56MO - Landscape of ESR1 mutations in advanced breast cancer using circulating tumor DNA (ctDNA) next-generation sequencing (NGS) in Asia and Middle East (AME)

Background

Endocrine therapy, including aromatase inhibitors (AI), is the foundation of treatment for patients (pts) with estrogen receptor-positive (ER+) advanced breast cancer (ABC). Mutations in ESR1 are a common resistance mechanism to AI. Treatment with emerging selective ER degraders may be effective for patients with ESR1-mutated ABC. Earlier studies {Turner (2020) Lancet Oncol} have demonstrated increased sensitivity and detection rate of ctDNA based NGS in detecting ESR1 mutations compared to ddPCR assays. The prevalence of ESR1 and associated co-alterations using ctDNA NGS in ABC pts from AME is unknown.

Methods

We reviewed results of Guardant360 (Guardant Health, Inc) ordered for patients with ABC in AME as part of routine clinical practice through December 2022. This comprehensive genomic profiling assay identifies single-nucleotide variants, insertions and deletions, fusions, and amplifications. All samples were analyzed by a single CLIA-certified and CAP-accredited laboratory in California. Prescribing physicians did not routinely provide tumor ER status or treatment history when ordering ctDNA NGS.

Results

Among 898 samples analyzed, ctDNA was detected in 796 (88.65%), representing 772 unique ABC pts, all women. Median pt age was 56 years (range 27-87). There were 309 ESR1 mutations detected in 211 (27.3%) patients [NS3]. Most mutations occurred between the hormone receptor and ESR1c domains. Common mutations were Y537 C/D/N/S (42.7%) and D538G (37.5%). Frequently co-mutated genes included PIK3CA (42%), TP53 (38%), GATA3 (26%), BRCA2 (13%), HER2 (10%) and BRCA1 (6.6%). Frequently amplified genes were CCND1 (23%), FGFR1 (22%), EGFR (18%) and PIK3CA (13%). ERBB2 and MET amplifications were each reported in 2% of pts. Two pts each had homozygous deletions in ATM, BRCA2 and CHEK2; another had FGFR2 fusion (FGFR2-KIAA1598).

Conclusions

Comprehensive ctDNA NGS can identify ESR1 mutations along with co-alterations that may inform therapeutic decisions for patients with ABC in AME.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Dawood: Financial Interests, Personal, Advisory Role: Guardant Health. N. Sandhir, S.S. Jain: Financial Interests, Personal, Full or part-time Employment: Guardant Health. All other authors have declared no conflicts of interest.