Version July 2025
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 with human epidermal growth factor receptor 2 (HER2) gene amplification or overexpression [with or without ER expression], and 3) those that do not have either of these, nor the progesterone receptor (PR; triple-negative).
Although metastatic breast cancer is unlikely to be cured, there have been meaningful improvements in survival due to more effective systemic therapies, including endocrine therapy (ET) in the treatment of hormone-sensitive disease.
ET alone or in combination with targeted for metastatic hormone receptor-positive, HER2-negative breast cancer is presented here. The treatment of HER2-positive disease is discussed elsewhere, as is chemotherapy for ET-resistant, metastatic hormone receptor-positive breast cancer. Other topics including the approach to breast cancer, the role of adjunctive therapy, such as bone-modifying agents, and poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA-associated breast cancer, are also covered separately.
●(See "Overview of the approach to metastatic breast cancer" and "Overview of the approach to metastatic breast cancer", section on 'BRCA 1/2 and PALB2 associated tumors'.)
●(See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer" and "Systemic treatment for HER2-positive metastatic breast cancer".)
●(See "Brain metastases in breast cancer" and "Radiation therapy for the management of painful bone metastases".)
GENERAL PRINCIPLES
Goals of therapy — Patients with estrogen receptor (ER)-positive metastatic breast cancer often respond to endocrine therapy (ET) alone or in combination with targeted agents, which can reduce tumor burden and symptoms with generally fewer side effects and toxicities than chemotherapy. Furthermore, modern ETs appear to prolong progression and possibly survival compared with older ETs. However, few if any patients with metastatic breast cancer will be cured, and the goal of therapy is, principally, palliation. We choose the therapy that is most likely to stabilize or reduce the burden of disease with the fewest side effects and maintain that therapy until either unacceptable toxicities are evident or disease progression occurs.
Types of ET and targeted agents — There are several types of ETs, as discussed:
●Strategies to deplete estrogen – In premenopausal patients, these strategies include oophorectomy or use of luteinizing hormone-releasing hormone agonists and antagonists. In postmenopausal patients, estrogen is derived from adrenal precursors, testosterone, and androstenedione that are converted to estradiol and estrone by aromatase activity in peripheral cells. There are three aromatase inhibitors (anastrozole and letrozole are azole compounds, while exemestane, is a 17-hydroxy steroid). Randomized clinical trials in both the adjuvant and metastatic setting have demonstrated that the clinical activity, side effects, and toxicity of these three aromatase inhibitors are virtually identical, and the choice of any one of them is appropriate. (See 'Alternative frontline 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 and elacestrant down-regulate ER. (See 'No alterations in PIK3CA, AKT1, or PTEN (PI3K pathway)' below.)
●Addition of targeted agents – The 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; and multiple agents that target the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway [1]. (See 'AIs plus CDK 4/6 inhibitors' below and 'Alterations in PI3K pathway' below.)
Biopsy of a metastatic lesion and evaluation for targetable mutations — For patients who develop metastatic disease, we biopsy a metastatic lesion upon presentation and often at disease progression.
●On the biopsy, we confirm ER, progesterone receptor (PR), and HER2 status, irrespective of whether the patient previously had early breast cancer. This is because up to 15 percent of metastatic cancers may have discordant ER measurement compared with the primary cancer [2]. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy", section on 'Interpretation of ER and PR tests'.)
•Approximately 20 percent of hormone receptor-positive breast cancers are also HER2-positive. These patients should receive HER2-directed therapy as part of their treatment regimen. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)
●For those in whom hormone receptor positivity is confirmed, we assess tumor tissue and/or blood for genomic alterations, including PIK3CA/ AKT1/PTEN and ESR1 status. We recommend the use of multigene panel–based assays [3]. Mutations in PIK3CA or ESR1 detected in either tumor tissue (preferably biopsy of a metastatic lesion) or blood are acceptable. Testing both tumor tissue and blood may increase the chance of detection [4]. Since ESR1 mutations are often acquired after an ET-based approach and the tumor evolves under treatment pressure, we recommend repeated or longitudinal genomic testing at disease progression [4,5].
CONSIDERATIONS FOR THOSE WITH EXTENSIVE VISCERAL METASTASES —
Our approach to endocrine versus chemotherapy in hormone receptor-positive, HER2-negative metastatic cancers is as follows:
●Since endocrine therapy (ET; alone or in combination with targeted agents) is generally less toxic than chemotherapy, with comparable outcomes [6-8], it is preferable for most patients with hormone receptor-positive disease to begin treatment with ET.
●For the minority of patients who have extensive visceral metastases, chemotherapy may be considered an appropriate alternative to ET plus targeted agents; however, there are no data suggesting a survival benefit to this approach.
•In one randomized phase II trial (RIGHT Choice study), in 222 pre- or perimenopausal patients with aggressive, hormone receptor-positive, HER2-negative breast cancer (half of whom had investigator-assessed visceral crisis), initial ET plus ribociclib improved progression-free survival relative to combination chemotherapy (24.0 versus 12.3 months; hazard ratio [HR] 0.54, 95% CI 0.36-0.79), with similar response rates (65 versus 60 percent) and fewer grade 3 to 4 adverse events (0.9 versus 7.0 percent) [9]. Time to tumor response was 4.9 months in the ET/ribociclib arm versus 3.2 months with chemotherapy, but this difference was not statistically significant. Median overall survival (OS) was not reached in either group; 30-month OS rates were 67 and 65 percent in the ET/ribociclib versus chemotherapy arms, respectively (HR 0.92, 95% CI 0.56-1.52) [10]. Although these results support frontline ET plus a cyclin-dependent kinase (CDK) 4/6 inhibitor for patients with aggressive hormone receptor-positive, HER2-negative disease, we note that the majority of patients in this trial had de novo metastatic disease. Many patients treated in the United States have received prior treatments in the neoadjuvant/adjuvant setting. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Special considerations for those with rapidly progressive disease'.)
●There are no data that combining ET (with or without targeted agents) with chemotherapy improves OS, and therefore we do not use this strategy [11].
PATIENTS WITH >12 MONTHS SINCE ADJUVANT ET OR NO PRIOR ET —
For patients who progress >12 months from the end of adjuvant endocrine therapy (ET) and patients who present with de novo metastatic breast cancer we offer first-line ET in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor, but ET alone is an acceptable alternative, as discussed below.
Initial endocrine therapy
AIs plus CDK 4/6 inhibitors — Our preferred initial regimen is a CDK 4/6 inhibitor with an aromatase inhibitor (AI). Premenopausal females must have ovarian suppression/ablation when on AIs. (See 'Ovarian suppression/ablation, in combination with ET' below.)
Rationale for use of a CDK 4/6 inhibitor — Among postmenopausal females 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 [12], 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 [13]. The CDK 4/6 inhibitors have not been directly compared in clinical trials. Available trials are summarized in the table (table 1). (See 'Alternative frontline options' below.)
Choosing between agents — Our approach to the choice of agents is as follows:
●Choosing between CDK 4/6 inhibitors – There are several factors that need to be considered regarding the choice of CDK 4/6 inhibitors. We consider any of the three CDK 4/6 inhibitors to be acceptable options, with a choice between them driven by efficacy and toxicity profile of the agents. Both ribociclib and abemaciclib have been associated with OS gains when used as initial therapy, which has not been observed with palbociclib. For those with advanced visceral disease, some evidence indicates that ribociclib or abemaciclib is associated with better outcomes compared with cytotoxic chemotherapy. (See 'Considerations for those with extensive visceral metastases' above.)
Palbociclib and ribociclib are associated with higher rates of neutropenia than abemaciclib, whereas abemaciclib more frequently causes diarrhea (table 1). Ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be less preferred for some patients (eg, those on QTc-prolonging agents). Palbociclib may be preferred over other agents in elderly patients where there may be concerns regarding treatment tolerance.
Of the three agents, abemaciclib has been evaluated in patients with brain metastases and may be preferred in this setting. However, this is a very rare occurrence in first- or second-line treatment of hormone receptor-positive breast cancer. Data are discussed elsewhere. (See "Brain metastases in breast cancer", section on 'Other options in specific subsets'.)
Overall survival data have emerged from the randomized trials of CDK 4/6 inhibitors in combination with an AI (table 1):
•Ribociclib has demonstrated OS benefit when added to an AI or AI plus ovarian function suppression in the MONALEESA-2 (64 versus 51 months; HR 0.76, 95% CI 0.63-0.93) [14] and MONALEESA-7 trials (58 versus 48 months; HR 0.76, 95% CI 0.61-0.96) [15].
•Palbociclib did not demonstrate OS benefit in the PALOMA-2 trial (54 versus 51 months; HR 0.96, 95% CI 0.78-1.2) [16]; however, there were significant missing follow-up data that were imbalanced between the arms. Combined analysis of PALOMA-1 and PALOMA-2 did show OS benefit in the group that had a disease-free interval over 12 months [17].
•In MONARCH 3, there was a trend toward longer OS with the addition of abemaciclib to an AI (median 67 versus 54 months; HR 0.80, 95% CI 0.64-1.02), which did not reach statistical significance but the absolute difference of 13 months is considered clinically significant [18].
In preclinical studies, ribociclib and abemaciclib are four- and five-times more selective toward CDK 4 over CDK 6 and abemaciclib has a broader CDK target including cyclin B-CDK1, cyclin A/E-CDK2, and cyclin T-CDK9 [19], suggesting potential differences among the three different CDK 4/6 inhibitors.
Novel CDK 4/6 inhibitors (eg, dalpiciclib) are under investigation [20], with promising results.
●Choosing between AIs – Although the AIs have not been compared when combined with a common CDK 4/6 inhibitor, randomized trials of single-agent AIs demonstrate that no one AI is better than the others. In one trial of 128 females 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) [21]. 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 [22,23].
Alternative frontline options — Acceptable alternatives to AIs plus CDK 4/6 inhibitors are discussed below. Ovarian suppression or ablation is added for premenopausal females. (See 'Ovarian suppression/ablation, in combination with ET' below.)
●Fulvestrant monotherapy – Fulvestrant is an alternative option, but is less preferable than frontline 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 [24-26]. Fulvestrant is administered as an intramuscular injection (500 mg loading dose on days 1, 15, and 29 of the first month, then maintenance dosing monthly at day 28, ±3 days).
Fulvestrant monotherapy has never been compared with the combination of an AI and a CDK 4/6 inhibitor. However, in the phase III FALCON trial, fulvestrant 500 mg improved PFS over anastrozole at a median follow-up of 25 months (16.6 versus 13.8 months; HR for progression or death 0.80, 95% CI 0.637-0.999) [27]. 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 [28-31], 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 [32]. Median PFS was 27.9 months for fulvestrant-palbociclib versus 32.8 months for letrozole-palbociclib, a difference that was not statistically significant.
In an FDA pooled analysis, in two trials evaluating the combination of CDK 4/6 inhibitors or placebo in combination with fulvestrant (396 patients), the estimated HR for overall survival was 0.74 (95% CI 0.52-1.07) favoring addition of CDK 4/6 inhibitors [33].
●Fulvestrant plus anastrozole – The combination of fulvestrant plus anastrozole is an acceptable alternative to the AI/CDK 4/6 inhibitor combination for the patient who presents with de novo metastatic breast cancer (and is therefore ET naïve).
Several trials investigating the combination of fulvestrant plus anastrozole versus anastrozole alone have been published, but with discrepant results [34-37]. PFS and OS benefits, when present, appeared to be greatest in those with de novo metastatic disease [37]. Of note, in these trials, fulvestrant was administered at a dose of 250 mg monthly, which is lower than the currently approved prescribed dose. Examples of these trials are discussed below.
●AI monotherapy – For patients who have not received an AI in the adjuvant setting and are unlikely to tolerate a CDK 4/6 inhibitor, AI monotherapy is an appropriate alternative. Although fulvestrant as a single agent has shown better activity than aromatase inhibition, some patients may prefer oral therapy to intramuscular injection.
Although we typically incorporate CDK 4/6 inhibitors in first-line treatment paradigms, there are data to support initiation of an AI alone, with deferral of CDK 4/6 inhibitors to the second-line setting. Although this is not our preferred treatment strategy, it is a reasonable option to consider for those with endocrine-sensitive disease (ie, metastatic recurrence occurred >12 months from adjuvant ET) who prefer to avoid initial treatment with a CDK 4/6 inhibitor (eg, due to concerns regarding toxicity, financial considerations, or need for radiation to symptomatic sites of disease).
The SONIA trial was developed by the Dutch government as a cost containment strategy and randomly assigned 1050 females to either first-line treatment with a nonsteroidal aromatase inhibitor (NSAI) plus a CDK 4/6 inhibitor, followed by single-agent fulvestrant upon disease progression; or to first-line treatment with an NSAI followed thereafter by fulvestrant plus a CDK 4/6 inhibitor upon progression [38]. At a median follow-up of 37 months, median OS was 46 months in the first-line CDK 4/6 inhibitor group and 54 months in the second-line CDK 4/6 inhibitor group (HR 0.98, 95% CI 0.80-1.20). The interval between randomization and progression on second-line therapy was 31 versus 27 months, respectively (HR 0.87, 95% CI 0.74-1.03). The first-line group remained on CDK 4/6 inhibitor for 25 months, versus 8.1 months for the second-line group, which was associated with an increase in drug expenditure of 185,000 dollars per patient. Given the longer time on CDK 4/6 inhibition, there were more grade ≥3 toxicities with first-line CDK 4/6 inhibition. In the CDK 4/6 inhibition-first group 83 percent experienced at least one grade ≥3 event versus 64 percent in the CDK 4/6 inhibition-second group.
A caveat to the interpretation of this study is that the first-line CDK 4/6 inhibitor group received single-agent fulvestrant in the second-line, which is no longer what most patients receive given the emergence of other targeted agents (eg, alpelisib, elacestrant). Nevertheless, deferring the CDK 4/6 inhibitor to the second-line setting is an appropriate strategy in select patients.
AIs have shown a survival benefit over tamoxifen in the first-line treatment of metastatic breast cancer. In a 2006 meta-analysis of 23 randomized trials (n = 8504 postmenopausal patients) [39], 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 initial therapy — 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 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. Patients with higher ER levels, longer duration of response (eg, more than six months), and more indolent disease often do well with another line of ET, if another option is available. Typically, we offer patients two to three lines of ET (including targeted agents) before moving to chemotherapy. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)
Many possible reasons exist for resistance to ET. For example, studies have suggested that up to 30 percent of metastatic ER-positive breast cancers may have activating mutations in the estrogen-binding domain of the gene that encodes for ER (ESR1) [40,41]. In this case, these cancers may be resistant to estrogen depletion (eg, AIs), but they may better respond to ER-targeting therapies such as fulvestrant or elacestrant. Elacestrant is superior to fulvestrant for the treatment of ESR1-mutated breast cancer. (See 'ESR1 mutation-positive' below.)
Choice of subsequent-line therapy, according to genetic alterations — Our approach to subsequent-line therapy considers the presence of actionable driver mutations. A tissue biopsy or liquid biopsy for circulating free tumor DNA is appropriate upon progression to assess for actionable genetic alterations. (See 'Biopsy of a metastatic lesion and evaluation for targetable mutations' above.)
No alterations in PIK3CA, AKT1, or PTEN (PI3K pathway)
ESR1 wild-type — For patients with PIK3CA/AKT1/PTEN and ESR1 wild-type tumors who have experienced progression on an AI plus CDK 4/6 inhibitor, we suggest the selective estrogen receptor degrader (SERD) fulvestrant, with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus or abemaciclib. A choice between these options is driven by patient preferences and considering the side effect profiles. Side effects of CDK 4/6 inhibitors are discussed above. (See 'Choosing between agents' above.)
Side effects of everolimus include mucositis, rash, fatigue, diarrhea, and pneumonitis. For patients who develop shortness of breath or increase in cough, everolimus should be held and patients assessed for pneumonitis. A brief course of steroids may be necessary. Additional information on the toxicity of everolimus is discussed separately. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Rapamycin and analogs' and "Oral toxicity associated with systemic anticancer therapy", section on 'Dexamethasone mouthwash'.)
●Fulvestrant – In the ET-refractory setting, fulvestrant monotherapy has shown equivalent activity as exemestane in postmenopausal females with hormone receptor-positive disease who had progressed on a nonsteroidal AI [30]. 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 [42].
●Fulvestrant plus everolimus – This combination has been studied in randomized trials in patients with progression after an AI, but only in a single arm phase II trial after an AI/CDK 4/6 inhibitor combination.
Results from the randomized phase II PrE0102 trial suggest the combination of everolimus and fulvestrant may also be an effective strategy for patients resistant to AIs, with a doubling in PFS compared with fulvestrant alone (10.3 versus 5.1 months; HR 0.61, 95% CI 0.4-0.92) [43]. Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53 versus 12 percent), fatigue (42 versus 22 percent), rash (38 versus 5 percent), anemia (31 versus 6 percent), and diarrhea (23 versus 8 percent), although grade 3 to 4 events were uncommon. Similar results were found in the MANTA trial (median PFS 12.2 versus 4.6 months, with and without everolimus) [44].
Separately, in a phase II single-arm study in 57 patients with progression on treatment including a CDK 4/6 inhibitor (the majority of whom had visceral metastases), the median PFS was 6.8 months and OS was 38 months [45].
●Fulvestrant plus a CDK 4/6 inhibitor – Data are mixed regarding a CDK 4/6 inhibitor plus fulvestrant after progression on an AI and CDK 4/6 inhibitor, but one trial has shown benefit for fulvestrant and abemaciclib over fulvestrant alone (PFS rate at six months of 50 versus 37 percent; these benefits were supported by a blinded independent review of PFS (HR 0.55, 95% CI, 0.39-0.77), and were independent of ESR1 or PIK3CA status [46]. A separate trial also found a PFS benefit when patients changed ET and received ribociclib following progression on ET and a CDK 4/6 inhibitor (median PFS 5.3 versus 2.8 months; HR 0.57, 95% CI 0.39-0.85) [47]. Most patients (85 percent) had previously received palbociclib as the initial CDK 4/6 inhibitor. However, other trials have not found benefit with continuation of a CDK 4/6 inhibitor with second-line ET compared with second-line ET alone [48,49]. Given the sum of data, we consider a change in ET and CDK 4/6 inhibitor to be an appropriate option, with consideration of the potential toxicities.
A number of alternative strategies exist which may be useful in certain circumstances. These are discussed below:
●Fulvestrant plus neratinib and trastuzumab, for cancers with HER2-activating mutations – In rare instances, breast cancers have HER2 mutations (not gene amplifications) on genomic sequencing. For patients with hormone receptor-positive, HER2-negative metastatic breast cancer with activating HER2 mutation(s) and prior CDK 4/6 inhibitor therapy, fulvestrant plus trastuzumab and neratinib is an acceptable option, and has been associated with an ORR of 39 percent and median PFS of 8.3 months in this population [50].
●Non-fulvestrant-based therapy – For patients who prefer to avoid the intramuscular injections of fulvestrant, alternatives exist. Studies show that everolimus pairs effectively with an AI or tamoxifen, for the treatment of AI-resistant, advanced, ER-positive breast cancer. Activating mutations in the alpha isoform of the catalytic subunit of PIK3CA and PIK3CA/AKT/mTOR pathway activation status are not predictive of benefit from everolimus.
•Everolimus plus AI – For patients who received a nonsteroidal AI (anastrozole, letrozole), another alternative is exemestane plus everolimus. The benefit of everolimus plus exemestane over exemestane alone was shown in the BOLERO-2 trial, which enrolled 724 females 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) [51,52]. 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) [51,52].
•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 females who had progressed on an AI were randomly assigned treatment with tamoxifen with or without everolimus [53]. 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.
ESR1 mutation-positive — Elacestrant (aka RAD1901) is a SERD that has regulatory approval in the United States for use in postmenopausal females and males with ESR1-mutated advanced hormone receptor-positive, HER2-negative breast cancer that has progressed on at least one line of prior ET [54]. Given PFS benefits over fulvestrant, as well as the ease of oral administration, we suggest its use in this setting, particularly in patients who experienced prolonged PFS on the prior lines of ET and CDK 4/6 inhibitors.
●Elacestrant – In the EMERALD trial, elacestrant was compared against standard of care (SOC) ET (investigator's choice of fulvestrant or an AI) among 477 patients who had received one or two prior lines of ET and up to one line of chemotherapy in the metastatic setting, and who had progressed on prior treatment with a CDK 4/6 inhibitor [55]. The majority of patients in the SOC group received fulvestrant. At 12 months, the elacestrant group had a better PFS rate than the SOC group and those specifically receiving fulvestrant (22 versus 9 and 10 percent, respectively). Greater PFS improvements were observed in the subgroup with ESR1 mutations with elacestrant versus SOC and fulvestrant (12-month PFS rates of 27 versus 8.2 and 8.4 percent, respectively). Benefit of elacestrant is more marked in patients who experienced longer PFS on the prior ET plus CDK 4/6 inhibitor (likely more endocrine-sensitive disease) [56]. Among patients who were on a prior CDK 4/6 inhibitor for at least 12 months, the median PFS was 8.6 months on elacestrant versus 1.9 months on SOC ET (HR 0.41). Overall survival results were immature, but there was a trend favoring elacestrant.
The most frequent toxicity with elacestrant was nausea, occurring in 35 percent. Grade ≥3 adverse events were observed among 7 percent of patients in the elacestrant arm and 3 percent in the SOC arm.
●Investigational strategies – The PADA1 trial found that, among patients who develop a blood ESR1 mutation on an AI plus a CDK 4/6 inhibitor, a switch from the AI to fulvestrant (with the same CDK 4/6 inhibitor) before clinical progression improved PFS over continuation of the AI/CDK 4/6 inhibitor [57]; but effect on OS was uncertain. We await further prospective data prior to using this strategy in routine clinical practice.
Lasofoxifene is an orally administered selective ER modulator under investigation in ESR1-mutated cancers and has shown promise [58,59]. Other investigational strategies are also being evaluated, including novel selective estrogen receptor modulators and degraders (eg, imlunestrant [60]), proteolysis targeting chimera, and complete estrogen receptor antagonists.
Alterations in PI3K pathway — 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 [61].
Fulvestrant plus capivasertib — For patients with hormone receptor-positive, HER2-negative advanced breast cancer with one or more alterations in PIK3CA/AKT1/PTEN who have experienced progression on at least one endocrine-based regimen in the metastatic setting (or recurrence on or within 12 months of completing adjuvant therapy), the AKT inhibitor capivasertib has regulatory approval by the FDA in combination with fulvestrant [62]. As such, patients with tumors harboring activating PIK3CA mutations are eligible for fulvestrant with either capivasertib or alpelisib. There have been no head-to-head trials of these strategies; however, we have a preference for capivasertib, based on seemingly better tolerability, including lower rates of hyperglycemia. If there is a coexisting ESR1 mutation and a PI3K pathway alteration, either fulvestrant/capivasertib or elacestrant are acceptable approaches. (See 'ESR1 mutation-positive' above.)
A randomized phase III trial (CAPItello-291) has shown PFS benefits with the addition of capivasertib to fulvestrant therapy among patients with progression on a previous AI, with or without a CDK 4/6 inhibitor [63,64]. Among 708 patients, the median PFS was 7.2 months in the capivasertib–fulvestrant group versus 3.6 months in the placebo-fulvestrant group (HR 0.60, 95% CI 0.51-0.71). Among patients with PI3K pathway-altered (PIK3CA, AKT1, or PTEN) tumors, benefits were comparable (PFS 7.3 versus 3.1 months; HR 0.50, 95% CI 0.38-0.65). The estimated OS at 18 months was 74 percent with capivasertib-fulvestrant and 65 percent with placebo-fulvestrant in the overall population (HR 0.74, 95% CI 0.56-0.98); and 73 versus 63 percent, respectively, in the AKT pathway-altered population (HR 0.69, 95% CI 0.45-1.05). While the outcomes in patients previously treated with a CDK 4/6 inhibitor also favored capivasertib, the absolute gains in PFS were smaller than in the overall group.
Although benefits were observed in the overall population, the previous randomized phase II FAKTION study demonstrated that benefit was limited to tumors with AKT1/PTEN/PIK3CA mutations. In this study, among the 76 patients with pathway-altered tumors, the addition of capivasertib to fulvestrant improved median PFS (12.8 months compared with 4.6 months with placebo; HR 0.44, 95% CI 0.26-0.72) [65]. OS was 39 versus 20 months, respectively (adjusted HR 0.46, 95% CI 0.27-0.79). PFS and OS benefits were not observed among the 64 patients lacking pathway alterations. Regulatory approval has only been granted in the United States to patients whose tumors harbor alterations in PIK3CA, AKT1, or PTEN.
The most frequent grade ≥3 adverse events in the capivasertib-fulvestrant group were rash (12 percent) and diarrhea (9.3 percent). Grade ≥3 hyperglycemia occurred in 2.3 percent. Adverse events leading to discontinuation were reported in 13 percent of the patients receiving capivasertib and in 2.3 percent of those receiving placebo.
The improvement in OS is encouraging; other targeted agents of the AKT pathway including alpelisib and everolimus have not yet shown such benefits. Longer term data are needed to confirm a survival benefit.
Alternatives
For those with tumor PIK3CA mutations whose cancers have progressed on or after treatment with an AI, the combination of the alpha isoform-specific PI3K inhibitor alpelisib and fulvestrant is an acceptable alternative to fulvestrant and capivasertib, but less preferred due to higher toxicities, particularly hyperglycemia.
In a phase III trial of 572 males and postmenopausal females 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) [66]. Median OS was 39 months for alpelisib-fulvestrant and 31 months for placebo-fulvestrant (HR 0.86, 95% CI 0.64-1.15) [67]. In the cohort without tumor PIK3CA mutations, the median PFS was 7.4 months in the alpelisib-fulvestrant group and 5.6 months in the fulvestrant-only group (HR 0.85, 95% CI 0.58-1.25). In the overall population, the most frequent adverse grade 3 or 4 events in the alpelisib-fulvestrant versus fulvestrant-only group, respectively, included hyperglycemia (37 and 0.7 percent), rash (10 and 0.3 percent), and diarrhea (7 and 0.3 percent). Permanent discontinuation of alpelisib or placebo due to adverse events occurred in 71 patients (25 percent) receiving alpelisib-fulvestrant and in 12 (4.2 percent) receiving placebo-fulvestrant.
However, this trial included a limited number of patients with prior therapy with CDK 4/6 inhibitors. Results from a single-arm phase II study in 127 patients with tumor PIK3CA mutations and prior AI/CDK 4/6 inhibitor treatment suggest activity of fulvestrant and alpelisib in this population, with approximately 50 percent of patients alive and not progressing after six months on treatment [68].
Alpelisib is associated with several important side effects that led to a 25 percent rate of permanent treatment discontinuation in the SOLAR1 trial, including stomatitis, diarrhea, rash, and hyperglycemia. Strategies for prevention and management of adverse events is described in the tables (table 2 and table 3 and table 4 and table 5 and table 6). Our approach is to treat hyperglycemia with metformin as it arises on alpelisib; however, an acceptable alternative is to administer prophylactic metformin, particularly for those at high risk of hyperglycemia [69]. In one nonrandomized phase II trial in 68 patients with normal baseline fasting glucose or prediabetic HbA1c level, prophylactic metformin beginning with initiation of alpelisib was associate with a low rate of grade 3 to 4 hyperglycemia by cycle 2 of alpelisib/fulvestrant therapy (5.9 percent), which compares favorably with that observed in the SOLAR1 trial (37 percent) [70].
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 [71-76]). Buparlisib was also associated with anxiety and depression [71-73].
PATIENTS WITH PROGRESSION ON OR WITHIN 12 MONTHS OF ADJUVANT ET —
Our approach to patients who progress on or within 12 months of completing adjuvant endocrine therapy (ET) considers the prior adjuvant endocrine agent, presence of genetic alterations, and the time since treatment.
For those with progression on or within a year of adjuvant AI
No alterations in the PI3K pathway — For cancers that are PIK3CA wild-type with progression on or within a year of an adjuvant aromatase inhibitor (AI), we suggest fulvestrant plus a cyclin-dependent kinase (CDK) 4/6 inhibitor (table 7). However, if an ESR1 mutation is present, elacestrant is a reasonable alternative, particularly if the patient prefers to avoid intramuscular injections. The strategies of fulvestrant/CDK 4/6 inhibitor versus elacestrant have not been compared. (See 'ESR1 mutation-positive' above.)
For patients who will receive a fulvestrant-based strategy, considerations are as follows:
●Rationale for incorporating CDK 4/6 inhibition – In a US Food and Drug Administration pooled analysis including three trials, among patients who were assigned to fulvestrant/CDK 4/6 inhibitors or fulvestrant/placebo as second-line or later-line ET, the CDK 4/6 inhibitor group experienced an improvement in overall survival (OS; hazard ratio [HR] 0.77, 95% CI 0·67-0·89) [33]. The difference in estimated median OS was seven months, favoring CDK inhibitors.
●Choosing between CDK 4/6 inhibitors – Both palbociclib and abemaciclib are approved for use in combination with fulvestrant in the subsequent-line setting in the United States. Ribociclib is approved for use with fulvestrant either in the first-line or subsequent-line setting. These are all appropriate combinations in patients with previous AI treatment.
In a separate network meta-analysis, no statistically significant differences in progression-free survival (PFS) were found among the three CDK 4/6 inhibitors in combination with fulvestrant: palbociclib versus abemaciclib (HR 0.83), palbociclib versus ribociclib (HR 0.77, 95% CI 0.44-1.35), and abemaciclib versus ribociclib (HR 0.93) [77]. However, this conclusion is based on cross-trial comparisons. Individual trials are included in the table (table 7).
Ribociclib and abemaciclib have both shown to improve OS when combined with fulvestrant when compared with fulvestrant alone in patients who had prior ET (MONALEESA-3 and MONARCH 2) [78,79]; but the improvement in OS with the addition of palbociclib to fulvestrant did not reach statistical significance [80]. Further discussion on the toxicities associated with each CDK 4/6 inhibitor is found above. (See 'Choosing between agents' above.)
●Strategies to avoid – The strategy of switching from one AI to another AI as monotherapy upon progression has shown mixed results, and we do not typically employ this strategy [51,81].
Alterations in the PI3K pathway — For patients with PIK3CA-mutated, hormone receptor-positive, locally advanced or metastatic HER2-negative breast cancer with progression on or within a year of an AI, we consider either fulvestrant plus a CDK 4/6 inhibitor, or the combination of the novel alpha isoform-specific PI3K inhibitor and degrader inavolisib with palbociclib and fulvestrant [82], or fulvestrant and capivasertib to be appropriate options [62,83]. Some contributors have a preference for inavolisib/fulvestrant/palbociclib because of an impressive PFS benefit over fulvestrant/palbociclib, while others feel that any of these options is appropriate, given that we do not have data addressing whether triplet therapy is preferable to sequential use of ET with a CDK 4/6 inhibitor and then a PI3K pathway inhibitor.
Fulvestrant and capivasertib may also be used in patients with either AKT1 or PTEN genetic mutations. Both fulvestrant plus a CDK 4/6 inhibitor and fulvestrant plus capivasertib are discussed above. (See 'No alterations in the PI3K pathway' above and 'Fulvestrant plus capivasertib' above.)
In a randomized trial, in 325 patients with advanced hormone receptor-positive/HER2-negative disease who experienced recurrence on or within 12 months of adjuvant ET, median PFS was 15 months with inavolisib, palbociclib, and fulvestrant and 7.3 months with placebo, palbociclib, and fulvestrant (HR 0.43, 95% CI 0.32-0.59) [84,85]. An objective response occurred in 58 percent of the patients in the inavolisib group and in 25 percent of those in the placebo group. There was a trend favoring OS as well that did not reach statistical significance, although survival data are immature (median OS not estimable versus 31 months respectively; stratified HR 0.64, 95% CI 0.43-0.97). Grade ≥3 adverse events with inavolisib versus placebo were neutropenia (80 versus 78 percent), thrombocytopenia (14 versus 4.3 percent), leukopenia (6.8 versus 11 percent), and anemia (6.2 versus 1.9 percent). Grade ≥3 adverse events that were seen with inavolisib but not placebo included hyperglycemia (5.6 percent), diarrhea (3.7 percent), and stomatitis and mucosal inflammation (5.6 percent).
For those with progression on or soon after adjuvant tamoxifen — For those treated with tamoxifen in the adjuvant setting, an AI with CDK 4/6 inhibition is the preferred initial therapy for metastatic disease. The CDK 4/6 inhibitor trials discussed above included patients who were treated for de novo metastatic disease, as well as those who had experienced progression after adjuvant ET. (See 'AIs plus CDK 4/6 inhibitors' above.)
Although less preferable to the CDK 4/6 inhibitor-based combinations discussed above, single-agent AIs are available as subsequent-line therapy to those who seek a single-agent oral treatment, particularly if they have not received AIs in the frontline. There have been no differences in efficacy between the AIs in the second-line setting [21,86,87]. For example, in a phase III trial, 713 females with disease progression on prior tamoxifen were randomly assigned to treatment with either letrozole or anastrozole [87]. Although the objective response rate was significantly higher with letrozole (19 versus 12 percent), there was no significant difference in time to progression or OS.
LATER-LINE THERAPY OR ALTERNATIVES —
For females with progressive disease after the options discussed above, 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 endocrine therapy (ET) should receive chemotherapy. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)
Antibody-drug conjugates — Antibody-drug conjugates that may be used in select patients are discussed below.
●Sacituzumab govitecan – Sacituzumab govitecan is an anti-Trop-2 antibody-drug conjugate for patients with hormone receptor-positive, HER2-negative cancers after prior treatment including ET, a cyclin-dependent kinase (CDK) 4/6 inhibitor, and at least two lines of chemotherapy (including a taxane in either neo/adjuvant or advanced disease setting) for advanced breast cancer [88,89]. Its use in hormone receptor-positive cancers is discussed elsewhere. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Sacituzumab govitecan'.)
●Fam-trastuzumab deruxtecan – For patients with tumors that are either HER2 immunohistochemistry 1+, or 2+, and in situ hybridization negative, who have received at least one prior line of chemotherapy for metastatic disease and, if tumor is hormone receptor-positive, are refractory to ET, fam-trastuzumab deruxtecan is an appropriate option [88]. Further details and supporting data are found elsewhere. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Sacituzumab govitecan'.)
Fam-trastuzumab deruxtecan has also shown benefit over chemotherapy among patients who are chemotherapy naïve, having progressed on at least one line of prior ET. However, given that it has not been compared directly with ET in an earlier line of treatment, we continue to prefer the options discussed above, given likely better safety and tolerability. (See 'Choice of subsequent-line therapy, according to genetic alterations' above.)
Other options — For patients who are asymptomatic with slowly progressive disease, continuation of ET is reasonable, with one of the options below:
●Tamoxifen plus abemaciclib – For patients without prior treatment with a CDK 4/6 inhibitor, the combination of tamoxifen plus abemaciclib has shown efficacy and tolerability, with improved outcomes over abemaciclib alone. In preliminary results of the phase II nextMONARCH study, patients randomly assigned to abemaciclib 150 mg plus tamoxifen 20 mg daily experienced a statistically significant improvement in median overall survival (OS), relative to those assigned to either abemaciclib 150 mg daily or abemaciclib 200 mg daily (24 versus 21 and 17 months, respectively) [90]. 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 frontline 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 frontline regimen.
In a meta-analysis of four randomized trials including 1560 postmenopausal females with hormone receptor-positive advanced breast cancer, frontline 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) [91].
In a combined analysis of two randomized trials evaluating a sequence strategy (ie, tamoxifen followed by anastrozole or vice versa) in 1021 females, 511 were assigned to anastrozole, and of these, 137 females crossed over to tamoxifen [92]. Second-line treatment with tamoxifen in these females 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 females with progressive disease after ET and chemotherapy [93]. Its activity for patients who previously received a different CDK 4/6 inhibitor is unknown.
In preliminary results from the phase II MONARCH 1 study, which enrolled 132 patients with a median of three prior lines of treatment (including one or two prior chemotherapy regimens in the metastatic setting), single-agent treatment with the novel CDK 4/6 inhibitor abemaciclib induced tumor response in 20 percent of patients, with a clinical benefit rate (stable or responding disease) of 42 percent, and median progression-free survival of six months [94].
●Hormones or intermittent endocrine therapy – We choose other options before hormones for treatment of metastatic breast cancer, though historical reports suggested some activity and these strategies were used more frequently in the past [95-104]. The value of such approaches in contemporary practice, when most patients receive adjuvant anti-estrogen therapy, and when multiple endocrine treatments with and without targeted therapy options exist, is not known. Similarly, the historical literature include reports of treatment response to withdrawal of ET [105,106]. While interruption or cessation of endocrine treatment is an option for patients with indolent tumors or those needing a break from therapy, such withdrawal responses are almost never encountered in contemporary practice. Both progestins and estrogens are associated with an increased risk of thromboembolic events, and their use should be avoided in patients with thromboembolic disorders or other risk factors for thromboembolic disease. (See "Overview of the causes of venous thrombosis in adults".)
ADDITIONAL CONSIDERATIONS FOR PREMENOPAUSAL FEMALES —
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 females <60 years using guidelines from the National Comprehensive Cancer Network [107]:
●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'.)
Females 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 females treated with endocrine therapy (ET), we suggest concurrent ovarian suppression or ablation, in order to suppress estrogen levels. This is imperative for premenopausal patients receiving aromatase inhibitors (AIs), given the potential for ovarian stimulation with these agents.
Additionally, ovarian suppression allows premenopausal females 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 females; for example, a regimen we commonly use for premenopausal females is a gonadotropin-releasing hormone agonist (GnRHa) plus the combination of an AI and a CDK 4/6 inhibitor. Data for CDK 4/6 inhibitors in premenopausal females are discussed here, while data in postmenopausal females are presented above. (See 'Patients with >12 months since adjuvant ET or no prior ET' above and 'Patients with progression on or within 12 months of adjuvant ET' above.)
Ovarian suppression and ablation have shown equivalent outcomes in clinical trials [108]. However, for females 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 [109]. Furthermore, small studies have suggested that the addition of a GnRHa to an AI is as effective in premenopausal females as an AI alone is in postmenopausal females [110,111].
Incorporation of targeted agents — Available data in premenopausal patients suggest that a CDK 4/6 inhibitor may be effectively combined with ovarian suppression/ablation and tamoxifen or an AI.
In MONALEESA-7, 672 pre- or perimenopausal females with hormone receptor-positive, HER2-negative advanced breast cancer were randomly assigned to frontline ribociclib or placebo to be taken concurrently with goserelin and either tamoxifen or a nonsteroidal AI. Progression-free survival (PFS) was improved with ribociclib (median PFS, 24 versus 13 months; hazard ratio [HR] 0.55, 95% CI 0.4-0.69) [112], as was the OS rate at 3.5 years (70 versus 46 percent; HR 0.71, 95% CI 0.54-0.95) [15]. 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 females. (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 females 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 females 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) [113]. 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 females 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 [114].
Versus chemotherapy — For most premenopausal females 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 females. (See "Overview of the approach to metastatic breast cancer", section on 'Hormone receptor-positive, HER2-negative disease'.)
In results of a randomized phase II study, among 184 premenopausal females 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) [115]. Nonhematologic toxicities were less common with ET/palbociclib compared with capecitabine (eg, diarrhea, 13 versus 39 percent; hand-foot syndromes, 1 versus 100 percent, respectively), but hematologic toxicity was more common (grade ≥3 neutropenia, 64 versus 16 percent, respectively).
Tamoxifen, as an alternative — Tamoxifen is a selective estrogen receptor (ER) modulator (SERM) with mixed ER antagonistic and agonistic properties. It is principally antagonistic in breast cancer and breast tissue, as well as brain, whereas it has agonistic effects in bone, liver, and uterus. While our preference is for ovarian suppression or ablation plus ET, single-agent treatment with a SERM alone is an alternative for those who wish to avoid ovarian suppression. In a 1991 review of phase II trials of tamoxifen in premenopausal females, the ORR was 45 percent among the 31 patients with confirmed ER-positive disease [116].
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'.)
Targeted therapy for tumor agnostic indications — Targeted therapy for primary site agnostic indications is discussed elsewhere. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden" and "TRK fusion-positive cancers and TRK inhibitor therapy".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Treatment of metastatic breast cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction – Although metastatic breast cancer is unlikely to be cured, there have been meaningful improvements in survival due to advances in systemic therapy, including endocrine therapy (ET) and targeted agents. (See 'Introduction' above.)
●General principles – In patients with new metastatic disease, we biopsy a metastatic lesion to confirm estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We also assess for mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT1, PTEN, and ESR1, in tumor tissue and/or blood, for eligibility for AKT inhibitors, PI3K inhibitors, and elacestrant. (See 'General principles' above.)
For most patients with hormone receptor-positive, HER2-negative metastatic breast cancer, we suggest initial treatment with ET plus targeted therapy, rather than chemotherapy (Grade 2B). This includes patients with rapidly progressive, symptomatic disease or visceral metastases, although chemotherapy is an acceptable alternative particularly in this subgroup. (See 'Considerations for those with extensive visceral metastases' above.)
●Treatment for those with >12 months since adjuvant endocrine therapy
•For initial therapy for patients with metastatic hormone receptor-positive, HER2-negative breast cancer progressing at least a year after ET, we suggest a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with an aromatase inhibitor (AI) rather than an AI alone (Grade 2B). However, other acceptable options include single-agent fulvestrant or anastrozole, or fulvestrant in combination with an AI. For premenopausal females treated with an AI, concurrent ovarian suppression is required, given the potential for ovarian stimulation with these agents. For premenopausal patients receiving other agents, we also suggest concurrent ovarian suppression or ablation (Grade 2C).
•For patients who have previously experienced progression on an AI and CDK 4/6 inhibitor, our approach is as follows:
-For patients with PIK3CA/AKT1/PTEN and ESR1 wild-type tumors, we suggest the selective estrogen receptor degrader fulvestrant, with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus or abemaciclib (Grade 2C). A choice between these options is driven by patient preferences, considering the side effect profiles. (See 'ESR1 wild-type' above.)
-For those with an ESR1 mutation, we suggest elacestrant rather than fulvestrant (Grade 2B). Fulvestrant, with or without everolimus, is a reasonable alternative. (See 'ESR1 mutation-positive' above.)
-For those harboring alterations in PIK3CA, AKT1, or PTEN, we suggest fulvestrant with capivasertib (Grade 2C). Fulvestrant with the alpha isoform-specific PI3K inhibitor alpelisib is an alternative option, but carries more toxicity. (See 'Alterations in PI3K pathway' above.)
-For those with coexisting ESR1 mutations and mutations in the PI3K pathway, either elacestrant alone or fulvestrant with capivasertib may be chosen, with selection driven by patient preference regarding administration and side effect profile.
●Treatment for those with <12 months since adjuvant endocrine therapy – For those who progress on or within 12 months of completing adjuvant ET, treatment selection is driven by the prior ET and presence of an actionable driver mutation. (See 'Patients with progression on or within 12 months of adjuvant ET' above.)
•If progressing on recent AI and PIK3CA wildtype, we suggest fulvestrant plus a CDK 4/6 inhibitor rather than fulvestrant alone (Grade 2B) (table 7). However, if an ESR1 mutation is present, elacestrant is a reasonable alternative, particularly if the patient prefers to avoid intramuscular injections.
•If progressing on recent AI and PIK3CA mutant, appropriate options include fulvestrant plus a CDK 4/6 inhibitor, or the combination of the novel alpha isoform-specific PI3K inhibitor and degrader inavolisib with palbociclib and fulvestrant, or fulvestrant and capivasertib. (See 'Alterations in the PI3K pathway' above.)
Fulvestrant and capivasertib may also be used if AKT or PTEN mutation positive.
•If progressing on tamoxifen, we suggest an AI plus CDK 4/6 inhibitor rather than an AI or fulvestrant alone (Grade 2B). (See 'For those with progression on or soon after adjuvant tamoxifen' 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 or alternatives' 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.
