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.

Keywords: Breast cancer; CDK4/6; Combination; ESR1 mutation; Hormone receptor/estrogen receptor; Resistance; SERCA; SERD; SERM.

Fig. 1

Mechanisms of resistance of ESR1 mutations. a Mutations and effects. All ESR1-MUT mutations are in the LBD. Mutations stabilize the active conformation in the absence of ligand, decreasing affinity for ligands, including estrogen, SERMs, and SERDs. This results in constitutive activity, increased basal activity, and proteolytic stability, enhancing cancer growth, metastasis, and resistance. E2: estradiol, AF-1: activation function 1 domain, LBD: ligand-binding domain, AF-2: activation function 2 domain, DBD: DNA-binding domain. b Key targeted pathways in HR-positive breast cancer and effects of ESR1-MUT. In the ESR1-WT situation, AI depletion of estrogen inhibits ESR1 activity, SERMs such as tamoxifen alter ESR1 binding partners and transactivation ability, and SERDs such as fulvestrant inhibit ESR1 activity and proteolytic stability. PI3Ki and mTORC1i inhibit upstream phospho-activation of ESR1 and additional growth-promoting signaling, and CDK4/6i inhibits the cell cycle machinery downstream of PI3K, mTORC1, and ESR1 signaling. In the ESR1-MUT situation, AI is ineffective since ESR1-MUT does not require estrogen, and tamoxifen and fulvestrant bind less strongly to ESR1-MUT (novel drugs in these categories are subject to ongoing study). PI3Ki and mTORC1i theoretically remain effective, although the crosstalk between ESR1-MUT and PI3K/mTORC1 signaling is not known. CDK4/6i is effective in both ESR1-WT and ESR1-MUT breast cancer. TF: transcription factor

Fig. 2

Trial design for testing the incorporation of ESR1 mutation monitoring into clinical decision-making. a Design. Patients with MBC start on standard treatment (such as AI plus CDK4/6i) with monitoring for the development of ESR1-MUT. Patients are excluded if they have clinical progression before ESR1-MUT arises (presumably due to development of other resistance mechanisms). Patients who develop ESR1-MUT are at that time randomized to continuing current therapy until progression, versus changing current therapy immediately. All patients change to next-line therapy at each progression. The main end points are OS, PFS, adverse events, and patient-reported outcomes. b Possible outcomes. Selection of endpoint is important: while for the “change” arm, longer PFS might be expected, OS has multiple plausible outcomes – (H0) no change in OS, due to the same clocklike rate of resistance development; (H1) longer OS, due to the “change” arm have a higher chance of durable response with earlier therapy switch; (H2) shorter OS, due to premature discontinuation of current therapy before attaining maximum benefit