Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.
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Authors
Paoletti, Costanza
Schiavon, Gaia
Dolce, Emily M
Darga, Elizabeth P
Carr, T Hedley
Geradts, Joseph
Hoch, Matthias
Klinowska, Teresa
Lindemann, Justin
Marshall, Gayle
Morgan, Shethah
Patel, Parul
Rowlands, Vicky
Sathiyayogan, Nitharsan
Aung, Kimberly
Hamilton, Erika
Patel, Manish
Armstrong, Anne
Jhaveri, Komal
Im, Seock-Ah
Iqbal, Nadia
Butt, Fouziah
Dive, Caroline
Harrington, Elizabeth A
Barrett, J Carl
Hayes, Daniel F
Publication Date
2018-12-01Journal Title
Clin Cancer Res
ISSN
1078-0432
Publisher
American Association for Cancer Research (AACR)
Volume
24
Issue
23
Pages
5860-5872
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., et al. (2018). Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.. Clin Cancer Res, 24 (23), 5860-5872. https://doi.org/10.1158/1078-0432.CCR-18-1569
Abstract
PURPOSE: 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 (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: 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 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five 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.
Keywords
Humans, Breast Neoplasms, Neoplasm Metastasis, Estrogen Antagonists, Estrogen Receptor alpha, Antineoplastic Agents, Hormonal, Neoplasm Staging, Prognosis, Immunohistochemistry, Drug Resistance, Neoplasm, Mutation, Female, Kaplan-Meier Estimate, Biomarkers, Tumor, Liquid Biopsy, Circulating Tumor DNA
Identifiers
External DOI: https://doi.org/10.1158/1078-0432.CCR-18-1569
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285383
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