ESR1 mutations in HR+/HER2-metastatic breast cancer: Enhancing the accuracy of ctDNA testing

Abstract

Activating mutations of the estrogen receptor alpha gene (ESR1) are common mechanisms of endocrine therapy (ET) resistance in hormone receptor-positive (HR + )/Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic breast cancer (MBC). Recent clinical findings emphasize that both old and new generations of selective ER degraders (SERDs) demonstrate enhanced clinical effectiveness in patients with MBC who have detectable ESR1 mutations via liquid biopsy. This stands in contrast to individuals with MBC carrying these mutations and undergoing conventional endocrine monotherapies like aromatase inhibitors (AIs). Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has emerged as a promising, minimally invasive alternative to conventional tissue-based testing for identifying ESR1 mutations. Within the context of the PADA-1 and EMERALD trials, distinct molecular methodologies and assays, specifically digital droplet PCR (ddPCR) and next-generation sequencing (NGS), have been employed to evaluate the mutational status of ESR1 within ctDNA. This manuscript critically examines the advantages and indications of various ctDNA testing methods on liquid biopsy for HR+/HER2-negative MBC. Specifically, we delve into the capabilities of ddPCR and NGS in identifying ESR1 mutations. Each methodology boasts unique strengths and limitations: ddPCR excels in its analytical sensitivity for pinpointing hotspot mutations, while NGS offers comprehensive coverage of the spectrum of ESR1 mutations. The significance of meticulous sample handling and timely analysis is emphasized, acknowledging the transient nature of cfDNA. Furthermore, we underscore the importance of detecting sub-clonal ESR1 mutations, as these variants can exert a pivotal influence on predicting both endocrine therapy resistance and responsiveness to SERDs. In essence, this work discusses the role of ctDNA analysis for detecting ESR1 mutations and their implications in tailoring effective therapeutic strategies for HR+/HER2- MBC.

Keywords: Digital droplet PCR; ESR1; Liquid biopsy; Metastatic breast cancer; Next-generation sequencing; ctDNA.