Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

Abstract

Hormone receptor-positive breast cancer is the most frequent breast cancer subtype. Endocrine therapy (ET) targeting the estrogen receptor (ER) pathway represents the main initial therapeutic approach. The major strategies include estrogen deprivation and the use of selective estrogen modulators or degraders, which show efficacy in the management of metastatic and early-stage disease. However, clinical resistance associated with progression of disease remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes the ER, have been increasingly recognized as an important mechanism of ET resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition. ESR1 mutations, most often detected from liquid biopsies, have been consistently associated with a worse outcome and are being currently evaluated as a potential biomarker to guide therapeutic decisions. At the same time, targeted therapy directed to ESR1-mutated clones is an appealing concept with preclinical and clinical work in progress.

The potential of combined mutation sequencing of plasma circulating cell‐free DNA and matched white blood cells for treatment response prediction

“…In addition, the analysis revealed that certain (likely) pathogenic mutations in ESR1 and SF3B1 might affect PFS and OS as well (P = 0.084 and P = 0.088). In line with previous reports, specific ESR1 mutations such as Y537S were considered as adverse prognostic biomarkers while other mutations, like in PIK3CA, do not affect PFS (Moynahan et al, 2017;Reinert et al, 2017). Besides, in a similar cohort using a larger gene panel, other specific mutations in AR, MUC16, and ERBB2 (not tested in the Kruger study) revealed that each separately had a significant association with survival in MBC (Keup et al, 2019).…”

FOXA1 levels are decreased in pleural breast cancer metastases after adjuvant endocrine therapy, and this is associated with poor outcome

“…Possibly, malignant pleural effusions are less enriched for ESR1 mutations as compared to solid metastases. However, our cohort is enriched for cases who received tamoxifen in the adjuvant setting, and activating ESR1 mutations are mostly identified in patients who previously received aromatase inhibitors and rarely observed in patients solely receiving tamoxifen (Reinert et al, 2017), indicating that our study is possibly underpowered for stronger conclusions.…”

Estrogen–gut microbiome axis: Physiological and clinical implications

“…Estrogen receptor positive breast cancer is the most common subtype of breast cancer [73]. This particular cancer subtype is significantly mediated by estrogen [71].…”