Authors:
C Paoletti, G Schiavon, EM Dolce, EP Darga, TH Carr, J Geradts, M Hoch, T Klinowska, JPO Lindemann, G Marshall, S Morgan, P Patel, V Rowlands, N Sathiyayogan, K Aung, EP Hamilton, MR Patel, AC Armstrong, K Jhaveri, S-A Im, N Iqbal, F Butt, C Dive, EA Harrington, JC Barrett, RD Baird, DF Hayes
Journal name: 
Clin Cancer Res
Abstract: 
BACKGROUND: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER) positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERDs). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) were explored as potential non-invasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. METHODS: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch® in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11/43 (25%) patients had ≥5CTC/7.5mL whole blood (WB), none of whom underwent reduction to <5CTC/7.5mL WB on C1D15. 5/11 patients had baseline CTC-ER+, 2 of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5CTC/7.5mL WB pre-treatment had worse progression-free survival (PFS) than patients with <5CTC (p=0.0003). Fourteen of 45 (31%) patients had ESR1LBDm+ ctDNA at baseline, 5 of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm+ ctDNA at C1D15 had worse PFS than patients who did not (p=0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
DOI: 
http://doi.org/10.1158/1078-0432.CCR-18-1569
E-pub date: 
31 Jul 2018