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Research Articles

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

Tanya T. Kwan, Aditya Bardia, Laura M. Spring, Anita Giobbie-Hurder, Mark Kalinich, Taronish Dubash, Tilak Sundaresan, Xin Hong, Joseph A. LiCausi, Uyen Ho, Erin J. Silva, Ben S. Wittner, Lecia V. Sequist, Ravi Kapur, David T. Miyamoto, Mehmet Toner, Daniel A. Haber and Shyamala Maheswaran
Tanya T. Kwan
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Aditya Bardia
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
2Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Laura M. Spring
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
2Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Anita Giobbie-Hurder
3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Mark Kalinich
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Taronish Dubash
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Tilak Sundaresan
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Xin Hong
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Joseph A. LiCausi
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Uyen Ho
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Erin J. Silva
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Ben S. Wittner
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
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Lecia V. Sequist
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
2Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Lecia V. Sequist
Ravi Kapur
4Center for Bioengineering in Medicine, Massachusetts General Hospital and Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts.
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David T. Miyamoto
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
5Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Mehmet Toner
4Center for Bioengineering in Medicine, Massachusetts General Hospital and Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts.
6Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Daniel A. Haber
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
2Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
7Howard Hughes Medical Institute, Chevy Chase, Maryland.
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  • For correspondence: dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu
Shyamala Maheswaran
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
6Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu
DOI: 10.1158/2159-8290.CD-18-0432 Published October 2018
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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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received April 23, 2018.
  • Revision received July 7, 2018.
  • Accepted August 8, 2018.
  • Published first August 13, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Discovery: 8 (10)
October 2018
Volume 8, Issue 10
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A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer
Tanya T. Kwan, Aditya Bardia, Laura M. Spring, Anita Giobbie-Hurder, Mark Kalinich, Taronish Dubash, Tilak Sundaresan, Xin Hong, Joseph A. LiCausi, Uyen Ho, Erin J. Silva, Ben S. Wittner, Lecia V. Sequist, Ravi Kapur, David T. Miyamoto, Mehmet Toner, Daniel A. Haber and Shyamala Maheswaran
Cancer Discov October 1 2018 (8) (10) 1286-1299; DOI: 10.1158/2159-8290.CD-18-0432

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A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer
Tanya T. Kwan, Aditya Bardia, Laura M. Spring, Anita Giobbie-Hurder, Mark Kalinich, Taronish Dubash, Tilak Sundaresan, Xin Hong, Joseph A. LiCausi, Uyen Ho, Erin J. Silva, Ben S. Wittner, Lecia V. Sequist, Ravi Kapur, David T. Miyamoto, Mehmet Toner, Daniel A. Haber and Shyamala Maheswaran
Cancer Discov October 1 2018 (8) (10) 1286-1299; DOI: 10.1158/2159-8290.CD-18-0432
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