Abstract 926: ESR1 mutations evolve during the treatment of metastatic breast cancer, and detection in ctDNA predicts sensitivity to subsequent hormone therapy

Abstract

Abstract Purpose: Mutations in the estrogen receptor gene (ESR1) have recently been described as a major mechanism of resistance to aromatase inhibitor (AI) therapy. We utilised digital PCR circulating tumour DNA (ctDNA) assays to investigate the clinical significance and origin of ESR1 mutations in advanced breast cancer (BC). Methods: Multiplex Digital PCR assays were optimised for hotspot mutations in the ESR1 ligand binding domain (LBD), and plasma samples assayed from a cohort of 171 women with advanced BC. All plasma samples were taken off treatment, at disease progression. A separate cohort of recurrent tumour biopsies from ER positive BC patients pre-treated with AI was analysed for validation. Results: ESR1 mutations were detected in the plasma of 14% (18/128) women with advanced ER positive and in 0% (0/43, p = 0.0074) women with advanced ER negative BC. ESR1 ctDNA analysis had 97% agreement (p = 0.0009) with contemporaneous recurrent tissue biopsies, and there was 100% agreement (p<0.0001) between technical repeat plasma samples. ESR1 mutations were shown to be polyclonal in 21% of ESR1 mutant patients, and apparently monoclonal in the remaining 79% patients. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy, both for AI given after disease progression (p = 0.008; HR 3.711, 95%CI 1.995-76.94) and including AI maintenance therapy (p = 0.0041; HR 3.068, 95%CI 1.867-23.08). The prevalence of ESR1 mutations differed markedly between cancers exposed to AI during the adjuvant and metastatic settings (5.8% vs 36.4% respectively, p = 0.0002). In an independent cohort of patients with recurrent breast cancer, ESR1 mutations were identified in 0% (0/32) tumour biopsies taken after progression on adjuvant AI. In patients with serial samples taken during metastatic treatment, ESR1 mutations were shown to be selected through AI therapy, supporting our observation that ESR1 mutations are acquired during the metastatic treatment of BC. Conclusions: ESR1 mutations can be robustly identified with ctDNA analysis, and predict for resistance to subsequent aromatase inhibitor therapy. ESR1 mutations are rarely acquired during adjuvant AI therapy, but are commonly selected by therapy for metastatic disease, providing evidence that the mechanisms of resistance to targeted therapy may be substantially different between the treatment of micro-metastatic and overt metastatic cancer. Citation Format: Gaia Schiavon, Sarah Hrebien, Isaac Garcia-Murillas, Alex Pearson, Noelia Tarazona, Elena Lopez-Knowles, Ricardo Ribas, Ashutosh Nerurkar, Peter Osin, Lesley-Ann Martin, Mitch Dowsett, Ian E. Smith, Nicholas C. Turner. ESR1 mutations evolve during the treatment of metastatic breast cancer, and detection in ctDNA predicts sensitivity to subsequent hormone therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2015-926