ESR1 analysis of liquid biopsy in breast cancer, one-year routine experience of an Italian clinical referral center

TL;DR

This study reports on the detection of ESR1 mutations in breast cancer patients using liquid biopsy, showing their frequency and co-occurring mutations.

Contribution

The paper provides real-world data on ESR1 mutation detection in a clinical setting using two NGS platforms.

Findings

ESR1 mutations were found in 29.1% of 141 analyzed cases.

The most common ESR1 variant was p.Asp538Gly, and co-mutations with PIK3CA and TP53 were frequent.

No significant difference in mutation frequency was found between the two NGS panels.

Abstract

Activating mutations in the ESR1 gene are a known mechanism of secondary resistance to endocrine therapy in metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancers. Liquid biopsy has become a non-invasive tool for molecularly characterizing these neoplasms and allows for dynamic monitoring through the analysis of circulating tumor DNA (ctDNA).

We analyzed 161 plasma samples from patients with metastatic ER+/HER2− breast cancer who had previously undergone treatment with endocrine therapy and CDK4/6 inhibitors. ESR1 mutation analysis was performed using two NGS panels: Oncomine™ Breast cfDNA Assay v2 (n = 102) and Oncomine™ Precision Assay GX (n = 59). The sensitivity threshold (Limit of Detection - LOD) for variant detection was set at ≤0.5 %.

Twenty-one samples (12.4 %) did not meet the quality criteria for ESR1 analysis. ESR1 mutations were identified in 29.1 % (n = 41) of the remaining 141 cases. The most frequent ESR1 variant was the p.Asp538Gly (53.7 %). Multiple ESR1 mutations were observed in 29.3 % of mutated cases, and co-mutations were detected in 61 % of cases, mainly with PIK3CA (36.6 %) and TP53 (12.2 %). The median variant allele frequency (VAF) of ESR1 mutations was 1.46 %. No statistically significant difference in mutation frequency emerged between the two panels (p = 0.6993).

ESR1 mutations are detectable in approximately one-third of ER+/HER2− metastatic patients undergoing liquid biopsy. NGS platforms allow for sensitive and in-depth analysis, highlighting co-mutations of potential clinical and therapeutic relevance.

Figures