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Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy
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Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy
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Literature review current through: Jul 2017. | This topic last updated: Jun 20, 2017.

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), 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 in the treatment of hormone-sensitive disease.

Endocrine therapy 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. 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 "Overview of the use of osteoclast inhibitors in early 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 endocrine therapy (ET), 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

Approach

Given that up to 15 percent of metastatic cancers may have discordant estrogen receptor (ER) measurement compared with the primary cancer [1], 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 "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, receive endocrine therapy (ET), respectively. For patients with 2 to 9 percent staining, 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'.)

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 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) in order to maximize the chances of an early, meaningful, and more rapid response than one might anticipate from ET. Other than in this rare circumstance, trials have not shown any benefit for using chemotherapy prior to ET [2].

End-organ dysfunction can be defined as pulmonary symptoms, such as dyspnea, or 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.

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.

Since ET 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 refractory to ET. Several studies have suggested that addition of targeted therapies to ET may improve progression-free survival (PFS), although overall survival (OS) results are still pending. These agents include the inhibitor of mechanistic target of rapamycin (mTOR), everolimus, as well as inhibitors of cyclin dependent kinase 4 and 6 (CDK 4/6), palbociclib and ribociclib.

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 endocrine treatment.

Those who progress on or within 12 months of completing adjuvant ET are eligible for subsequent-line endocrine treatment. Patients who progress on first-line ET for metastatic disease are also eligible for second-line treatment.

For women who progress after two lines of ET, treatment should be based on their prior treatment response, tumor burden, and individual preferences. (See 'Resistance to treatment' below.)

There are no data that combining ET with chemotherapy improves OS, and therefore we do not use them together [3].

Types of endocrine therapies — There are several types of ETs. These can be characterized as strategies to deplete estrogen and strategies to directly target the 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 dehydroepiandrostenedione (DHEA) 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 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 inhibitors' 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, 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 downregulates 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 [4,5]. (See 'Fulvestrant with or without an AI' below.)

While estrogen obviously has agonistic activity for ER and could be considered a prototype SERM, 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.)

Resistance to treatment — The presence of new metastatic lesions, clinical deterioration, or growth of lesions suggest 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 patients fail to respond or stop responding to a given line of ET, an important consideration is whether or not to proceed with another line of ET or move to chemotherapy. The relative level of ER in the tissue (2 to 9 percent versus ≥10 percent), the duration of response to the prior ET, the patient’s tolerance of ET, 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 or move to chemotherapy. We often offer patients two to three lines of ET before moving to 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) [6,7]. In this case, these cancers may be totally resistant to estrogen depletion (eg, AIs), but they may 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 limited available data and lack of validated assays, we do not test for or use ESR1 mutational status to direct care.

Some data have suggested that altered tamoxifen metabolism may affect its activity. However, we do not test for germline CYP2D6 status or use it to direct therapy for ER-positive patients with metastatic disease. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators", section on 'Altered tamoxifen metabolism'.)

SELECTION OF ENDOCRINE THERAPY — As discussed above, endocrine therapy (ET) is not appropriate for those with rapidly progressive visceral metastases with evidence of end-organ dysfunction. (See 'Approach' above.)

Such patients should be offered chemotherapy instead. (See "Systemic treatment of metastatic breast cancer in women: Chemotherapy".)

For others, ET is appropriate and selection of regimen is discussed below. We do not reintroduce the same treatment regimen if a patient has been treated with it in the adjuvant setting within 12 months of developing metastatic disease.

Premenopausal women — We define menopause in women <60 years using guidelines from the National Comprehensive Cancer Network (NCCN) [8]:

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'.)

For premenopausal women, options for ET include:

Ovarian suppression or ablation in combination with endocrine treatment (following the approach for endocrine treatment used for a postmenopausal woman). (See 'Postmenopausal women' below.)

Tamoxifen alone.

Our preference is for ovarian suppression or ablation plus ET rather than single-modality treatment. In a randomized trial, the combination of tamoxifen and ovarian suppression with buserelin improved overall survival (OS) compared with treatment with either agent alone [9]. Furthermore, small studies have suggested that the addition of a gonadotropin-releasing hormone (GnRH) agonist to an aromatase inhibitor (AI) is as effective in premenopausal women as an AI alone is in postmenopausal women [10,11]. Ovarian suppression also 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 4/6 (CDK 4/6) inhibitors and 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 GnRH agonist plus the combination of an AI and CDK inhibitor. (See 'Preferred first-line regimen' below.)

Ovarian suppression and ablation have shown equivalent outcomes in clinical trials [12]. 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.

While our preference is for ovarian suppression or ablation plus ET, single-agent treatment with a selective estrogen receptor modulator (SERM) alone is an option for those who wish to avoid combined modality treatment. In a 1991 review of phase II trials of tamoxifen in premenopausal women, the objective response rate was 45 percent among the 31 patients with confirmed estrogen receptor (ER)-positive disease [13].

Postmenopausal women

Preferred first-line regimen — Women who progress at least 12 months from 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 CDK inhibitor with an AI, although single-agent treatment with fulvestrant or an AI may be appropriate for those with low disease burden or those who are less likely to tolerate combination treatment. Other front-line options are discussed below. (See 'Other options (first- or subsequent-line)' below.)

The option of CDK inhibitor with an AI is also appropriate as a subsequent-line treatment for those who have not received prior treatment with a CDK inhibitor.

Aromatase inhibitors plus CDK 4/6 inhibitors — The 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 inhibitors (palbociclib or ribociclib) have demonstrated improved progression-free survival (PFS) relative to letrozole alone.

Palbociclib (formerly known as PD 0332991) is a highly selective, orally administered inhibitor of CDK 4/6. Palbociclib plus an AI was US Food and Drug Administration (FDA)-approved for metastatic, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in February 2015 [14]. In a phase III study including 666 postmenopausal patients with metastatic, ER-positive, HER2-negative breast cancer, 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 (42 versus 35 percent) compared with letrozole alone [15]. Neutropenia was also 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. OS data are not yet available pending longer follow-up.

Ribociclib, another selective CDK 4/6 inhibitor, has also been FDA-approved in combination with letrozole, demonstrating improved efficacy over letrozole alone. In a phase III study in which 668 postmenopausal women with hormone receptor-positive, HER2-negative recurrent or metastatic breast cancer were treated with first-line letrozole, with or without ribociclib, those receiving ribociclib experienced an improved PFS (not reached versus 14.7 months; HR for progression or death 0.56, 95% CI 0.43-0.72) [16]. At 18 months, the PFS rate was 63 percent with the combination versus 42 percent among those receiving letrozole only. The overall response rates were 41 and 28 percent, respectively. Grade 3 or 4 adverse events were more common with the combination, notable for neutropenia (59 versus 0.9 percent), leukopenia (21 versus <1 percent), and increased alanine aminotransferase (9 versus 1 percent) and aspartate aminotransferase (5.7 versus 1.2 percent) levels. Despite this higher frequency of adverse events, only 7.5 percent of patients required permanent discontinuation of both ribociclib and letrozole. OS data are not yet available pending longer follow-up.

Ribociclib and palbociclib have not been directly compared in clinical studies.

Other options (first- or subsequent-line) — Given the consistent benefits observed with CDK inhibitors and AI, we prefer those regimens in the front-line setting. However, CDK/AI has never been compared directly with fulvestrant or fulvestrant in combination with an AI. Given results of the FALCON trial discussed below, we consider fulvestrant to be an acceptable alternative to CDK/AI. Particularly, for patients with low burden of disease or those who are unlikely to tolerate combination treatment, a single-agent option is appropriate. 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.

One contributor uses fulvestrant plus 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, though with a modification of the dose of fulvestrant to 500 mg intramuscularly rather than 250 mg intramuscularly. (See 'Fulvestrant with or without an AI' below.)

There is no optimal sequence for ET upon progression. Options available in the second-line setting include fulvestrant, with or without palbociclib; and everolimus, with either an AI or tamoxifen. An alternative AI or tamoxifen may also be offered, though these are less preferred options. 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 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 with or without an AI' below and 'Aromatase inhibitors' below and 'Fulvestrant plus palbociclib' below and 'Everolimus plus endocrine therapy' below.)

Fulvestrant with or without an AI — Fulvestrant is an ER antagonist that blocks ER dimerization and DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor [17-19]. 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 [20]. 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 [21-24]. 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 estrogen receptor down-regulators (SERDs) are under investigation. (See 'Investigational agents' below.)

First-line setting – The benefit of fulvestrant monotherapy over an AI 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 who had not received prior hormone therapy, 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) [4]. 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) showed equivalent PFS between fulvestrant and AIs [23,25-27], and therefore we use the higher dose.

In addition to single-agent therapy, several trials investigating the combination of fulvestrant plus anastrozole have been published, but with discrepant results [28-30]. 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 Southwest Oncology Group (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 [28]. 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. Compared with anastrozole alone, combined treatment resulted in an improvement in PFS (15 versus 14 months; HR 0.80, 95% CI 0.68-0.94), with a trend towards improvement in OS (48 versus 41 months; HR 0.81, 95% CI 0.65-1.00). 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 half-way through accrual, the 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.

In the Fulvestrant and Anastrozole Combination Trial (FACT) trial, survival outcomes were similar between the combination of fulvestrant and anastrozole and anastrozole alone [29]. Among 514 women with relapsed hormone receptor-positive disease (one-third of whom were ET-naϊve), 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.

Second-line setting – Fulvestrant may be used in the subsequent-line setting as monotherapy or, for those who have not been treated with a CDK inhibitor, in combination with palbociclib. (See 'Fulvestrant plus palbociclib' below.)

As monotherapy, it was shown to have equivalent activity as exemestane in postmenopausal women with hormone receptor-positive disease who had progressed on a nonsteroidal AI [26]. 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 [24].

Preliminary results from one trial of everolimus and fulvestrant are discussed below. (See 'Everolimus plus endocrine therapy' below.)

Aromatase inhibitors — 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 setting – 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) [31]. 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 objective response rate (ORR, 15 percent in both groups) and OS (31 and 33 months, respectively) [32]. 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 [33,34].

Second-line setting – There are no differences in efficacy between the AIs in the second-line setting [32,35,36]. For example, in a phase III trial, 713 women with disease progression on a prior antiestrogen were randomly assigned to treatment with either letrozole or anastrozole [36]. Although the ORR was significantly 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 [37]. 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 [38].

Options reserved for subsequent-line treatment

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. Fulvestrant as a single agent is discussed in more detail below. (See 'Fulvestrant with or without an AI' above.)

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 [39,40]. 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 [39]. At a median follow-up of 8.9 months, compared with fulvestrant plus placebo, fulvestrant plus palbociclib resulted in [40]:

An improvement in PFS (median, 9.5 versus 4.6 months with fulvestrant plus placebo; HR 0.46, 95% CI 0.36-0.59).

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 [41]. Patient-reported quality of life outcomes were higher among those receiving fulvestrant and palbociclib compared with fulvestrant alone [42].

The study was stopped early because of the positive efficacy data observed at interim analysis. These data support the combination of palbociclib plus fulvestrant for women with metastatic hormone receptor-positive breast cancer. Longer follow-up will be required to inform the impact of treatment on OS.

Alternative CDK inhibitors have also combined effectively with fulvestrant. For example, in a phase III trial of 669 patients randomly assigned to fulvestrant with or without the investigational CDK 4/6 inhibitor abemaciclib, those receiving abemaciclib 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) [43]. Patients receiving abemaciclib had higher rates of diarrhea, neutropenia, nausea, and fatigue.

Everolimus plus endocrine therapy — 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 [44]. Studies show that the mechanistic target of rapamycin (mTOR) inhibitor everolimus, in combination with either an AI or tamoxifen, 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 Breast Cancer Trials of Oral Everolimus (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) [38,45]. 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) [38,45]. 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 [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.

Preliminary results from the randomized phase II PrECOG 0102 trial suggest the combination of exemestane and fulvestrant may also be an effective strategy, with a doubling in PFS compared with fulvestrant alone (10.4 versus 5.1 months; HR 0.60, 95% CI 0.4-0.92) [47]. However, further data are necessary before using this combination.

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. However, for patients who are asymptomatic with slowly progressive disease, continuation of ET is reasonable. Special considerations for those who harbor germline mutations in BRCA are discussed elsewhere. (See "Systemic treatment for metastatic breast cancer: General principles", section on 'Treatment selection' and "Systemic treatment for metastatic breast cancer: General principles", section on 'Special considerations for BRCA carriers'.)

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 [48]. 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.

Hormones — We opt for other options before hormones for treatment of metastatic breast cancer, though they do show some activity and were used more frequently in the past.

ProgestinsMegestrol 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 [49,50]. 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 [49,51]. 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 [52]. They may also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor.

Progestins 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".)

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 [53].

The efficacy of estrogens was shown in a trial involving 143 women who were randomly assigned to diethylstilbestrol (DES) or tamoxifen [54]. 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.

As with progestins, estrogens are contraindicated if the patient has a thromboembolic disorder or other risk factors for thromboembolic disease. For patients who experience vaginal bleeding on estrogens, progestin therapy is effective treatment [53]. In addition, patients with bone metastasis should be treated with bisphosphonates before giving estradiol to avoid hypercalcemia.

Androgens – Androgens, including testosterone, fluoxymesterone, and danazol, are inferior to high-dose estrogens and are rarely used to treat metastatic breast cancer [55]. Although they have response rates of 10 to 20 percent in pretreated patients, side effects include virilization, edema, and jaundice [56-58]. 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).

INVESTIGATIONAL AGENTS — The combination of endocrine therapy (ET) plus a molecular-targeted agent continues to be explored in clinical trials with the aim to overcome endocrine resistance.

Examples include:

Novel SERDS Novel selective estrogen receptor down-regulators (SERDs) are appealing because they may be effective in targeting ESR1 mutations and because the existent SERD, fulvestrant, is limited by its intramuscular administration in regards to how much can be delivered.

Studies conducted using specimens collected from women with metastatic breast cancer following disease progression on ETs have identified recurrent mutations in ESR1, the gene that encodes estrogen receptor 1, as an acquired resistance mechanism to ET, particularly aromatase inhibitors (AIs) [59-61]. In contrast to the rare occurrence in primary breast tumor, ESR1 mutation was found in 11 to 55 percent of metastatic biopsies. These mutations cluster in the ligand binding domain of the estrogen receptor (ER), with Y537S, C or N, and D538G being the most common, leading to a constitutive agonist conformation, and therefore resistance to AI treatment. In addition, in preclinical studies, a higher dose of tamoxifen or fulvestrant was needed to suppress tumor cell proliferation in the presence of ESR1 mutation. Novel SERDs with the ability to degrade mutant ER 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 'Estrogen receptor (ER) α (ESR1 gene) mutations'.)

Novel CDK inhibitors – While cyclin-dependent kinase (CDK) inhibitors have been shown to combine effectively with ET, some evidence suggests single-agent activity. For example, in preliminary results from the phase II MONARCH 1 study, which enrolled 132 patients with a median of three prior lines of treatment, single-agent treatment with the novel CDK inhibitor abemaciclib induced tumor response in 19 percent of patients, with a clinical benefit rate (stable or responding disease) of 42 percent, and median progression-free survival (PFS) of 5.7 months [62].

PI3K inhibitors – The 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. For example, mutations in PIK3CA, which encodes the alpha catalytic subunit of PI3K, are detected in over 40 percent of ER-positive breast cancers [44]. A number of agents that target various components of the PI3K pathway are being evaluated in clinical trials. For example, results from BELLE-2, evaluating the pan-isoform PI3K inhibitor buparlisib with fulvestrant, demonstrate an improvement in PFS with the combination compared with fulvestrant alone (6.8 versus 4.5 months), particularly among those with a PIK3CA mutation (6.8 versus 4.0 months) [63]. Buparlisib is, however, associated with a rise in liver enzymes and psychiatric side effects. Other inhibitors of the PI3K pathway, including isoform-specific inhibitors and those that target mTOR or AKT, are in development.

Endocrine therapy 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 [64]. 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 PFS in one trial (but not another), but with increased toxicity and no demonstrated improvement in overall survival in either trial [65,66]. 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).

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

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.)

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). However, patients who demonstrate a good clinical response 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 metastasis are appropriate candidates for ET.

For such patients who are premenopausal, we offer ovarian suppression or ablation in combination with endocrine treatment (following the approach for endocrine treatment used for postmenopausal women). Single-agent treatment with a selective estrogen receptor modulator (SERM) alone is an acceptable alternative for those who wish to avoid combined modality treatment.

-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 'Postmenopausal women' above.)

For such patients who are postmenopausal, our preference for first-line ET is a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with an aromatase inhibitor (AI), although other options including single-agent fulvestrant, or an AI, or the combination of fulvestrant and an AI are appropriate alternatives for some patients. (See 'Preferred first-line regimen' above and 'Other options (first- or subsequent-line)' 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. The combinations of palbociclib plus fulvestrant and everolimus plus either an AI or tamoxifen are reserved for patients who have progressed on at least one line of ET.

-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.

ACKNOWLEDGMENT — The authors and editors would like to recognize Drs. Matthew Ellis and Michael J. Naughton, who contributed to previous versions of this topic review.

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