Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

Abstract

Endocrine therapy is the main treatment option for estrogen receptor-positive (ER+) breast cancer (BC). Compared with other clinical subtypes, ER+ BC patients usually have a more favorable prognosis. However, almost all ER+ BCpatients develop endocrine resistance and disease progression eventually. A large number of studies based on liquid biopsy suggest that ESR1 mutations may play a key role in this process. For patients with ER+ metastatic BC (MBC), ESR1 is an important prognostic factor and may associate with the resistance to endocrine therapy, like aromatase inhibitors. The advances of sequencing technologies allow us to conduct longitudinal monitoring of disease and unveil the clinical implications of each ESR1 sub-clone in ER+ MBC. Moreover, since the ESR1-related endocrine resistance has not been fully addressed by existing agents, more potent cornerstone drugs should be developed as soon as possible. Herein, we reviewed the recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ MBC and discussed its clinical impacts and prospects.

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

“…ESR1-MUT clearly predicts poor response to single-agent AI, as previously reviewed [ 21 , 24 ] (Table 1 ). For example, the SoFEA and EFECT trials of fulvestrant versus exemestane for patients with MBC after prior progression on non-steroidal AI were retrospectively analyzed for preexisting ESR1-MUT in cfDNA [ 12 , 42 ].…”

“…There are many technologies for detecting ESR1 mutations in MBC. Sample sources include solid tissue biopsy, CTCs, and cell-free DNA (cfDNA); detection assays include next-generation sequencing (NGS) and droplet digital PCR (ddPCR), with ddPCR the most sensitive [ 21 ]. All ESR1 resistance mutations are in the LBD: the most common are D538G and Y537S; others include Y537N, Y537C, L536H, L536P, L536R, S463P, and E380Q [ 13 , 22 – 25 ] (Fig.…”

“…Prior reviews have discussed key conclusions from the literature on ESR1 mutations in MBC [ 2 , 21 – 25 ]. Well-established findings are: (1) ESR1 mutations are acquired during AI treatment in the metastatic setting; (2) ESR1 mutations predict resistance to AI monotherapy; and (3) prospective studies on incorporating ESR1 mutation status in clinical decisions are lacking.…”

Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients

“…Several ESR1 hotspot mutations within the ligand-binding domain, including D538G and Y537S/N/C, were also detected at a lower frequency (4%). Given established treatment-associated patterns of acquired mutations in ESR1, it is not surprising that the mutation rate was not high in the setting of first-line treatment [55]. ERBB2 was the gene with the most frequent occurrence of CNVs and had an amplification rate of 22.7% (32/141) in the entire cohort and 70.5% (31/44) in the HER2 + population.…”

Cell-free DNA comparative analysis of the genomic landscape of first-line hormone receptor-positive metastatic breast cancer from the US and China

“…ESR1 mutations are associated with poor prognosis in ER+ MBC patients [ 37 ]. Chandarlapaty et al reported that cfDNA ESR1 mutations were associated with shorter OS of MBC patients from the BOLERO-2 study [ 10 ].…”