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 the availability of more effective systemic therapies, including endocrine therapy (ET) in the treatment of hormone-sensitive disease.
ET alone or in combination with targeted agents (phosphoinositide 3-kinase [PI3K], mechanistic target of rapamycin [mTOR], or cyclin-dependent kinase [CDK] 4/6 inhibitors) for metastatic hormone receptor-positive, HER2-negative breast cancer is presented here. The treatment of HER2-positive disease is discussed elsewhere, as is chemotherapy for metastatic hormone receptor-positive breast cancer. Poly(ADP-ribose) polymerase (PARP) inhibitors in patients with metastatic breast cancer and a germline breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutation are also discussed separately. Other topics including the approach to breast cancer and the role of adjunctive therapy, such as pain medications and bone-modifying agents, are also covered separately.
●(See "Overview of the approach to metastatic breast cancer".)
●(See "Treatment of endocrine therapy resistant/refractory 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 ET alone or in combination with targeted agents, which can reduce tumor burden and symptoms with generally fewer side effects and toxicities than chemotherapy. Furthermore, modern ETs appear to prolong progression and possibly survival compared with older ETs. However, few if any patients with metastatic breast cancer will be cured, and the goal of therapy is, principally, palliation. We make efforts to choose the therapy that is most likely to stabilize or reduce the burden of disease with the fewest side effects and maintain that therapy until either unacceptable toxicities are evident or disease progression occurs.
GENERAL PRINCIPLES
Types of ET and targeted agents — There are several types of ETs. These can be characterized as strategies to deplete estrogen and strategies to directly target the estrogen receptor (ER).
●Strategies to deplete estrogen – While initial therapies to deplete estrogen were accomplished in premenopausal women by oophorectomy, estrogen can now be suppressed with the use of luteinizing hormone-releasing hormone 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 androstenedione that are converted to estradiol and estrone by aromatase activity in peripheral cells and even in the cancers themselves. Specific inhibitors of aromatase are available. Two of these, anastrozole and letrozole, are azole compounds, while the third, exemestane, is a 17-hydroxy steroid. Prospective randomized clinical trials in both the adjuvant and metastatic setting have demonstrated that the clinical activity, side effects, and toxicity of these three aromatase inhibitors are almost 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 ER signaling: the use of selective ER modulators such as tamoxifen or raloxifene, or selective ER down-regulators. Fulvestrant is the only available agent that down-regulates ER. (See 'PIK3CA wild-type' below.)
●Addition of targeted agents – Over the last decade, several prospective, randomized clinical trials have demonstrated that addition of agents that mechanistically work in different ways than through ER interference can enhance the benefit seen with ET alone. These include cyclin-dependent kinase (CDK) 4/6 inhibitors; everolimus (an inhibitor of the mechanistic target of rapamycin [mTOR]); 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 'PIK3CA mutated' below and 'Alternatives to fulvestrant' below.)
Biopsy of a metastatic lesion
●For patients who develop metastatic disease, irrespective of whether they previously had early breast cancer, we first biopsy a metastatic lesion to confirm estrogen receptor (ER), progesterone receptor (PR), and HER2 status. This is because up to 15 percent of metastatic cancers may have discordant ER measurement compared with the primary cancer [2]. (See "Overview of the approach to metastatic breast cancer", section on 'Biopsy of metastatic lesion'.)
•According to American Society of Clinical Oncology/College of American Pathologists criteria, immunohistochemical (IHC) staining of 0 to <1 percent should be considered negative, whereas ≥10 percent should be considered positive, and patients should not, or should, be candidates for ET, respectively. Tumors with ER 1 to 9 percent IHC staining are considered positive and ET should be considered, but may be less likely to be effective. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy", section on 'Interpretation of ER and PR tests'.)
•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 PIK3CA status, either at initial diagnosis of metastatic disease, or at the time of progression on first-line therapy. We assess this using the companion diagnostic test approved by the US Food and Drug Administration to select patients for possible second-line treatment with the alpha isoform-specific phosphoinositide 3-kinase inhibitor alpelisib [3]. The diagnostic test is approved for use on tumor tissue specimens and circulating tumor DNA for the detection of 11 PIK3CA activating mutations. We prefer to use tissue, if it is available, given available trial data. However, if tumor tissue is not available, we assess plasma specimens for PIK3CA mutations. If the test is negative for PIK3CA mutations in plasma, more tissue should be acquired, when possible, for repeat testing for PIK3CA mutations in tumor tissue [4,5].
CHOOSING BETWEEN ET AND CHEMOTHERAPY
●Since 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, reserving chemotherapy for patients whose cancers appear to be either refractory to ET or have extensive symptomatic visceral involvement.
●For the minority of patients who have extensive visceral metastases with evidence of end-organ dysfunction, we treat with first-line chemotherapy for several cycles (three to six months) rather than ET. We take this approach in order to maximize the chances of an early, meaningful, and more rapid response than one might anticipate from ET alone or in combination with targeted agents. Other than in this rare circumstance, trials have not shown any benefit for using chemotherapy prior to ET [8]. (See "Treatment of endocrine therapy resistant/refractory hormone receptor-positive, HER2-negative advanced breast cancer".)
•End-organ dysfunction can include pulmonary symptoms, such as dyspnea; evidence of pulmonary lymphangitic disease; or elevated liver function tests. Presence of a visceral metastasis alone, in the absence of these findings, is not an indication to proceed with chemotherapy in lieu of a trial of ET or ET in combination with targeted agents.
•For patients with confirmed hormone receptor-positive disease who have initiated chemotherapy, if a satisfactory response is achieved after several cycles (three to six months) with reduction of the patients' symptoms, it is reasonable to discontinue chemotherapy and introduce some form of "maintenance" ET. For others, either continuing chemotherapy (if there is evidence of partial response or stabilization of disease), switching to another chemotherapy regimen, or shifting to palliative care only are appropriate options.
●For women who progress after two lines of ET (with or without a targeted agent), treatment should be based on their prior treatment response, tumor burden, and individual preferences. (See 'Later-line therapy' below.)
●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 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 4/6 inhibitor. (See 'Preferred first-line therapy' below.)
●Those who progress on or within 12 months of completing adjuvant ET are eligible for subsequent-line ET or ET in combination with a targeted agent. Patients who progress on first-line ET for metastatic disease are also eligible for second-line treatment. (See 'Subsequent-line options' below.)
PREFERRED FIRST-LINE THERAPY
AIs plus CDK 4/6 inhibitors — Women who progress at least 12 months after the end of adjuvant ET and patients who present with de novo metastatic breast cancer are offered first-line ET. Our preferred regimen for most such patients 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.)
Data regarding available combinations — 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 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.
Trials have largely evaluated AIs plus CDK 4/6 inhibitors in postmenopausal women receiving first-line treatment for metastatic disease (ie, they may have received adjuvant ET). As examples:
●Palbociclib – Palbociclib was approved by the FDA based upon a phase III study that included 666 postmenopausal patients with metastatic, estrogen receptor (ER)-positive, HER2-negative breast cancer who had not had prior treatment for advanced disease. The combination of palbociclib and letrozole demonstrated improved PFS (24.8 versus 14.5 months; HR 0.58, 95% CI 0.46-0.72) and objective response rate (ORR; 42 versus 35 percent) compared with letrozole alone [12]. In a post-hoc analysis excluding patients lost to follow-up, palbociclib plus letrozole did not result in a statistically significant improvement in overall survival relative to letrozole alone (52 versus 45 months, HR 0.87, 95% CI 0.71-1.1) [13].
Neutropenia was higher with the combination (79.5 versus 6.3 percent), though neutropenic fever was uncommon. Fatigue, nausea, and alopecia were also more common among patients taking the combination relative to an AI alone. OS data are not yet available pending longer follow-up.
●Ribociclib – Ribociclib was FDA approved in combination with letrozole, based upon a phase III study in which 668 postmenopausal women with hormone receptor-positive, HER2-negative recurrent or metastatic breast cancer were treated with front-line letrozole, with or without ribociclib. Those receiving ribociclib experienced an improved PFS (25.3 versus 16.0 months; HR for progression or death 0.56, 95% CI 0.45-0.70) at a median follow-up of 26 months [14]. The overall response rates were 43 and 29 percent, respectively. In results presented at longer follow-up (of 6.6 years), the addition of ribociclib improved OS (median, 63.9 versus 51.4 months; HR 0.76, 95 CI 0.63-0.93) [15].
Grade 3 or 4 adverse events were more common with the combination, notable for neutropenia (62 versus 1.2 percent), leukopenia (21 versus <1 percent), and increased liver function tests (10.2 versus 2.4 percent). Despite this higher frequency of adverse events, only 8.1 percent of patients required permanent discontinuation of both ribociclib and letrozole. Data and FDA approval for ribociclib in the pre/perimenopausal setting are discussed below. (See 'Incorporation of targeted agents' below.)
●Abemaciclib – Abemaciclib is FDA approved in combination with an AI for the initial treatment of postmenopausal women with hormone receptor-positive, HER2-negative breast cancer. In the MONARCH 3 trial, the combination of abemaciclib with an AI (letrozole or anastrozole) was compared with AI monotherapy for the front-line treatment of women with advanced hormone receptor-positive, HER2-negative breast cancer. PFS, the primary endpoint of the trial, was increased with the combination compared with an AI alone (median not reached versus 14.7 months, respectively; HR 0.54, 95% CI 0.41-0.72) [16]. In addition, the ORR was higher with the combination (59 versus 44 percent).
The most frequent grade 3 or higher adverse events for abemaciclib versus placebo included diarrhea (9.5 versus 1.2 percent), neutropenia (21 versus 1.2 percent), and fatigue (2 versus 0 percent), respectively.
Choosing between agents
●Choosing between CDK 4/6 inhibitors – In a network meta-analysis, in cross-trial comparisons, no statistically significant differences in PFS were found among the three CDK 4/6 inhibitors in combination with an AI [17]. Therefore, decisions are driven largely based on cost and side-effect profile, although we acknowledge that ribociclib has demonstrated OS benefits when combined with an AI, but these data are immature for abemaciclib. Palbociclib and ribociclib are associated with higher rates of neutropenia than abemaciclib, whereas abemaciclib more frequently causes diarrhea. 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 'Endocrine therapy for hormone receptor-positive disease'.)
●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 ORR (15 percent in both groups) and OS (31 and 33 months, respectively) [18]. 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 [19,20].
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-based treatment
●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 [21-23]. 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). Oral ER down-regulators are under investigation. (See 'Investigational agents' below.)
Fulvestrant monotherapy has never been compared with the combination of an AI and a CDK 4/6 inhibitor. However, in the phase III FALCON trial, fulvestrant 500 mg 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) [24]. 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 [25-28], 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 [29]. Median PFS was 27.9 months for fulvestrant-palbociclib versus 32.8 months for letrozole-palbociclib, a difference that was not statistically significant.
The 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 'Fulvestrant plus CDK 4/6 inhibitor' below.)
In an FDA pooled analysis, in two trials evaluating the combination of CDKs 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 inhibitors [30].
●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 anastrazole alone have been published, but with discrepant results [31-33]. Of note, in these trials, fulvestrant was administered at a dose of 250 mg monthly, which is lower than the currently approved prescribed dose. Examples of these trials are discussed below:
•In the SWOG S0226 trial, among 707 women (60 percent endocrine naïve) with metastatic hormone-positive breast cancer, those randomly assigned to fulvestrant plus anastrozole had superior outcomes relative to those assigned to single-agent anastrozole [31,34]. Most of the patients assigned to fulvestrant received 250 mg/month, although a fraction of patients was permitted to receive 500 mg/month after release of the data from the trial that demonstrated the superiority of the higher dose. At a median follow-up of seven years, compared with anastrozole alone, combined treatment resulted in an improvement in PFS (15 versus 14 months; HR 0.81, 95% CI 0.69-0.94) and OS (50 versus 42 months; HR 0.82, 95% CI 0.69-0.98) [34]. These improvements were despite the fact that approximately 45 percent of the patients in the anastrozole-alone group crossed over to receive fulvestrant. On subgroup analysis, the benefit of combination therapy appeared to be restricted to previously untreated patients.
Accrual to this trial was unique. Designed as a first-line ET trial in the metastatic setting, any patient who had prior AI was ineligible. Roughly halfway through accrual, the 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 FACT trial, survival outcomes were similar between the combination of fulvestrant and anastrozole and anastrozole alone [32]. Among 514 women with relapsed hormone receptor-positive disease (one-third of whom were ET naïve), those randomly assigned to anastrozole plus fulvestrant (500 mg loading dose, 250 mg on days 14 and 28, then 250 mg every 28 days) experienced equivalent median time to progression (11 versus 10 months; HR 0.99, 95% CI 0.81-1.20) and OS (38 months in both arms; HR 1.0, 95% CI 0.76-1.32) as those receiving anastrozole alone.
There were significantly more cases of endocrine-naïve patients in the SWOG S0226 trial than the FACT trial, whereas there were many patients with non-metastatic locally advanced cancers in the FACT trial (all patients in S0226 must have had distant metastases). These two factors, or other unknown ones, might explain the difference in trial outcomes. Further studies are needed to confirm the findings from the SWOG S0226 trial and to determine whether this combination is superior to anastrozole or fulvestrant alone.
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 may be appropriate. 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) [35]. 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 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. Testing of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation status is necessary for treatment with alpelisib plus fulvestrant. (See 'Biopsy of a metastatic lesion' above.)
We often offer patients two to three lines of ET (including targeted agents) before moving to chemotherapy. (See "Treatment of endocrine therapy resistant/refractory 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) [36,37]. In this case, these cancers may be resistant to estrogen depletion (eg, aromatase inhibitors), but they may better respond to ER-targeting therapies, perhaps requiring higher doses of selective ER modulators or selective ER down-regulators than needed for wild-type cancers. Newer drugs are being developed to target mutated ER more effectively. (See 'Investigational agents' below.)
Clinical trials are being conducted to test this hypothesis, but given limited available data and lack of validated assays, we do not routinely test for or use ESR1 mutational status to direct care for those not enrolled in a clinical trial.
SUBSEQUENT-LINE OPTIONS
Choosing between options — The optimal sequence upon progression on ET is not well defined, and multiple strategies are possible. Our approach is outlined below, and takes into account the patient's previous treatment history and the side effect profiles of treatment.
●For most women who progress on adjuvant ET or within 12 months of completion, or who progress on first-line treatment for metastatic disease, we move to subsequent-line ET options. However, for the minority of patients with evidence of end-organ damage from extensive visceral metastases, chemotherapy is appropriate. (See "Treatment of endocrine therapy resistant/refractory hormone receptor-positive, HER2-negative advanced breast cancer".)
●Fulvestrant-based treatment is often an appropriate option for patients who have experienced progression on a previous aromatase inhibitor (AI).
•If they have not previously been treated with a cyclin-dependent kinase (CDK) 4/6 inhibitor, fulvestrant plus a CDK 4/6 inhibitor is appropriate treatment. (See 'Fulvestrant plus CDK 4/6 inhibitor' below.)
•If they have been previously treated with a CDK 4/6 inhibitor, our approach is determined by tumor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) status:
-If they have a PIK3CA wild-type tumor, we suggest fulvestrant monotherapy or everolimus-based combinations. (See 'PIK3CA wild-type' below.)
-If they have a PIK3CA-mutant tumor, we suggest fulvestrant plus alpelisib. (See 'PIK3CA mutated' below.)
●For those with progression on previous tamoxifen, we typically suggest an AI plus a CDK 4/6 inhibitor (although AI without a CDK 4/6 inhibitor is an appropriate alternative in select patients). (See 'AIs plus CDK 4/6 inhibitors' above.)
●Premenopausal women should have concurrent treatment with ovarian suppression, or should have ovarian ablation when receiving ET. (See 'Ovarian suppression/ablation, in combination with ET' below.)
●Everolimus plus ET is an alternative, which we often use as a later-line option, given its toxicities, but may be substituted as an earlier line of treatment in select patients. (See 'Later-line therapy' below.)
In the absence of randomized trials, other sequences are also reasonable. For example, a patient with a PIK3CA-mutant tumor who has experienced progression on adjuvant AI may reasonably proceed with fulvestrant and alpelisib rather than fulvestrant and a CDK 4/6 inhibitor, depending on individual patient circumstances.
For those previously treated with an AI — For those who have previously been treated with an aromatase inhibitor (AI), we typically opt for another class of agent or a combination with a targeted agent. The strategy of switching from one AI to another as monotherapy upon progression has shown mixed results, and we do not typically employ this strategy [38,39].
Fulvestrant plus CDK 4/6 inhibitor — Fulvestrant plus a cyclin-dependent kinase (CDK) 4/6 inhibitor is often chosen as next-line therapy for patients with progression on AI monotherapy. (See 'Fulvestrant, with or without everolimus' below.)
In a US Food and Drug Administration (FDA) pooled analysis, among patients who received CDK inhibitors or placebo in combination with fulvestrant as second-line or later systemic ET (three trials, 1552 patients), 52 percent of patients had died at a median follow-up of 45.1 months [30]. The estimated hazard ratio [HR] for overall survival was 0.77 (95% CI 0·67-0·89), and the difference in estimated median overall survival was 7.0 months, favoring CDK inhibitors.
Both palbociclib and abemaciclib are approved for use in combination with fulvestrant in the subsequent-line setting. Ribociclib is approved for use with fulvestrant either in the first-line or subsequent-line setting. These are all appropriate in patients with previous AI treatment. Choosing between CDK 4/6 inhibitors is discussed above. (See 'Choosing between agents' above.)
●Fulvestrant plus palbociclib – The combination of palbociclib plus fulvestrant is a reasonable option for women who progress after front-line ET for metastatic disease or on or within 12 months of adjuvant ET.
This was supported by the PALOMA3 trial, which randomly assigned 521 women with advanced hormone receptor-positive and HER2-negative breast cancer to receive palbociclib and fulvestrant or placebo and fulvestrant [40,41]. 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 [40]. At a median follow-up of 8.9 months, compared with fulvestrant plus placebo, fulvestrant plus palbociclib resulted in [41]:
•An improvement in progression-free survival (PFS; median, 9.5 versus 4.6 months with fulvestrant plus placebo; HR 0.46, 95% CI 0.36-0.59). The study was stopped early because of the positive efficacy data observed at interim analysis. A subsequent updated analysis continues to show an improvement in PFS (median, 11.2 versus 4.6 months with fulvestrant plus placebo; HR 0.5, 95% CI 0.40-0.62; absolute difference, 6.6 months) [42].
•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 [43]. Patient-reported quality of life outcomes were higher among those receiving fulvestrant and palbociclib compared with fulvestrant alone [44].
•A delay to receive chemotherapy (median, 17.6 versus 8.8 months; HR 0.58, 95% CI 0.47-0.73) [45].
•A median overall survival of 34.9 versus 28.0 months; HR 0.81, 95% CI 0.64-1.03 [45], at a median follow-up of 45 months and 60 percent data maturity. At a follow-up of 73 months, overall survival was 35 versus 28 months respectively (HR 0.81, 95% CI 0.65-0.99) [46].
The planned OS analysis was performed at 60 percent maturity (310 of 521 patients enrolled had died at the time of data cutoff). The sample size had only approximately 46 percent power to detect an HR of 0.8 in OS improvement. Additionally, 16 percent of patients assigned to fulvestrant plus placebo received a CDK 4/6 inhibitor after progression. These issues limit the ability of the analysis to detect a statistically significant OS difference between the groups. Overall, the data from PALOMA3 support the combination of palbociclib plus fulvestrant for women with metastatic hormone receptor-positive breast cancer.
●Fulvestrant plus abemaciclib – Abemaciclib is approved by the FDA in combination with fulvestrant for women with progressive disease after prior ET [47]. Use of abemaciclib as monotherapy in patients with progressive disease after ET and chemotherapy is discussed below. (See 'Later-line therapy' below.)
Abemaciclib has been shown to combine effectively with fulvestrant. In the MONARCH 2 phase III trial, 669 patients who had progressed while receiving ET were randomly assigned to fulvestrant with or without the CDK 4/6 inhibitor abemaciclib [48]. Those receiving abemaciclib-fulvestrant experienced an improved PFS relative to those receiving fulvestrant alone (16.4 versus 9.3 months; HR 0.55, 95% CI 0.45-0.68). The objective response rate (ORR) was higher in those receiving abemaciclib-fulvestrant (48 versus 21 percent). In MONARCH 2, abemaciclib-fulvestrant also improved OS (47 versus 37 months; HR 0.68, 95% CI 0.56-0.82) [49]. Patients taking abemaciclib were able to defer chemotherapy for 50 versus 22 months for those on fulvestrant alone. Patients receiving abemaciclib had higher rates of diarrhea, neutropenia, nausea, and fatigue.
●Fulvestrant plus ribociclib – Results of MONALEESA-3 suggest efficacy of ribociclib in combination with fulvestrant [50], and this combination is FDA approved for initial- or subsequent-line ET for postmenopausal women with metastatic hormone receptor-positive, HER2-negative breast cancer [51]. In this phase III trial, 726 patients with advanced hormone receptor-positive breast cancer were included, approximately one-half receiving first-line ET for advanced disease, and one-half receiving second-line treatment having progressed on one prior line of ET. Overall, the addition of ribociclib to fulvestrant versus fulvestrant alone improved PFS (21 versus 13 months, respectively; HR 0.59, 95% CI 0.48-0.73). Benefits were consistent across patients with and without prior ET. In subsequent reporting, at a median follow-up of 56 months, median OS was longer for the ribociclib arm versus the placebo arm overall: 54 versus 42 months (HR 0.73, 95% CI 0.59-0.90) [52]. Subgroup analyses were consistent with overall population. In the first-line setting, the majority of patients (approximately 60 percent) in the ribociclib arm lived longer than median follow-up; median OS was 52 months in the placebo arm (HR 0.64, 95% CI 0.46-0.88). In the second-line setting, median OS was 40 months with ribociclib versus 34 months with placebo (HR 0.78, 95% CI 0.59-1.04).
In the network meta-analysis described above, no statistically significant differences in PFS were found among the three CDK 4/6 inhibitors in combination with fulvestrant: palbociclib plus fulvestrant versus abemaciclib plus fulvestrant (HR 0.83, 95% CI 0·47-1·46), palbociclib plus fulvestrant versus ribociclib plus fulvestrant (HR 0.77, 95% CI 0·44-1·35), and abemaciclib plus fulvestrant versus ribociclib plus fulvestrant (HR 0.93, 95% CI 0·54-1·61) [17]. However, this conclusion is based on cross-trial comparisons. Further discussion of this analysis is found above. (See 'Preferred first-line therapy' above.)
Preliminary results from one trial of everolimus and fulvestrant are discussed below, as are data in premenopausal women. (See 'Alternatives to fulvestrant' below and 'Incorporation of targeted agents' below.)
For those previously treated with an AI plus CDK 4/6 inhibitor
PIK3CA wild-type
Fulvestrant, with or without everolimus — Patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) wild-type tumors who have experienced progression on the combination of an aromatase inhibitor (AI) plus cyclin-dependent kinase (CDK) 4/6 inhibitor, we often suggest fulvestrant, with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus. A choice between these options is driven by patient preferences, considering the side-effect profile of everolimus, which includes mucositis, rash, fatigue, and diarrhea.
●Fulvestrant monotherapy – In the ET-refractory setting, fulvestrant monotherapy has shown equivalent activity as exemestane in postmenopausal women with hormone receptor-positive disease who had progressed on a nonsteroidal AI [27]. 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 [53].
●Fulvestrant plus everolimus – Results from the randomized phase II PrE0102 trial suggest the combination of everolimus and fulvestrant may also be an effective strategy for patients resistant to AIs, with a doubling in PFS compared with fulvestrant alone (10.3 versus 5.1 months; HR 0.61, 95% CI 0.4-0.92) [54]. Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53 versus 12 percent), fatigue (42 versus 22 percent), rash (38 versus 5 percent), anemia (31 versus 6 percent), and diarrhea (23 versus 8 percent), although grade 3 to 4 events were uncommon. Similar results were found in the MANTA trial, a randomized phase II trial in 324 patients with AI-resistant metastatic breast cancer comparing fulvestrant alone or in combination with either everolimus or with one of two different schedules of the dual TORC1-2 inhibitor vistusertib [55]. The addition of everolimus improved median PFS (4.6 versus 12.2 months; HR 0.64, 95% CI 0.43-0.94), whereas no improvement was observed with addition of vistusertib. The adverse event profile was consistent with the known profile of everolimus.
Alternatives to fulvestrant — For patients who prefer to avoid the intramuscular injections of fulvestrant, alternatives exist. Studies show that everolimus pairs effectively with an AI or tamoxifen as well, for the treatment of AI-resistant, advanced, estrogen receptor (ER)-positive breast cancer. The data regarding the combination of everolimus with fulvestrant are discussed above, while other combinations are discussed here.
●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 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) [39,56]. 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) [39,56]. 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'.)
●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 [57]. 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.
PIK3CA mutated
Fulvestrant plus alpelisib — For those with tumor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations whose cancers have progressed on or after treatment with an AI, we suggest the combination of the alpha isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and fulvestrant. Determination of PIK3CA status is discussed above. (See 'Biopsy of a metastatic lesion' above.)
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 [58].
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).
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 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]. Clinical trials are ongoing to evaluate the activity of PI3K inhibitors in delaying or overcoming resistance to CDK 4/6 inhibitors.
Earlier trials evaluating combinations of fulvestrant with either pan-isoform PI3K inhibitors (eg, buparlisib and pictilisib) or the beta isoform-sparing agent taselisib suggested limited improvements in PFS in patients with ET-resistant disease, but a narrow therapeutic window due to toxicities (eg, gastrointestinal side effects, transaminitis, and hyperglycemia [62-67]). Buparlisib was also associated with anxiety and depression [62-64].
●Management of toxicities of alpelisib – Alpelisib is associated with several important side effects, including stomatitis, diarrhea, rash, and hyperglycemia. Management of adverse events is described in the tables (table 1 and table 2 and table 3 and table 4 and table 5).
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 front line. There have been no differences in efficacy between the AIs in the second-line setting [18,68,69]. 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 [69]. 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 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 "Treatment of endocrine therapy resistant/refractory hormone receptor-positive, HER2-negative advanced breast cancer".)
Antibody drug-conjugates
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 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 [70,71]. Its use is discussed in hormone receptor-positive cancers is discussed elsewhere. (See "Treatment of endocrine therapy resistant/refractory 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 IHC 1+, or 2+, and in situ hybridization (ISH) negative, who have received at least 1 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 [70]. Further details and supporting data are found elsewhere. (See "Treatment of endocrine therapy resistant/refractory 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 cyclin-dependent kinase (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 OS, relative to those assigned to either abemaciclib 150 mg daily or abemaciclib 200 mg daily (24 months versus 21 and 17 months, respectively) [72]. 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) [73].
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 [74]. 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 [47]. 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 PFS of six months [75].
●Hormones – We choose other options before hormones for treatment of metastatic breast cancer, though they do show some activity and were used more frequently in the past [76-85]. 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 [86]:
●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 ET, we suggest concurrent ovarian suppression or ablation, in order to suppress estrogen levels. This is particularly important 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 aromatase inhibitor (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 [87]. 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 [88]. 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 [89,90].
Incorporation of targeted agents — While the majority of the trials that combined targeted agents have been limited to postmenopausal women or included premenopausal women on ovarian suppression as a small subset, MONALEESA-7 focused specifically on pre- or perimenopausal women with advanced, hormone receptor-positive, and HER2-negative breast cancer, and demonstrated that a CDK 4/6 inhibitor may be effectively combined with ovarian suppression/ablation and tamoxifen or an AI.
In MONALEESA-7, 672 pre- or perimenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer were randomly assigned to front-line ribociclib or placebo to be taken concurrently with goserelin, and either tamoxifen or a nonsteroidal AI. 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) [91], as was the OS rate at 3.5 years, in subsequent reporting (70 versus 46 percent; HR 0.71, 95% CI 0.54-0.95) [92]. 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) [93]. 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 [94].
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 patients'.)
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) [95]. 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, with or without a targeted agent, single-agent treatment with a SERM alone is an alternative for those who wish to avoid combined-modality treatment. In a 1991 review of phase II trials of tamoxifen in premenopausal women, the ORR was 45 percent among the 31 patients with confirmed ER-positive disease [96].
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'.)
Investigational agents — The combination of ET plus a molecular-targeted agent continues to be explored in clinical trials with the aim to overcome ET resistance in hormone receptor-positive breast cancer.
Examples include:
●Novel SERDs – Novel selective estrogen receptor (ER) down-regulators (SERDs) are appealing because they may be effective in targeting estrogen receptor 1 (ESR1) mutations and because the existent SERD, fulvestrant, is limited by its intramuscular administration in regards to how much can be delivered. Novel SERDs with the ability to degrade mutant ERs are being investigated. Examples include elacestrant (RAD1901) and amcenestrant (SAR439859). In the EMERALD trial, elacestrant was compared against standard of care (SOC) ET (investigator's choice of fulvestrant or an aromatase inhibitor) 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 cyclin-dependent kinase 4/6 inhibitor [97]. The majority of patients in the SOC group received fulvestrant. At 12 months, the elacestrant group had a better progression-free survival (PFS) than the SOC group (22 versus 9 percent; hazard ratio [HR] 0.70, 95% CI 0.55-0.88). Greater PFS improvements were observed in the subgroup with ESR1 mutations (HR, 0.55). 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. Further discussion of ESR1 mutations is found elsewhere. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators", section on 'ESR1 gene mutations' and "Mechanisms of action of selective estrogen receptor modulators and down-regulators", section on 'Fulvestrant, oral SERDs, and SERM/SERD hybrids'.)
●ET plus AR blockade – Androgen receptor (AR) expression is observed in majority of ER-positive breast cancers. Preclinical evidence indicated synergism between ER and AR targeting [62]. This strategy is being examined in a randomized phase II trial (NCT02007512).
The addition of bevacizumab to letrozole in hormone receptor-positive metastatic disease has been shown to improve progression-free survival in one trial (but not another), but with increased toxicity and no demonstrated improvement in overall survival in either trial [63,64]. 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).
Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 the availability of more effective systemic therapies, including endocrine therapy (ET) and targeted therapy, in the treatment of hormone-sensitive disease. (See 'Introduction' above.)
●General principles – Given that up to 15 percent of metastatic cancers may have discordant estrogen receptor (ER) measurement compared with the primary cancer, we biopsy a metastatic lesion in patients with new metastatic disease to confirm ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. (See 'General principles' above.)
Since ET (alone or in combination with targeted agents) is generally less toxic than chemotherapy, it is preferable for most patients with hormone receptor-positive disease to begin treatment with ET, with or without a targeted agent.
However, for patients with rapidly progressive or extensive visceral metastasis with end-organ dysfunction, we suggest chemotherapy rather than ET as their first-line treatment (Grade 2C). Patients who demonstrate a good clinical response to chemotherapy may become candidates for discontinuation of chemotherapy and initiation of ET. (See "Overview of the approach to metastatic breast cancer".)
●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 ET or ET in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor. (See 'Preferred first-line therapy' above.)
•Those who progress on or within 12 months of completing adjuvant ET are eligible for subsequent-line ET or ET in combination with a targeted agent. Patients who progress on first-line ET for metastatic disease are also eligible for second-line treatment. (See 'Subsequent-line options' above.)
●Initial treatment – Patients without rapidly progressive or extensive visceral metastases are appropriate candidates for ET. Our approach to first-line therapy in such patients is as follows:
•For such patients, we recommend a CDK 4/6 inhibitor in combination with an aromatase inhibitor (AI) rather than an AI alone (Grade 1B). However, other acceptable options include single-agent fulvestrant or anastrozole, or fulvestrant in combination with an AI or ribociclib.
•For premenopausal women treated with ET, we suggest concurrent ovarian suppression or ablation (Grade 2C). This is particularly important for premenopausal patients receiving AIs, given the potential for ovarian stimulation with these agents.
●Subsequent-line treatment – The optimal sequence upon progression on ET is not well defined, and multiple strategies are possible. Our approach is outlined below, and takes into account the patient's previous treatment history and tolerance of treatment.
•For patients who have previously experienced progression on an AI without a CDK 4/6 inhibitor, we recommend fulvestrant plus a CDK 4/6 inhibitor rather than fulvestrant alone (Grade 1B).
•For patients who have previously experienced progression on an AI and CDK 4/6 inhibitor, our approach takes into account tumor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) status:
-PIK3CA-mutant cancers– For those with PIK3CA-mutant cancers progressive on the combination of AIs and CDK 4/6 inhibitors, we suggest the combination of fulvestrant with the alpha isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor alpelisib rather than other options (Grade 2C). (See 'PIK3CA mutated' above.)
-PIK3CA-wildtype cancers – For those with PIK3CA-mutant cancers progressive on the combination of AIs and CDK 4/6 inhibitors, options include fulvestrant monotherapy or everolimus-based combinations, with a choice between them driven by side-effect profiles. (See 'Alternatives to fulvestrant' 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.
