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Blog | Dec. 07, 2022

The Prevalence and Outcomes of ESR1 Mutations in Breast Cancer

Most common cancer diagnosed in women worldwide

Breast cancer (BC) is the most common cancer diagnosed in women worldwide, having recently surpassed lung cancer, and accounts for more than 25% of new cancer diagnoses.1,2 It is also the leading cause of death among cancers in women.2 According to the CDC, BC care in the U.S. cost the country 16.5 billion USD annually in 2010, and has the highest treatment cost of any cancer.3

Among BCs, more than 70% are classified as estrogen receptor positive (ER+). This classification is based on the ER expression determined by immunohistochemistry in at least 1% of tumor cells. Estrogen receptor alpha (ERα) and its natural ligand, estrogen, are major drivers of tumor development and disease progression in BCs. Targeting ERα has led to several highly successful BC therapeutics that are widely utilized in both early stage BC and metastatic BC.4 In 1997, the selective estrogen receptor modulator Tamoxifen was approved for use in combatting BC, and it still represents the standard of care for adjuvant treatment of early stage BC.5 Tamoxifen is especially useful in postmenopausal patients, though use of aromatase inhibitors (AIs) that inhibit biosynthesis of estrogen are often utilized in adjuvant treatment and represent the standard of care in advanced metastatic breast cancer in postmenopausal patients.6,7

Intrinsic and acquired resistance to breast cancer therapies

Even though these various anti-hormonal therapies have proven effective at combatting BC, intrinsic and acquired resistance to these therapies is and remains a persistent problem. The issue is especially apparent when it comes to ER+ metastatic breast cancer (MBC), where up to half of patients will demonstrate intrinsic resistance and no benefit from these therapies, and eventually all the ER+ MBC patients will develop acquired resistance.7 Patients who grow resistant to the first-line treatments experience a drop in progression-free survival (PFS) when they move onto second-line therapies.8 A mechanism of acquired resistance that has come into focus is the mutation of the ligand binding domain (LBD) of Estrogen Receptor 1 (ESR1), and it has been intensely studied over the last decade plus to elucidate its role in therapy resistance and to guide selection of appropriate treatments and therapeutic vulnerabilities.9

ESR1 mutations

The first ESR1 mutations were discovered in 1997,10 however, their role in BC resistance to first line therapies was not firmly established until 2013 with genomic sequencing of MBCs.11 The prevalence of ESR1 mutations has since been measured among BC patients and is dependent on prior duration and setting of hormonal therapy. ESR1 mutations in ER+ BC occur almost exclusively after AI therapy in the metastatic setting, and among patients who have received AIs, approximately 20-40% have mutations in ESR1.9,11,12

The simplest mechanism through which ESR1 mutations result in resistance to hormone therapy is constitutive activity. Wild-type ESR1 requires estrogen in order to function and the mutations can remove the need for estrogen to bind to ESR1 before assuming its active conformation. Thus, therapies that rely on depleting the amount of estrogen in the system to deactivate ESR1 are no longer effective. Alternatively, ESR1 mutations can result in relative resistance to ER-targeted therapies like Tamoxifen and Fulvestrant, a selective estrogen receptor degrader. ESR1 mutants have demonstrated up to 30-fold decreased binding affinity for Tamoxifen and up to 40-fold decreased binding affinity for Fulvestrant (varying by specific mutation) requiring higher dosages in order to elicit therapeutic effects.14,15,16

In addition to the general resistance mechanisms, there are mutation-specific and context-specific mutations to ESR1 that effect therapeutic options for treatment of BC and MBC. For example, among two of the most commonly observed mutations, Y537S, has greater resistance to estrogen deprivation, Tamoxifen, Fulvestrant, and several novel drugs; and D538G results in greater metastatic potential, especially to the liver.12,13,15,16

Clinical utility of mutation detection

These mutations may bear out their effects not just in a pre-clinical theoretical setting, but also in clinical practice, however, the results of how ESR1 mutations manifest in clinical practice are mixed. In the plasmaMATCH trial, it was found that Fulvestrant monotherapy may not be effective for patients in the late-line setting with ESR1 mutations.17 However, in the PALOMA-3 trial, it was found that ESR1 mutations in general do not result in resistance to Fulvestrant plus a CDK4/6 inhibitor, but the Y537S mutation deserves further study as it may have an effect on treatment.18,19,20

There is a glaring need to elucidate further the effects of specific mutations of ESR1 on BC and MBC. The effects of mutations can potentially be used for therapy selection as well as monitoring of response to therapy. With technologies like Plasma-Safe-SeqS (PSS) we are able to detect mutations to ESR1 with great specificity and sensitivity.21 This type of monitoring will allow for further study of ESR1 mutations and can also be useful in the clinical application of findings concerning ESR1 mutations and how they affect the clinical application of cancer treatment.


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