive, HER2-
negative breast cancer. In 325 such patients who experienced recurrence on or within
12 months of adjuvant endocrine therapy, median PFS was 15 months with inavolisib,
palbociclib, and fulvestrant and 7.3 months with placebo, palbociclib, and fulvestrant
(HR 0.43, 95% CI 0.32-0.59) [64]. There was a trend favoring OS as well that did not
reach statistical significance, although survival data are immature (median OS not
estimable versus 31 months respectively; stratified HR 0.64, 95% CI 0.43-0.97). Grade
≥3 adverse events with inavolisib versus placebo were neutropenia (80 versus 78
percent), thrombocytopenia (14 versus 4.3 percent), leukopenia (6.8 versus 11
percent), and anemia (6.2 versus 1.9 percent). Grade ≥3 adverse events that were seen
with inavolisib but not placebo included hyperglycemia (5.6 percent), diarrhea (3.7
percent), and stomatitis and mucosal inflammation (5.6 percent). Inavolisib is not as
yet approved for any indication.

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 ET-resistant disease, but a
narrow therapeutic window due to toxicities (eg, gastrointestinal side effects,
transaminitis, and hyperglycemia [65-70]). Buparlisib was also associated with anxiety
and depression [65-67].

For patients treated with other initial strategies

For those on an AI alone, or relapse on or soon after adjuvant AI — Fulvestrant

plus a CDK 4/6 inhibitor is often chosen as next-line therapy for patients previously
treated with an aromatase inhibitor (AI) alone; or who experience relapse on an
adjuvant AI or within 12 months of completing an adjuvant AI ( table 7). If an ESR1
mutation is present, elacestrant is a reasonable alternative. (See 'ESR1 mutation-
positive' above.)
● Rationale for incorporating CDK 4/6 inhibition – In a US Food and Drug
Administration pooled analysis including three trials, among patients who were
assigned to fulvestrant/CDK 4/6 inhibitors or fulvestrant/placebo as second-line
or later-line ET, the CDK 4/6 inhibitor group experienced an improvement in
overall survival (HR 0.77, 95% CI 0·67-0·89) [32]. The difference in estimated
median overall survival was seven months, favoring CDK inhibitors.
● Choosing between CDK 4/6 inhibitors – Both palbociclib and abemaciclib are
approved for use in combination with fulvestrant in the subsequent-line setting in
the United States. Ribociclib is approved for use with fulvestrant either in the first-
line or subsequent-line setting. These are all appropriate combinations in patients
with previous AI treatment.

In a separate network meta-analysis, no statistically significant differences in PFS

were found among the three CDK 4/6 inhibitors in combination with fulvestrant:
palbociclib versus abemaciclib (HR 0.83), palbociclib versus ribociclib (HR 0.77,
95% CI 0·44-1·35), and abemaciclib versus ribociclib (HR 0.93) [71]. However, this
 conclusion is based on cross-trial comparisons. Individual trials are included in
the table ( table 7).

Ribociclib and abemaciclib have both shown to improve OS when combined with
fulvestrant when compared with fulvestrant alone in patients who had prior ET
(MONALEESA-3 and MONARCH 2) [72,73]; but the improvement in OS with the
addition of palbociclib to fulvestrant did not reach statistical significance [74].
Further discussion on the toxicities associated with each CDK 4/6 inhibitor is
found above. (See 'Choosing between agents' above.)
● Strategies to avoid – The strategy of switching from one AI to another AI as
monotherapy upon progression has shown mixed results, and we do not typically
employ this strategy [44,75].

For those previously treated on tamoxifen — For those treated with tamoxifen in
the adjuvant setting, an AI with CDK 4/6 inhibition is preferred initial therapy for
metastatic disease. The CDK 4/6 inhibitor trials discussed above included patients who
were treated for de novo metastatic disease, as well as those who had experienced
progression after adjuvant ET. (See 'AIs plus CDK 4/6 inhibitors' above.)

Although less preferable to the CDK 4/6 inhibitor-based combinations 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
[20,76,77]. For example, in a phase III trial, 713 women with disease progression on
prior tamoxifen were randomly assigned to treatment with either letrozole or
anastrozole [77]. Although the ORR was significantly higher with letrozole (19 versus
12 percent), there was no significant difference in time to progression or OS.

LATER-LINE THERAPY

For women who progress after two lines of endocrine therapy (ET), treatment must be
individualized based on their prior treatment response, tumor burden, and
preferences for treatment. Options include the following:
Chemotherapy — In general, patients who have progressed after multiple lines of ET
should receive chemotherapy. (See "Endocrine therapy resistant, hormone receptor-
positive, HER2-negative advanced breast cancer".)

Antibody drug-conjugates — Antibody drug conjugates that may be used in select

patients are discussed below.
● Sacituzumab govitecan – Sacituzumab govitecan is an anti-Trop-2 antibody drug
conjugate for patients with hormone receptor-positive, HER2-negative cancers
after prior treatment including ET, a cyclin-dependent kinase (CDK) 4/6 inhibitor,
and at least two lines of chemotherapy (including a taxane in either neo/adjuvant
or advanced disease setting) for advanced breast cancer [78,79]. Its use is
discussed in hormone receptor-positive cancers is discussed elsewhere. (See
"Endocrine therapy resistant, hormone receptor-positive, HER2-negative
advanced breast cancer", section on 'Sacituzumab govitecan'.)

Its role in triple-negative breast cancers is also discussed elsewhere. (See "ER/PR
negative, HER2-negative (triple-negative) breast cancer", section on 'Sacituzumab
govitecan'.)
● Fam-trastuzumab deruxtecan – For patients with tumors that are either HER2
immunohistochemistry 1+, or 2+, and in situ hybridization negative, who have
received at least one prior line of chemotherapy for metastatic disease and, if
tumor is hormone receptor-positive, are refractory to ET, fam-trastuzumab
deruxtecan is an appropriate option [78]. Further details and supporting data are
found elsewhere. (See "Endocrine therapy resistant, hormone receptor-positive,
HER2-negative advanced breast cancer", section on 'Sacituzumab govitecan'.)

Other options — For patients who are asymptomatic with slowly progressive disease,
continuation of ET is reasonable, with one of the options below:
● Tamoxifen plus abemaciclib – For patients without prior treatment with a CDK
4/6 inhibitor, the combination of tamoxifen plus abemaciclib has shown efficacy
and tolerability, with improved outcomes over abemaciclib alone. In preliminary
results of the phase II nextMONARCH study, patients randomly assigned to
abemaciclib 150 mg plus tamoxifen 20 mg daily experienced a statistically
significant improvement in median overall survival (OS), relative to those assigned
 to either abemaciclib 150 mg daily or abemaciclib 200 mg daily (24 months versus
21 and 17 months, respectively) [80]. Although patients were heavily pretreated,
prior receipt of a CDK 4/6 inhibitor was an exclusion criterion for this trial.

This trial shows that the addition of ET to a CDK 4/6 inhibitor is of value and also
demonstrates a role for late introduction of tamoxifen.
● Tamoxifen monotherapy – 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 the front-line setting, tamoxifen has yielded lower
response rates relative to aromatase inhibitors (AIs), but similar OS; however,
comparisons are not available for tamoxifen versus the combination of AIs and
CDK 4/6 inhibitors, which is a more typical front-line regimen.

In a meta-analysis of four randomized trials including 1560 postmenopausal

women with hormone receptor-positive, advanced breast cancer, front-line
treatment with AIs improved the clinical benefit rate (stable disease for >24 weeks
or response) compared with tamoxifen (odds ratio [OR] 1.6), although the OS rate
was similar between the two groups (OR 1.05) [81].

In a combined analysis of two randomized trials evaluating a sequence strategy

(ie, tamoxifen followed by anastrozole or vice versa) in 1021 women, 511 were
assigned to anastrozole, and of these, 137 women crossed over to tamoxifen [82].
Second-line treatment with tamoxifen in these women resulted in a 10 percent
objective response rate and a clinical benefit rate of 49 percent.
● Abemaciclib monotherapy – 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 US Food and Drug Administration approved for use as
monotherapy for women with progressive disease after ET and chemotherapy
[83]. Its activity for patients who previously received a different CDK 4/6 inhibitor
is unknown.

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 in 20
 percent of patients, with a clinical benefit rate (stable or responding disease) of 42
percent, and median progression-free survival of six months [84].
● Hormones or intermittent endocrine therapy – We choose other options
before hormones for treatment of metastatic breast cancer, though historical
reports suggested some activity and these strategies were used more frequently
in the past [85-94]. The value of such approaches in contemporary practice, when
most patients receive adjuvant anti-estrogen therapy, and when multiple
endocrine treatments with and without targeted therapy options exist, is not
known. Similarly, the historical literature include reports of treatment response to
withdrawal of endocrine therapy [95,96]. While interruption or cessation of
endocrine treatment is an option for patients with indolent tumors or those
needing a break from therapy, such withdrawal responses are almost never
encountered in contemporary practice. 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".)

ADDITIONAL CONSIDERATIONS FOR PREMENOPAUSAL WOMEN

For patients with metastatic hormone receptor-positive breast cancer, menopausal

status must first be ascertained to determine the approach to treatment. (See
'Ovarian suppression/ablation, in combination with ET' below.)

We define menopause in women <60 years using guidelines from the National
Comprehensive Cancer Network [97]:
● Prior bilateral oophorectomy.
● No menstrual periods in the preceding 12 or more months occurring either:

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

suppression, or

• 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
'Laboratory testing'.)

Women who do not fit into the above categories are considered premenopausal, and
as such, ovarian suppression/ablation becomes a consideration.

Ovarian suppression/ablation, in combination with ET — For premenopausal

women treated with endocrine therapy (ET), we suggest concurrent ovarian
suppression or ablation, in order to suppress estrogen levels. This is imperative for
premenopausal patients receiving aromatase inhibitors (AIs), given the potential for
ovarian stimulation with these agents.

Additionally, ovarian suppression allows premenopausal women to take advantage of

the addition of targeted agents that have been evaluated in the postmenopausal
setting, such as cyclin-dependent kinase (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 gonadotropin-releasing hormone agonist (GnRHa) plus
the combination of an AI and a 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.)

Ovarian suppression and ablation have shown equivalent outcomes in clinical trials
[98]. However, for women with disease progression on a regimen including ovarian
suppression, some contributors assess serum estradiol levels 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.

In a randomized trial, the combination of tamoxifen and ovarian suppression with

buserelin improved overall survival (OS) compared with treatment with either agent
alone [99]. Furthermore, small studies have suggested that the addition of a GnRHa to
an AI is as effective in premenopausal women as an AI alone is in postmenopausal
women [100,101].

Incorporation of targeted agents — Available data in premenopausal patients

suggest 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 frontline
ribociclib or placebo to be taken concurrently with goserelin and either tamoxifen or a
nonsteroidal AI. Progression-free survival (PFS) was improved with ribociclib (median
PFS, 24 versus 13 months; hazard ratio [HR] 0.55, 95% CI 0.4-0.69) [102], as was the OS
rate at 3.5 years (70 versus 46 percent; HR 0.71, 95% CI 0.54-0.95) [14]. 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 'AIs 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 ET for
pre-/perimenopausal women with hormone receptor-positive, HER2-negative
advanced breast cancer.

Similarly, a CDK 4/6 inhibitor may effectively combine with fulvestrant and ovarian
suppression. Among the 108 premenopausal women with advanced ET-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) [103].
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 [104].
 Versus chemotherapy — For most premenopausal women with hormone
receptor-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 "Overview of the approach to metastatic breast
cancer", section on 'Hormone receptor-positive, HER2-negative disease'.)

In results of a randomized phase II study, among 184 premenopausal women with

advanced hormone receptor-positive, HER2-negative breast cancer, those assigned to
exemestane, palbociclib, and a GnRHa experienced a better PFS than those assigned
to capecitabine (20 versus 14 months; HR 0.66, 95% CI 0.44-0.99) [105].
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, as an alternative — Tamoxifen is a selective estrogen receptor (ER)

modulator (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. While our preference is for ovarian
suppression or ablation plus ET, single-agent treatment with a SERM alone is an
alternative for those who wish to avoid ovarian suppression. In a 1991 review of phase
II trials of tamoxifen in premenopausal women, the ORR was 45 percent among the
31 patients with confirmed ER-positive disease [106].

SPECIAL CONSIDERATIONS

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(ADP-ribose) polymerase inhibitors is discussed elsewhere. (See "Overview of the
approach to metastatic breast cancer", section on 'Special considerations'.)

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".)

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

SUMMARY AND RECOMMENDATIONS

● Introduction – Although metastatic breast cancer is unlikely to be cured, there
have been meaningful improvements in survival due to advances in systemic
therapy, including endocrine therapy (ET) and targeted agents. (See 'Introduction'
above.)
● General principles – In patients with new metastatic disease, we biopsy a
metastatic lesion to confirm estrogen receptor (ER), progesterone receptor (PR),
and human epidermal growth factor receptor 2 (HER2) status. We also assess for
mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit
alpha (PIK3CA), AKT1, PTEN, and ESR1, in tumor tissue and/or blood, for eligibility
 for AKT inhibitor, PI3K inhibitor, and elacestrant, respectively. (See 'General
principles' above.)

For most patients with hormone receptor-positive, HER2-negative metastatic

breast cancer, we suggest initial treatment with ET plus targeted therapy, rather
than chemotherapy (Grade 2B). This includes patients with rapidly progressive,
symptomatic disease or visceral metastases, although chemotherapy is an
acceptable alternative. (See 'Choosing between endocrine therapy and
chemotherapy' above.)
● Special considerations for those who received adjuvant ET

• Women who progress ≥12 months from the end of adjuvant ET and patients
who present with de novo metastatic breast cancer are offered first-line
endocrine-based therapies. (See 'Preferred first-line therapy' above.)

• Those who progress on or within 12 months of completing adjuvant ET are

eligible for subsequent-line endocrine-based therapies. Patients who progress
on first-line ET for metastatic disease are also eligible for subsequent-line
treatment. (See 'Subsequent-line options' above.)
● Initial treatment

• For initial therapy for patients with metastatic hormone receptor-positive,

HER2-negative breast cancer, 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 anastrozole, or fulvestrant in combination with an AI.

• For premenopausal women treated with ET, we suggest concurrent ovarian

suppression or ablation (Grade 2C). This is imperative for premenopausal
patients receiving AIs, given the potential for ovarian stimulation with these
agents.
● Subsequent-line treatment – For patients who have previously experienced
progression on an AI and CDK 4/6 inhibitor, our approach is as follows:

• For those harboring alterations in PIK3CA, AKT1, or PTEN, we suggest the

combination of fulvestrant with capivasertib (Grade 2C). Fulvestrant with the
 alpha isoform-specific PI3K inhibitor alpelisib is an alternative option for
PIK3CA-mutant breast cancer. For those with coexisting ESR1 mutations,
elacestrant is a reasonable alternative especially if patients had a prolonged
progression-free survival on prior ET with a CDK 4/6 inhibitor. (See 'Alterations
in PIK3CA, AKT1, or PTEN' above.)

• For those with PIK3CA-wild-type cancers,

- If the tumor is ESR1 wild-type, options include fulvestrant monotherapy or
everolimus-based combinations, with a choice between them driven by
side-effect profiles. (See 'ESR1 wild-type' above.)
- If an ESR1 mutation is present, we suggest elacestrant rather than
fulvestrant (Grade 2B). Fulvestrant, with or without everolimus, is a
reasonable alternative. (See 'ESR1 mutation-positive' above.)
● Later-line treatment – 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 UpToDate editorial staff acknowledges Matthew Ellis, MD, PhD, FRCP; Michael J
Naughton, MD; and Maura Dickler, MD, who contributed to an earlier version of this
topic review.
REFERENCES

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consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020;
31:1623.
2. Lindström LS, Karlsson E, Wilking UM, et al. Clinically used breast cancer markers
such as estrogen receptor, progesterone receptor, and human epidermal growth