Circulating biomarkers and resistance to endocrine therapy in metastatic breast cancers: correlative results from AZD9496 oral SERD Phase I trial

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 (ESR1_LBDm). 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 ESR1_LBDm 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 ESR1_LBDm+ ctDNA at baseline, 5 of whom had ≥2 unique mutations. Baseline ESR1_LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1_LBDm+ 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 ESR1_LBDm+ 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.

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