A majority of breast cancers are hormone receptor (HR) positive and are responsive to various types of hormone manipulation. Endocrine therapy is the preferred first-line therapy for patients with advanced estrogen receptor (ER)-positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapy is often continued in the second- and third-line settings, with chemotherapy deferred until the tumor becomes endocrine therapy refractory and/or a visceral crisis is imminent.

Therapeutic options vary based on clinical presentation and include single-agent therapies such as tamoxifen, aromatase inhibitors (AIs), and fulvestrant (Faslodex), as well as combination therapy options. Over the past few years, the results of multiple trials have shown significant improvement in outcomes when endocrine therapy is combined with CDK4/6 inhibitors or mammalian target of rapamycin (mTOR) inhibitors. Improved efficacy comes at a cost of a modest increase in toxicity.

Mechanisms of ER resistance have been defined, leading to multiple strategies to improve efficacy and overcome resistance. These include the combination therapy options mentioned above and other novel drugs that are in development.

Hormonal manipulation has been an established paradigm in the treatment of breast cancer for over 100 years. Early trial results demonstrated the regression of advanced breast cancer after oophorectomy or ovarian radiation, and it It has since been shown that approximately 70% of breast cancers are HR positive. Although a majority of breast cancers are curable, approximately 20% to 30% of patients present with de novo metastatic disease or progress to metastatic disease following an early-stage diagnosis. Treatment of metastatic disease is influenced by menopausal status, HR status, and other molecular features. This discussion will focus on the postmenopausal patient with HR-positive metastatic breast cancer (MBC).

Endocrine therapy is the preferred choice of first-line therapy for patients with advanced ER-positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapies work through various mechanisms including decreasing estrogen production (AIs), blocking signaling through the ER (tamoxifen), or antagonizing the receptor itself (fulvestrant).

First-line endocrine therapy is continued until disease progression or unacceptable toxicity. A change to second-line endocrine therapy can be considered at the time of disease progression. Chemotherapy is typically recommended when the benefit of endocrine therapy lessens (with each prior endocrine therapy), the tumor becomes endocrine therapy refractory, and/or a visceral crisis is imminent.

Although metastatic ER-positive breast cancers can respond well to sequential endocrine therapies, most patients will become resistant to these therapies, eventually require chemotherapy, and inevitably die of their disease. Mechanisms of ER resistance have been defined, however, leading to the development of novel therapies to improve efficacy and overcome resistance, including CDK 4/6 inhibitors, mTOR inhibitors, and others.

In patients with hormone-sensitive advanced breast cancer, there is a rich history of investigation that started with ablation of hormonesecreting organs (ie, ovaries, adrenals and pituitary) long before there was a clear understanding of the underlying biology controlling the growth of breast cancer cells via the ER pathway. Over many decades, the use of agents in the clinic has largely supplanted ablative surgery, including progestins, aminoglutethimide, testosterones, and estrogens.

Once ER biology was elucidated, the development of drugs such as tamoxifen replaced older strategies because of their efficacy and a better toxicity profile. Eventually, AIs (eg, letrozole, anastrozole, and exemestane) were developed that bettered tamoxifen as a firstchoice for most postmenopausal women with advanced ER-positive MBC. Subsequently, fulvestrant, a selective ER down-regulator was developed; it can be used early in MBC or later in the sequence of treatment.

Ultimately, all of these agents lose their effectiveness and patients develop resistance to treatment, after which they often proceed to chemotherapy.

Cyclin-dependent kinases (CDKs) represent a major advance in the treatment of ER-positive MBC. Data from large, randomized clinical trials are robust and consistent. The benefit of adding CDK 4/6 agents to single-agent endocrine therapy has been observed in both premenopausal and postmenopausal women with MBC. CDKs regulate cell-cycle progression by interacting with specific cyclin proteins. Interfering with them leads to cell-cycle arrest.

Although single-agent endocrine therapies have demonstrated modest benefit in the first and subsequent lines of therapy for women with ER-positive MBC, combination therapies have emerged as a more effective alternative for many patients. The growth of HR-positive breast cancer is dependent on CDKs 4 and 6, which promote progression from the G1 to the S phase of the cell cycle. CDK inhibitors block the cyclin D1-CDK 4/6 complex, prevent RB protein phosphorylation, and stop the cell cycle from progressing to the S phase, thereby preventing cancer cell proliferation.

The first CDK 4/6 inhibitor, palbociclib (Ibrance), received accelerated FDA approval in February 2015 based on phase II data from the PALOMA-1 trial. This study randomized women with no prior therapy for advanced breast cancer and no AI therapy in the 12 months before randomization to letrozole alone or letrozole plus palbociclib.

The combination therapy arm showed an improved progression-free survival (PFS) of 20.2 months compared with 10.2 months with letrozole alone (hazard ratio, 0.49). The combination of letrozole and palbociclib was well tolerated, with neutropenia and leukopenia as the most common grade 3 and 4 adverse events (AEs). Fatigue, anemia, nausea, arthralgia, and alopecia were also reported.

PALOMA-2 was a randomized phase III study evaluating the same study population as PALOMA-1. A total of 666 postmenopausal women with ER-positive MBC were randomized 2:1 between letrozole and palbociclib versus letrozole and placebo. The combination therapy arm showed benefit similar to the phase II trial, with a PFS of 24.8 months compared with 14.5 months in the single-agent letrozole arm (hazard ratio, 0.58). There was a nonstatistically significant improvement in overall survival (OS).

Since those first trials, numerous other trials have been completed and published, establishing the role of the 3 FDA-approved agents (palbociclib, ribociclib [Kisqali], and abemaciclib [Verzenio]) as treatments in the first- and second-line settings of patients with ER-positive MBC. Only abemaciclib is approved as monotherapy for ER-positive MBC. 

The impact that CDK 4/6 inhibitors have made in treating ER-positive MBC raises the issue of whether monotherapy with any endocrine agent is optimal. Ellis and colleagues conducted the randomized, double-blind, phase III FALCON trial comparing the ER antagonist fulvestrant with the AI anastrozole in 462 patients with ER-positive, locally advanced or metastatic disease who had not received prior endocrine therapy. At 25 months’ median followup, PFS was prolonged with fulvestrant versus anastrozole (16.6 vs 13.8 months; hazard ratio, 0.797; 

 = .049). Measures of quality of life and AEs were similar between the 2 groups.

These results suggest that fulvestrant could be acceptable as first-line therapy for metastatic disease in certain patients. When there are concerns regarding compliance and need for minimal toxicity due to age or comorbidities, fulvestrant could be considered earlier in the course of disease.

Other data suggest that either palbociclib, abemaciclib, or riboclclib combined with an AI appear to confer better PFS than an AI alone. Also, the FALCON trial recruited very pristine patients who had not been exposed to endocrine therapy, which may represent a small fraction of patients with breast cancer.

Resistance to endocrine therapy in breast cancer can be associated with activation of the mTOR intracellular signaling pathway. Early study results showed that the mTOR inhibitor everolimus (Afinitor) added to endocrine therapy improved antitumor activity.

The BOLERO-2 study evaluated postmenopausal women with MBC who developed disease recurrence within 12 months of completion of adjuvant endocrine therapy or within 1 month of treatment for advanced disease. A total of 724 patients were randomized 2:1 to everolimus plus exemestane versus exemestane alone. Median PFS was 6.9 months in the combination arm versus 2.8 months in the single-agent exemestane arm. There was not a statistically significant OS benefit.

The addition of everolimus is associated with increased toxicity, including mouth sores and rashes, compared with endocrine therapy alone. Ongoing studies are evaluating the addition of mTOR inhibitors to endocrine therapy in the adjuvant setting for patients with early stage, ER-positive breast cancer.

Some cancers initially are refractory to estrogen-blocking therapies (de novo resistance), but more commonly, tumors become resistant to endocrine therapy as they are exposed to more and different agents over time. Resistance to estrogen deprivation involves activation of growth factor pathways to bypass endocrine dependence.

 ligand—binding domain have been demonstrated in hormoneresistant breast cancer. Somatic mutations of 

have been found in <1 % of primary breast cancers and in 19% of advanced breast cancers. Acquisition of mutations increase with increasing tumor burden. In an analysis of 

 mutations by circulating tumor DNA in samples from the PALOMA-3 study, mutations were detected in 25% of baseline plasma samples. Mutations were detected in 29% of patients treated with an AI, 2% treated with tamoxifen, and 32% treated with tamoxifen and an AI.

In the PALOMA-3 samples, mutations were neither prognostic nor predictive. Response rates were not significantly different between the 

 wild-type patients. The addition of palbociclib offered similar benefit regardless of mutation status.

In the SoFEA trial, patients were randomized to fulvestrant plus anastrozole or placebo versus exemestane. Interestingly, 39% of patients were found to have 

 mutations, and of this group, those treated with exemestane had a PFS of 2.6 months versus 5.7 months for those treated with fulvestrant (hazard ratio, 0.52,

 wild-type disease had no statistically significant difference in PFS when treated with exemestane versus fulvestrant. Within the exemestane group, patients with 

 mutations had worse PFS than those who were 

 wild-type. In this study, mutations were found to be both predictive and prognostic. The data from SoFEA provide early clinical evidence of the utility of

 mutational status in selecting appropriate endocrine therapy.

Emerging data regarding mechanisms of endocrine resistance led to several possible strategies for overcoming resistance. These include fulvestrant, combination therapies with CDK 4/6 and mTOR inhibitors, and other novel therapies in development that are discussed below. Therapies are also being developed to target the mutations in the ER, including some novel ER down-regulators with the ability to degrade mutant ERs.

The PI3K/AKT/mTOR signaling pathway plays a critical role in mediating cell growth, survival, and angiogenesis. Mutations in this pathway are frequently seen in ER-positive breast cancer. Numerous agents are in development, including PI3K inhibitors or agents that have multiple targets along the signaling pathway.

Recently, earlier disappointing results from trials incorporating PIK3 inhibitors were offset by the results of the SOLAR-1 trial. Juric and colleagues updated findings from the SOLAR-1 randomized phase III trial of alpelisib plus fulvestrant, involving 572 postmenopausal patients with HER2-negative, ER-positive MBC who developed recurrence or progression after prior AI therapy. The trial included a 

-nonmutant cohort. Patients were randomized to fulvestrant plus the PIK3CA inhibitor alpelisib versus fulvestrant plus placebo.

-mutant group improved with alpelisib versus placebo (11.0 vs. 5.7 months; hazard ratio, 0.65; 

 = .00065). Alpelisib conferred an advantage in all subgroups regardless of line of therapy. The effect was observed whether the 

mutation was determined by analysis of tumor tissue or circulating tumor DNA. Specific grade 3 AEs that were more pronounced in those receiving alpelisib versus placebo, respectively, were hyperglycemia (32.0% vs 0.3%) and rash (10.0% vs 0.3%). Only 5% of patients had received prior CDK 4/6 therapy.

These results show a significant PFS advantage with the addition of alpelisib to fulvestrant for patients with HER2-negative, ER-positive advanced breast cancer and a 

 mutation. How this drug would perform in the current environment in which most patients have received a CDK 4/6 inhibitor remains to be determined. If alpelisib becomes available, it will likely be used primarily after CDK 4/6 exposure.

There has been much progress in the treatment of ER-positive MBC over the past 40 years. Combination regimens with CDK 4/6 inhibitors and mTOR inhibitors have been shown to be superior to their monotherapy counterparts— but with a modest increase in toxicities.

Novel therapies are further expanding our therapeutic options. In the future, 

 mutation status and other molecular markers will likely be used more frequently to guide therapy.

Specific treatment recommendations must take into account tumor biology, clinical features, and patient characteristics and require a thoughtful conversation with the patient about the benefits and toxicities of various options.

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Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. 

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Neven P, Rugo HS, Tolaney SM, et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 1002. meetinglibrary.asco.org/record/160554/abstract.

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There has been much progress in the treatment of estrogen receptor-positive metastatic breast cancer over the past 40 years, and novel therapies are further expanding therapeutic options.

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