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

// Florian Clatot 1,2,3 , Anne Perdrix 3,4 , Laetitia Augusto 1 , Ludivine Beaussire 3,5 , Julien Delacour 3,5 , Celine Calbrix 4 , David Sefrioui 3,5,6 , Pierre-Julien Viailly 2 , Michael Bubenheim 7 , Cristian Moldovan 1 , Cristina Alexandru 1 , Isabelle Tennevet 1 , Olivier Rigal 1 , Cecile Guillemet 1 , Marianne Leheurteur 1 , Sophie Gouerant 1 , Camille Petrau 1,3 , Jean-Christophe Thery 1,5 , Jean-Michel Picquenot 1,2,4 , Corinne Veyret 1 , Thierry Frebourg 5 , Fabrice Jardin 2 , Nasrin Sarafan-Vasseur 3,5,* and Frederic Di Fiore 1,3,5,6,* 1 Department of Medical Oncology, Henri Becquerel Centre, Rouen, France 2 INSERM U918, Henri Becquerel Centre, Rouen, France 3 EquIpe de Recherche en Oncologie, Rouen, France 4 Department of Biopathology, Henri Becquerel Centre, Rouen, France 5 INSERM U1079, Faculty of medecine, Rouen, France 6 Department of Gastroenterology, Rouen University Hospital, Rouen, France 7 Department of Biostatistics, Rouen University Hospital, Rouen, France * These authors have contributed equally to the work Correspondence to: Florian Clatot, email: // Keywords : ESR1 mutation, digital PCR, breast cancer, aromatase inhibitor, kinetics Received : October 12, 2016 Accepted: October 24, 2016 Published: October 27, 2016 Abstract 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.