41MO - ESR1 mutation in untreated endometrial cancer: Prevalence, characteristics and prognostic implications from the UTOLA trial

Background

Aromatase inhibitors (AIs) are a therapeutic option for estrogen receptor (ER)-positive endometrial cancer (EC) especially for low-grade endometrioid EC. ESR1 somatic mutations result in constitutive ligand-independent activation of ER and resistance to AIs in pts with breast cancer (BC). In BC, these mutations are rare at diagnosis (<1%) but are acquired in up to 36% of cases that become resistant to AIs. Here, we aimed to describe the prevalence of ESR1 mutations (ESR1m) in a cohort of treatment naïve EC samples and correlate it with molecular profile, ER expression and outcomes.

Methods

147 patients (pts) with relapsed/metastatic EC and controlled after first-line platinum chemotherapy were recruited into the academic UTOLA trial. Archival EC FFPE tumor tissues were subjected to large panel sequencing encompassing 127 genes and including the ESR1 gene. Only hotspot mutations in the ligand-binding domain (LBD) and reported in BC were considered. All tumors were defined as POLE, MMRd, TP53mut or NSMP according to the PROMISE classification.

Results

137/147 (93%) pts had enough tumor material for sequencing. Eight tumors (6%) harbored a pathogenic ESR1m, including Y537S/C/N (N=4), L536H/P (N=2) and E380Q (N=2). All ESR1m cases had low grade endometrioid histology, were ER-positive and classified as NSMP. Among the 43 pts with metastatic endometrioid NSMP EC, 19% (8/43) were ESR1m in archival treatment naïve tumor tissue. When comparing outcomes, overall survival was similar in pts with ESR1m EC compared to pts with ESR1-wt NSMP EC (median not achieved versus 25.3 months, p=0.114).

Conclusions

Our data suggest that activating mutations in the LBD of ESR1 are frequent among EC tumors traditionally considered good candidates for hormonal therapy, detected in almost 20% of pts with relapsed/metastatic low grade endometrioid NSMP EC. Importantly, these ESR1 mutations were found in treatment naïve archival tissue. ESR1-mutated EC are unlikely to benefit from AIs, thus we would advocate that ESR1 mutational status should be considered in the selection of a hormonal agent and a stratification factor in trials of AIs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Blanc-Durand: Other, Personal, Invited Speaker, Travel expenses: GSK; Non-Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo, Sutro; Financial Interests, Personal, Advisory Role: Eisai; Non-Financial Interests, Institutional, Product Samples: Cyclacel. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen, Eisai, AstraZeneca, Seagen, MSD, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Exact Sciences, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Non-Financial Interests, Personal, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi Sankyo, MSD. F. Selle: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, GSK/Tesaro, Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, GSK/Tesaro. P. Follana: Financial Interests, Personal, Invited Speaker: GSK, Eisai, MSD; Financial Interests, Personal, Expert Testimony: Clovis, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Congress invitation: Gilead. J. Alexandre: Financial Interests, Personal, Advisory Board: Eisai, MSD, GSK, Janssen, Pfizer; Financial Interests, Personal, Invited Speaker: Eisai, MSD, AstraZeneca, GSK, Novartis; Financial Interests, Institutional, Research Grant: Janssen, GSK, MSD; Financial Interests, Institutional, Invited Speaker: MSD, Eisai, Agenus, GSK, Immunogen, Incyte. F. Joly Lobbedez: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, MSD, Janssen, Ipsen, Bayer, Astellas, Eisai, Seagen, Novocure, Pfizer; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, MSD, Janssen, Ipsen, Amgen, Novartis/3A, Eisai, Amgen, Eisai; Financial Interests, Institutional, Invited Speaker: Viatris, GSK, AstraZeneca; Financial Interests, Institutional, Research Grant: BMS, Astellas; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Personal, Member: GCIG; Other, Personal, Travel and Congress: MSD, Ipsen, Chugai; Other, Personal, Other, travel: GSK, Eisai. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering Committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AstraZeneca, Clovis, Ability Pharma, MSD, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Other, consultancy: Owkin; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AstraZeneca; Financial Interests, Institutional, Funding, CI clinical trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AstraZeneca; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC Chair: Pfizer; Non-Financial Interests, Personal, Member: GCIG. All other authors have declared no conflicts of interest.