Mutations on the ESR1 gene, which encodes the estrogen receptor, have emerged as an important driver of resistance to endocrine therapies, which form the backbone of treatment for patients with ER-positive, HER2-negative breast cancer.
Mutations on the ESR1 gene, which encodes the estrogen receptor (ER), have emerged as an important driver of resistance to endocrine therapies, which form the backbone of treatment for patients with ER-positive, HER2-negative breast cancer.1,2
Patients with these mutations, which arise largely in response to the selective pressure of aromatase inhibitor (AI) therapy, have a poorer prognosis.3-5 As investigators have uncovered more details of the role of ESR1 mutations in resistance, novel treatment strategies that could improve patient outcomes have begun to emerge.4,5
Studies have suggested that monitoring the emergence of ESR1 mutations in the blood could help guide treatment decisions, but demonstration of clinical utility has remained elusive.3,6 The PADA-1 trial (NCT03079011), results from which were presented at the 2021 San Antonio Breast Cancer Symposium (2021 SABCS), was the first to demonstrate that ESR1 mutations can be detected before tumor progression and can be effectively targeted by switching from an AI to fulvestrant (Faslodex), a selective estrogen receptor downregulator (SERD).7
Investigators are also pursuing next-generation endocrine therapies that they hope will have more efficacy against ESR1-mutant tumors; such agents could complement AIs or fulvestrant as the standard of care if efficacy is established.
Among these newer agents are oral SERDs, such as elacestrant (RAD-1901), which is under investigation in the phase 3 EMERALD trial (NCT03778931). Data presented at 2021 SABCS suggest that although elacestrant is effective in the study population as a whole, its effects are most significant in patients with ESR1 mutations.
Novel selective estrogen receptor modulators (SERMs)—the drug class of tamoxifen, the first endocrine therapy approved for the treatment of breast cancer9—have also demonstrated antitumor activity in ESR1-mutant breast cancer.5 Among the forerunners, lasofoxifene is now in phase 2 testing, including in a head-to-head comparison with fulvestrant in patients with ESR1 mutations in the ELAINE trial (NCT03781063). The study is fully enrolled and expected to report top-line data later this year.10
Endocrine therapies comprise several distinct classes of drugs that are designed to either inhibit the production of estrogen with AIs such as letrozole, anastrozole, and exemestane or block its effects on the ER, with therapies such as SERMs (eg, tamoxifen) and SERDs (eg, fulvestrant).11
Endocrine therapies have now been incorporated into the neoadjuvant, adjuvant, and metastatic settings for the treatment of patients with ER-positive, HER2-negative disease.11 Although most patients initially derive benef it from these drugs, resistance presents a major challenge to their efficacy. Seeking to improve patient outcomes, investigators have long sought a better understanding of the mechanisms underlying this resistance.2
Research in this field has already led to significant gains in patient outcomes as combination therapies have been introduced. Endocrine therapies have been successfully combined with targeted therapies, including CDK4/6 inhibitors and PI3K inhibitors, drugs that target pathways implicated in endocrine resistance.12
The discovery that activating mutations in ESR1, the gene encoding the ER, are enriched in patients with metastatic ER-positive breast cancer has led to a growing appreciation of the importance of these mutations as a key mechanism of resistance.3,5,13 Studies examining metastatic ER-positive breast cancer have revealed that ESR1 mutations occur in less than 1% of patients who are endocrine therapy naïve, but the prevalence is as great as 40% among those treated with endocrine therapy. ESR1 mutations are also found in patients treated with neoadjuvant and adjuvant endocrine therapy, but at approximately 2% to 7%, the incidence is significantly lower than in the metastatic setting.3,5,13
ESR1 mutations may have important implications for the selection of endocrine therapy for metastatic breast cancer because studies suggest that these alterations are predominantly acquired after treatment with AIs. Although preclinical studies suggest that ESR1 mutations significantly reduce the ER-binding affinity of both fulvestrant and tamoxifen, retrospective analyses of clinical trials found that ESR1 mutations were not enriched following treatment with either of these drugs.3,5,13
However, the evolution of these mutations may be more nuanced than that. Findings from an analysis of the phase 3 PALOMA-3 trial (NCT01942135), in which patients who had progressed on endocrine therapy were randomized to fulvestrant or fulvestrant plus the CDK4/6 inhibitor palbociclib (Ibrance), found that although overall ESR1 mutations were not enriched following fulvestrant treatment, the Y537S mutation was selectively enriched. This result suggests that ESR1 Y537S specifically drives resistance to fulvestrant.14
In retrospective analyses, ESR1 mutations have been shown to be associated with poorer outcomes in patients treated with AIs. In the AI arms of the SoFEA (NCT00253422) and EFECT (NCT00065325) trials, which evaluated the efficacy of fulvestrant compared with exemestane after progression on a nonsteroidal AI, patients with ESR1 mutations had significantly shorter median progression-free survival (PFS) and lower rates of 1-year overall survival (OS) compared with patients with wild-type ESR1.15,16
Although ESR1 mutations are clearly an important mechanism of resistance to AI monotherapy, single-agent endocrine therapies are not among the preferred regimens for second and subsequent lines of therapy in the current treatment paradigm, according to National Comprehensive Cancer Network guidelines. Instead, they are frequently used in combination regimens with CDK4/6 inhibitors (palbociclib, abemaciclib [Verzenio], or ribociclib [Kisqali]), the mTOR inhibitor everolimus (Afinitor), or the PI3K inhibitor alpelisib (Piqray) in patients with PIK3CA mutations.17
Analyses of data from clinical trials have revealed that ESR1 mutations predict poorer outcomes for patients treated with an AI in combination with palbociclib or ribociclib, but not for patients treated with fulvestrant in combination with these CDK4/6 inhibitors; this mirrors findings for AI and fulvestrant as monotherapies. Perhaps because it is the only CDK4/6 inhibitor with singleagent activity, abemaciclib (either as monotherapy or, notably, combined with an AI) does not show reduced efficacy in patients with ESR1 mutations.5
In the BOLERO-2 trial (NCT00863655), although there was a median PFS benefit from the addition of everolimus to exemestane irrespective of patients’ ESR1 status, ESR1 mutations were associated with shorter median OS.18 Meanwhile, in a phase 1/2 trial (NCT01870505) evaluating the combination of alpelisib and an AI, ESR1 mutations were significantly associated with a lack of clinical benefit.19
The ongoing phase 2 BYLieve trial (NCT03056755) is evaluating alpelisib combined with fulvestrant (cohort A) or letrozole (cohort B) in patients with PIK3CA-mutated ER-positive, HER2-negative advanced breast cancer after progression on a CDK4/6 inhibitor plus an AI or fulvestrant.
At 2021 SABCS, results of an analysis of the impact of ESR1 mutations on efficacy in both cohorts were presented. In the fulvestrant plus alpelisib cohort, there was no significant difference in median PFS between patients with and without ESR1 mutations (5.55 months vs 8.28 months; HR, 0.76; 95% CI, 0.44-1.33; P = .3). In the letrozole plus alpelisib cohort, however, median PFS was significantly reduced in patients with ESR1 mutations (4.57 months vs 7.03 months; HR, 0.55; 95% CI, 0.32-0.92; P = .02).20
Studies show that the development of acquired ESR1 mutations occurs prior to clinical progression in patients treated with AIs; thus, serial monitoring of ESR1 mutations during treatment could facilitate therapeutic decision-making at a critical time.21
Circulating tumor DNA (ctDNA), extracted from blood plasma, can be used to detect ESR1 mutations in patients with metastatic ER-positive breast cancer. This has demonstrated excellent sensitivity and concordance with mutation status according to tumor tissue biopsy.22-24
The clinical utility of ESR1 mutations in guiding management decisions is an open question, and the ongoing phase 3 PADA-1 study is the first prospective clinical trial specifically seeking to provide an answer. Patients with previously untreated ER-positive, HER2-negative metastatic breast cancer received a combination of an AI and palbociclib as frontline therapy and underwent ctDNA ESR1 mutation testing every 2 months7 in the first part of this trial. In the second part of the trial, patients with ctDNA evidence of ESR1 mutation emergence were randomized to either continue with the same treatment regimen or switch to a combination of fulvestrant and palbociclib.
Data from part 1 were presented at a conference in 2020. Of the 1017 patients evaluated, 3.2% had an ESR1 mutation at baseline, and these patients had a worse prognosis (median PFS, 11.0 months vs 26.7 months; HR, 2.3; P < .001). Patients treated with an AI as adjuvant therapy were more likely to have an ESR1 mutation (P < .01). In 69% of the patients with a baseline ESR1 alteration, the mutation was cleared after 4 weeks of treatment; these patients experienced improved median PFS compared with those without mutation clearance (24.1 months vs 7.4 months, respectively).25,26
A total of 172 patients were randomized in part 2 of PADA-1. After a median follow-up of 26 months, median PFS was significantly prolonged by switching from the AI to fulvestrant upon ctDNA detection of emerging ESR1 mutation (11.9 months for patients who switched vs 5.7 months for those who did not; HR, 0.63; 95% CI, 0.45-0.88; P = .007).7
Several clinical trials are now evaluating this “watch and switch” strategy in the frontline setting in metastatic breast cancer. These include the phase 3 SERENA-6 trial (NCT04964934), which is testing the switch to a novel oral SERD, camizestrant (AZD9833), from an AI following detection of ESR1 mutations.
A significant focus of ongoing clinical research is the pursuit of more effective treatment strategies for ESR1-mutant disease.
Numerous drugs are being developed, including novel SERMs such as lasofoxifene; orally bioavailable SERDs (fulvestrant is administered intramuscularly), such as elacestrant and amcenestrant (SAR439859); a SERM/SERD hybrid, bazedoxifene (Duavee); and the first-in-class selective ER covalent antagonist H3B-6545.5,27
These agents have been shown to retain efficacy in the presence of ESR1 mutations and in models of endocrine resistance in preclinical studies.5 Preliminary clinical trial data have recently emerged for several of these drugs.
In the phase 1/2 AMEERA-1 trial (NCT03284957), patients with ER-positive, HER2-negative metastatic breast cancer who had previously received endocrine therapy were treated with amcenestrant, either as monotherapy or in combination with palbociclib. Both amcenestrant regimens demonstrated promising antitumor activity, regardless of patients’ ESR1 mutation status.28,29
Results from the phase 1 EMBER trial (NCT04188548) suggested clinical benefit of monotherapy with another oral SERD, imlunestrant (LY3484356), irrespective of ESR1 mutation status, in patients with heavily pretreated ER-positive, HER2-negative metastatic breast cancer.30
These drugs and others are being evaluated in ongoing phase 3 clinical trials that are assessing the impact of ESR1 mutations on patient outcomes. A presentation at 2021 SABCS described results from the phase 3 EMERALD trial comparing elacestrant to endocrine therapy (fulvestrant or an AI) in patients with ER-positive, HER2-negative metastatic breast cancer previously treated with 1 or 2 lines of endocrine therapy, including in combination with a CDK4/6 inhibitor.
Of the 477 patients who were randomized, 228 had ESR1 mutations. In the overall population, elacestrant reduced the risk of disease progression or death by 30% (HR, 0.697; 95% CI, 0.387-0.768; P = .0018). The efficacy of elacestrant was even more pronounced among patients with ESR1 mutations, with a 45% reduction in the risk of disease progression or death (HR, 0.546; 95% CI, 0.387-0.768; P = .0005). In an interim OS analysis, elacestrant also showed a trend toward improved OS among all patients and in patients with ESR1 mutations.8
Other ongoing trials of novel endocrine therapies are exclusively enrolling patients with ESR1 mutations. Lasofoxifene, which is leading the pack for novel SERMs in clinical development, is currently being evaluated in the phase 2 ELAINE and ELAINE-2 trials (NCT04432454). In the former, lasofoxifene is being compared against fulvestrant in patients with ESR1-mutant, ER-positive, HER2-negative metastatic breast cancer that has progressed following treatment with a combination of an AI and a CDK4/6 inhibitor. In ELAINE-2, lasofoxifene is combined with abemaciclib in a similar setting.31,32