Introduction/Background Endocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of anti-aromatase (AA) resistance in HR+ metastatic breast cancer and can be monitored using circulating tumor DNA (ctDNA). The aim of this study was to explore the incidence of circulating ESR1 mutations in patients treated by AA or megestrol acetate (M) for advanced endometrial carcinoma.

Methodology This single-center retrospective study was performed at the Henri Becquerel Center (Rouen) and looked for circulating ESR1 gene mutations by droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) in patients with advanced HR+ endometrial carcinoma treated between 2008 and 2020 for at least 30 days by AA or M. Timepoints were before exposure and at progression/during endocrine therapy.

Results 22 patients were included: 13 were treated with AA, 12 of whom progressed; 9 patients were treated with M, 8 of whom progressed. 68.1% of the patients had low-grade endometrial carcinoma and 54.5% had received chemotherapy in the metastatic setting. The median duration of treatment was 106 days (min 47 – max 358) with AA and 132 days (min 91-max 272) with M. Under AA, there was no ESR1 mutation at baseline, and one Y537C mutation at progression with a variant allele frequency (VAF) of 0.14%. Under M, one patient had a Y537C (VAF 0.2%) at baseline that disappeared during treatment. Another patient had a Y537S mutation emergence at progression after 91 days of treatment (VAF 1.83%). There was no significant difference between the circulating DNA concentration before and after hormone therapy (p = 0.16).

Conclusion ESR1 mutations do not seem to be involved in the mechanisms of resistance to AA or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated.