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Cancer Discov. 2018 Oct;8(10):1286-1299. doi: 10.1158/2159-8290.CD-18-0432. Epub 2018 Aug 13.

A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
2
Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
4
Center for Bioengineering in Medicine, Massachusetts General Hospital and Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts.
5
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
6
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts. dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu.
8
Howard Hughes Medical Institute, Chevy Chase, Maryland.
#
Contributed equally

Abstract

The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)-derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery (P = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival (P = 0.02), as does persistent CTC signal after 4 weeks of treatment (P = 0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression (P = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer.Significance: Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. Cancer Discov; 8(10); 1286-99. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.

PMID:
30104333
PMCID:
PMC6170694
[Available on 2019-10-01]
DOI:
10.1158/2159-8290.CD-18-0432

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