Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

Florian Clatot (1, 2) , Anne Perdrix (2, 1) , Laetitia Augusto (3, 2, 1) , Ludivine Beaussire (4, 2) , Julien Delacour (4, 2) , Céline Calbrix (2, 1) , David Sefrioui (4, 2) , Pierre-Julien Viailly (2, 1) , Michael Bubenheim (5) , Cristian Moldovan (3) , Cristina Alexandru (3) , Isabelle Tennevet (3) , Olivier Rigal (6, 3) , Cécile Guillemet (7, 3) , Marianne Leheurteur (3) , Sophie Gouérant (8, 3) , Camille Petrau (1, 3) , Jean-Christophe Thery (2, 4) , Jean-Michel Picquenot (1, 2) , Corinne Veyret (9, 3) , Thierry Frébourg (4) , Fabrice Jardin (2, 1) , Nasrin Sarafan-Vasseur (4, 2) , Frédéric Di Fiore (8, 2, 3)

1 GPL - Groupe d'étude des proliférations lymphoïdes
2 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
3 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
4 GMFC - Génétique du cancer et des maladies neuropsychiatriques
5 Unité de Biostatistiques [CHU Rouen]
6 soins de supports
7 Service d'Oncologie Médicale
8 Département d'oncologie médicale [Rouen]
9 Service d'Oncologie médicale [Rouen]

Purpose: To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment.Patients and methods: ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas.Results: Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome.Conclusion: ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

Domaines: Sciences du Vivant [q-bio]

Florian Clatot, Anne Perdrix, Laetitia Augusto, Ludivine Beaussire, Julien Delacour, et al.. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget, 2016, 7 (46), ⟨10.18632/oncotarget.12950⟩. ⟨hal-02353218⟩