Abstract LB-069: ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials
Authors: O’Leary Ben , Fribbens Charlotte , Kilburn Lucy , Hrebein Sarah , Garcia-Murillas Isaac , Beaney Matthew , Cristofanilli Massimo , Andre Fabrice , Loi Sherene , Loibl Sibylle , Jiang John , Huang Bartlett Cynthia , Koehler Maria , Dowsett Mitch , Bliss Judith , Johnston Stephen , Turner Nicholas 
Published: July 2016

Abstract
Background. ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy for advanced breast cancer. We addressed the impact of ESR1 mutations on sensitivity to standard therapies in SoFEA and PALOMA3, two phase III randomised trials that represent the trends in the current therapy for estrogen receptor positive advanced breast cancer.
Methods. We assessed plasma DNA ESR1 mutations in the SoFEA trial that compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to non-steroidal AI, and in the PALOMA3 trial that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression on prior endocrine therapy. We developed and validated multiplex digital droplet PCR assays to detect ESR1 mutations in circulating free DNA. Plasma had been immediately processed in PALOMA3 but there was a delay of up to 9 days before processing of EDTA samples in the SoFEA trial.
Results. In SoFEA we demonstrated that delayed processing of plasma samples had no effect on detection rate of ESR1 mutations (p = 0.71), which were found in 39.1%(63/161) patients. Patients with ESR1 mutations had improved progression free survival (PFS) on fulvestrant compared to exemestane (HR = 0.52, 95%CI 0.30 to 0.92, p = 0.02), while patients with wild type ESR1 had similar PFS on either treatment (HR = 1.07, 95%CI 0.68 to 1.67, p = 0.77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3%(91/360) patients. ESR1 mutations were almost exclusively found in patients with prior AI exposure with or without tamoxifen, and were very rare with prior tamoxifen exposure only (28.9% (90/311) versus 2.0% (1/49) respectively, p&lt;0.001). ESR1 mutations were strongly associated with sensitivity to prior
endocrine therapy (sensitive to prior endocrine therapy, 29.8% (85/285) versus resistant 8.0% (6/75), p&lt;0.001), bone metastases (p = 0.001), prior lines of therapy for metastatic disease (p = 0.01), and with a trend towards ER and PR positive disease as opposed to ER positive but PR negative disease. Fulvestrant plus palbociclib improved PFS compared to fulvestrant plus placebo in both ESR1 mutant (HR = 0.43, 95%CI 0.25 to 0.74, p = 0.002) and ESR1 wild type patients (HR = 0.49 95%CI 0.35 to 0.70, p&lt;0.001). ESR1 mutations were polyclonal in up to 49% of patients, with outcome on fulvestrant similar for polyclonal and monoclonal mutations. In an exploratory analysis there was no association between specific mutations and outcome on fulvestrant.
Conclusions. ESR1 mutation analysis in plasma after progression on prior AI therapy has clinical utility in directing choice of further endocrine therapy.
Citation Format: Ben O’Leary, Charlotte Fribbens, Lucy Kilburn, Sarah Hrebein, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith Bliss, Stephen Johnston, Nicholas Turner. ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-069.