Intérêt clinique des mutations circulantes d'ESR1 dans le cancer de l’endomètre hormono-dépendant

Introduction : 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. 68.2% of the patients had low-grade endometrial carcinoma and 40.9% had received chemotherapy in the metastatic setting. The median duration of treatment was 152 days (min 47 – max 629) with AA and 155 days (min 91-max 1297) 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 = 0,131). There was a significant difference between CA125 rate before and after hormone therapy (p = 0,003). 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.Introduction : Une hormonothérapie est fréquemment administrée aux patientes atteintes d'un cancer de l'endomètre métastatique hormonodépendant (RH+). Les mutations ESR1 sont apparues comme un mécanisme clé de la résistance aux anti-aromatase (AA) dans le cancer du sein métastatique RH+ et peuvent être surveillées à l'aide de l'ADN tumoral circulant (ADNc). L'objectif de cette étude est d'explorer l'incidence des mutations ESR1 circulantes chez les patientes traitées par AA ou acétate de mégestrol (M) pour un cancer de l'endomètre à un stade avancé. Méthode : Cette étude rétrospective monocentrique a été réalisée au Centre Henri Becquerel (Rouen) et a recherché les mutations circulantes du gène ESR1 par droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) chez les patientes atteintes d'un cancer de l'endomètre avancé RH+ traitées entre 2008 et 2020 pendant au moins 30 jours par AA ou M, avant l'exposition et à progression/pendant l’hormonothérapie. Résultats : 22 patientes ont été incluses : 13 ont été traitées par AA, dont 12 en progression ; 9 patientes ont été traitées par M, dont 8 en progression. 68,2% des patientes avaient un carcinome de l'endomètre de bas grade et 40,9% avaient reçu une chimiothérapie dans un contexte métastatique. La durée médiane du traitement était de 152 jours (min 47 – max 629) sous AA et de 155 jours (min 91-max 1297) sous M. Sous AA, il n'y avait aucune mutation ESR1 à l’initiation et une mutation Y537C apparaît à progression avec une VAF de 0,14%. Sous M, une patiente présentait une mutation Y537C (VAF 0,2 %) à l’initiation, qui a disparu pendant le traitement. Une autre patiente présentait une émergence de la mutation Y537S au moment de la progression après 91 jours de traitement (VAF 1,83 %). Il n'y avait pas de différence significative entre la concentration d'ADNc avant et après l'hormonothérapie (p = 0,131). Il existe une différence significative entre le taux de CA125 avant la mise sous hormonothérapie et à progression (p =0,003) Conclusion : Les mutations ESR1 ne semblent pas être impliquées dans les mécanismes de résistance à l'AA ou au M dans le cancer de l'endomètre RH+. La pertinence clinique de leur détection n'est pas démontrée

Clinical relevance of circulating ESR1 mutations during endocrine therapy for advanced hormone-dependent endometrial carcinoma

Abstract Objective Endocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of aromatase inhibitor (AI) 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 and clinical relevance of circulating ESR1 mutations in patients treated by AI 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 AI or M. Analyses were performed before exposure and at progression/during endocrine therapy. Results Twenty-two patients were included: 13 were treated with AI, 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 152 days (min 47 – max 629) with AI and 155 days (min 91-max 1297) with M. Under AI, 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 AI or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated