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Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

Publication ,  Journal Article
Paoletti, C; Schiavon, G; Dolce, EM; Darga, EP; Carr, TH; Geradts, J; Hoch, M; Klinowska, T; Lindemann, J; Marshall, G; Morgan, S; Patel, P ...
Published in: Clin Cancer Res
December 1, 2018

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

December 1, 2018

Volume

24

Issue

23

Start / End Page

5860 / 5872

Location

United States

Related Subject Headings

  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Mutation
  • Liquid Biopsy
  • Kaplan-Meier Estimate
  • Immunohistochemistry
  • Humans
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., … Hayes, D. F. (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
Paoletti, Costanza, Gaia Schiavon, Emily M. Dolce, Elizabeth P. Darga, T Hedley Carr, Joseph Geradts, Matthias Hoch, et al. “Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.Clin Cancer Res 24, no. 23 (December 1, 2018): 5860–72. https://doi.org/10.1158/1078-0432.CCR-18-1569.
Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, et al. Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial. Clin Cancer Res. 2018 Dec 1;24(23):5860–72.
Paoletti, Costanza, et al. “Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.Clin Cancer Res, vol. 24, no. 23, Dec. 2018, pp. 5860–72. Pubmed, doi:10.1158/1078-0432.CCR-18-1569.
Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann J, Marshall G, Morgan S, Patel P, Rowlands V, Sathiyayogan N, Aung K, Hamilton E, Patel M, Armstrong A, Jhaveri K, Im S-A, Iqbal N, Butt F, Dive C, Harrington EA, Barrett JC, Baird R, Hayes DF. Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial. Clin Cancer Res. 2018 Dec 1;24(23):5860–5872.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

December 1, 2018

Volume

24

Issue

23

Start / End Page

5860 / 5872

Location

United States

Related Subject Headings

  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Mutation
  • Liquid Biopsy
  • Kaplan-Meier Estimate
  • Immunohistochemistry
  • Humans
  • Female