ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

Abstract

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.

Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

“…Interestingly, the prevalence of BC cells with estrogen receptor 1 (ESR1) mutations is much higher in patients with MBC who received AI (up to 40% versus 1% in MBC patients without prior ET). Despite a clear association between ESR1 mutations and endocrine resistance, data about predicting the response to AI and/or CDK4/6 inhibitors are contradictory [ 48 ]. Further studies are warranted to clarify whether the detection of ESR1 mutations may influence clinical decisions and the indication of CDK4/6 inhibitors in the metastatic or adjuvant setting [ 49 ].…”

Expert Discussion: Predictive Markers

“…The simplest mechanism by which ESR1 mutations produce resistance is the lifelong constitutive activity that keeps estrogen receptors unaffected by AI depletion of estrogen. In view of this biological mechanism, several retrospective studies have evaluated the interest of selective estrogen receptor modulators (such as tamoxifen) and selective estrogen receptor degraders (such as fulvestrant) with encouraging results [10]. To date, prospective studies are rare but the phase III PADA-1 trial has nevertheless shown that the presence of an ESR1 mutation at baseline leads to a worse prognosis but that the disappearance of the mutation (on cell-free DNA) after 1 month of letrozole + palbociclib improved the prognosis of patients initially positive for ESR1 [11].…”

Endocrine resistant breast cancer: brain metastasis

“…Resistance to endocrine therapy can develop due to mutation or loss of endocrine receptors on tumor cells (e.g., hormone receptor-negative and ESR1 gene mutations) or via the upregulation of pathways independent of endocrine receptors altogether [ 6 , 7 , 16 , 17 ].…”

“…ESR1 gene mutations in breast cancer tumor ER are frequently associated with the development of endocrine resistance [ 16 , 17 ]. Mutations in ESR1 can cause activation of ER independent of estrogen levels, allowing for the upregulation of breast cancer cell proliferation in an endocrine therapy-resistant mechanism [ 18 ].…”