ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials

Nicholas C. Turner*, Claire Swift, Lucy Kilburn, Charlotte Fribbens, Matthew Beaney, Isaac Garcia-Murillas, Aman U. Budzar, John F.R. Robertson, William Gradishar, Martine Piccart, Gaia Schiavon, Judith M. Bliss, Mitch Dowsett, Stephen R.D. Johnston, Stephen K. Chia

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Purpose: ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. Experimental Design: The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. Results: ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P ¼ 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P ¼ 0.69). There was an interaction between ESR1 mutation and treatment (P ¼ 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P ¼ 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P ¼ 0.69). Conclusions: Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.

Original languageEnglish (US)
Pages (from-to)5172-5177
Number of pages6
JournalClinical Cancer Research
Volume26
Issue number19
DOIs
StatePublished - Oct 1 2020

Funding

We thank the patients who participated in the SoFEA and EFECT studies, along with investigators and site staff. SoFEA (NCT00253422) and EFECT (NCT00065325) were supported by AstraZeneca. AstraZeneca provided financial assistance for ESR1 mutational analysis in EFECT. Other funding was provided by Le Cure, Cancer Research UK funding to the ICR Clinical Trials and Statistics Unit, and Breast Cancer Now. support from Cancer Research UK (support with analysis work) during the conduct of the study; grants and non-financial support from AstraZeneca, Merck Sharpe & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen Cilag, and Novartis (previously GSK) outside the submitted work, and grants from Medivation. M. Dowsett reports personal fees from NanoString (lecture fees), Myriad (lecture fees), and Radius (scientific advisory board) outside the submitted work. S.R.D. Johnston reports grants and personal fees from AstraZeneca (speaker honoraria/research funding to institution) during the conduct of the study; grants and personal fees from Pfizer (consultancy/speaker honoraria/research funding to institution), and Eli Lilly (consultancy/research funding to institution), and personal fees from Novartis (consultancy) and Eisai (consultancy) outside the submitted work. S.K. Chia reports grants from AstraZeneca (for conduct of the EFECT trial) and personal fees from AstraZeneca (participation of the advisory board) during the conduct of the study; grants and personal fees from Novartis (participation in advisory board and conduct of clinical trials), Hoffmann LaRoche (participation in advisory board and conduct of clinical trials), Pfizer (participation in advisory board and conduct of clinical trials), and Merck (participation in advisory board and conduct of clinical trials) outside the submitted work. No potential conflicts of interest were disclosed by the other authors. N.C. Turner reports grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Bristol-Myers Squibb, Lilly, Merck Sharpe & Dohme, and Novartis, grants and personal fees from Pfizer, Roche/Genentech, Tesaro, and Bicycle Therapeutics, grants from BioRad and Clovis, and non-financial support from Guardant Health outside the submitted work. J.F.R. Roberston reports grants from AstraZeneca (investigator in the EFECT study) during the conduct of the study; personal fees from AstraZeneca (honoraria from advisory boards and lectures), other from AstraZeneca (expert testimony), grants from AstraZeneca (chief investigator of FIRST and FALCON trials), and other from University of Nottingham (member of DSM of SoFEA trial) outside the submitted work. M. Piccart reports grants and personal fees from Pfizer, AstraZeneca, and Novartis outside the submitted work. G. Schiavon reports other from AstraZeneca (employee) during the conduct of the study. J.M. Bliss reports grants, non-financial support, and other from Astra-Zeneca (supply of study drug, database and financial support) and non-financial

ASJC Scopus subject areas

  • General Medicine

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