Data from Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients

Abstract

<div>Abstract<p><b>Purpose:</b> Given the clinical relevance of <i>ESR1</i> mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of <i>ESR1</i> mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA).</p><p><b>Experimental Design:</b> Six <i>ESR1</i> mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (<i>n</i> = 43), bone (<i>n</i> = 12) and brain metastases (<i>n</i> = 38), and cfDNA (<i>n</i> = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed.</p><p><b>Results:</b> <i>ESR1</i> mutations were detected for D538G (<i>n</i> = 13), Y537S (<i>n</i> = 3), and Y537C (<i>n</i> = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one <i>ESR1</i> mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (<i>n</i> = 5), mutations were detected in both (<i>n</i> = 3) or in cfDNA only (<i>n</i> = 2). Treatment was associated with changes in <i>ESR1</i> mutation detection and allele frequency.</p><p><b>Conclusions:</b> <i>ESR1</i> mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare <i>ESR1</i>-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of <i>ESR1</i> mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. <i>Clin Cancer Res; 22(5); 1130–7. ©2015 AACR</i>.</p><p><i>See related commentary by Gu and Fuqua, p. 1034</i></p></div>