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Research Briefs

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Priscilla K. Brastianos, Scott L. Carter, Sandro Santagata, Daniel P. Cahill, Amaro Taylor-Weiner, Robert T. Jones, Eliezer M. Van Allen, Michael S. Lawrence, Peleg M. Horowitz, Kristian Cibulskis, Keith L. Ligon, Josep Tabernero, Joan Seoane, Elena Martinez-Saez, William T. Curry, Ian F. Dunn, Sun Ha Paek, Sung-Hye Park, Aaron McKenna, Aaron Chevalier, Mara Rosenberg, Frederick G. Barker II, Corey M. Gill, Paul Van Hummelen, Aaron R. Thorner, Bruce E. Johnson, Mai P. Hoang, Toni K. Choueiri, Sabina Signoretti, Carrie Sougnez, Michael S. Rabin, Nancy U. Lin, Eric P. Winer, Anat Stemmer-Rachamimov, Matthew Meyerson, Levi Garraway, Stacey Gabriel, Eric S. Lander, Rameen Beroukhim, Tracy T. Batchelor, José Baselga, David N. Louis, Gad Getz and William C. Hahn
Priscilla K. Brastianos
1Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
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  • For correspondence: pbrastianos@partners.org william_hahn@dfci.harvard.edu carter.scott@jimmy.harvard.edu gadgetz@broadinstitute.org
Scott L. Carter
5Broad Institute, Boston, Massachusetts.
6Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • For correspondence: pbrastianos@partners.org william_hahn@dfci.harvard.edu carter.scott@jimmy.harvard.edu gadgetz@broadinstitute.org
Sandro Santagata
7Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
8Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Daniel P. Cahill
9Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Amaro Taylor-Weiner
5Broad Institute, Boston, Massachusetts.
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Robert T. Jones
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
10Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Eliezer M. Van Allen
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
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Michael S. Lawrence
5Broad Institute, Boston, Massachusetts.
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Peleg M. Horowitz
11Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Kristian Cibulskis
5Broad Institute, Boston, Massachusetts.
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Keith L. Ligon
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
8Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Josep Tabernero
12Department of Medical Oncology, Vall d'Hebron University, Barcelona, Spain.
13Department of Pathology, Vall d'Hebron University, Barcelona, Spain.
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Joan Seoane
12Department of Medical Oncology, Vall d'Hebron University, Barcelona, Spain.
13Department of Pathology, Vall d'Hebron University, Barcelona, Spain.
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Elena Martinez-Saez
14Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain.
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William T. Curry
9Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Ian F. Dunn
11Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Sun Ha Paek
15Department of Neurosurgery, Seoul National University College of Medicine, Seoul, South Korea.
16Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
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Sung-Hye Park
15Department of Neurosurgery, Seoul National University College of Medicine, Seoul, South Korea.
16Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
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Aaron McKenna
5Broad Institute, Boston, Massachusetts.
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Aaron Chevalier
5Broad Institute, Boston, Massachusetts.
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Mara Rosenberg
5Broad Institute, Boston, Massachusetts.
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Frederick G. Barker II
9Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Corey M. Gill
3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Paul Van Hummelen
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
10Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Aaron R. Thorner
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
10Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Bruce E. Johnson
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Mai P. Hoang
17Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Toni K. Choueiri
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Sabina Signoretti
8Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Carrie Sougnez
5Broad Institute, Boston, Massachusetts.
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Michael S. Rabin
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Nancy U. Lin
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Eric P. Winer
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Anat Stemmer-Rachamimov
17Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Matthew Meyerson
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
8Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
10Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Levi Garraway
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
6Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Stacey Gabriel
5Broad Institute, Boston, Massachusetts.
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Eric S. Lander
5Broad Institute, Boston, Massachusetts.
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Rameen Beroukhim
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
7Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Tracy T. Batchelor
2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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José Baselga
18Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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David N. Louis
17Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Gad Getz
3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
17Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: pbrastianos@partners.org william_hahn@dfci.harvard.edu carter.scott@jimmy.harvard.edu gadgetz@broadinstitute.org
William C. Hahn
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5Broad Institute, Boston, Massachusetts.
10Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • For correspondence: pbrastianos@partners.org william_hahn@dfci.harvard.edu carter.scott@jimmy.harvard.edu gadgetz@broadinstitute.org
DOI: 10.1158/2159-8290.CD-15-0369 Published November 2015
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Abstract

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.

Significance: Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy. Cancer Discov; 5(11); 1164–77. ©2015 AACR.

See related commentary by Stricker and Arteaga, p. 1124.

This article is highlighted in the In This Issue feature, p. 1111

Footnotes

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

  • Received March 30, 2015.
  • Revision received August 8, 2015.
  • Accepted August 11, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Discovery: 5 (11)
November 2015
Volume 5, Issue 11
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Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
Priscilla K. Brastianos, Scott L. Carter, Sandro Santagata, Daniel P. Cahill, Amaro Taylor-Weiner, Robert T. Jones, Eliezer M. Van Allen, Michael S. Lawrence, Peleg M. Horowitz, Kristian Cibulskis, Keith L. Ligon, Josep Tabernero, Joan Seoane, Elena Martinez-Saez, William T. Curry, Ian F. Dunn, Sun Ha Paek, Sung-Hye Park, Aaron McKenna, Aaron Chevalier, Mara Rosenberg, Frederick G. Barker II, Corey M. Gill, Paul Van Hummelen, Aaron R. Thorner, Bruce E. Johnson, Mai P. Hoang, Toni K. Choueiri, Sabina Signoretti, Carrie Sougnez, Michael S. Rabin, Nancy U. Lin, Eric P. Winer, Anat Stemmer-Rachamimov, Matthew Meyerson, Levi Garraway, Stacey Gabriel, Eric S. Lander, Rameen Beroukhim, Tracy T. Batchelor, José Baselga, David N. Louis, Gad Getz and William C. Hahn
Cancer Discov November 1 2015 (5) (11) 1164-1177; DOI: 10.1158/2159-8290.CD-15-0369

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Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
Priscilla K. Brastianos, Scott L. Carter, Sandro Santagata, Daniel P. Cahill, Amaro Taylor-Weiner, Robert T. Jones, Eliezer M. Van Allen, Michael S. Lawrence, Peleg M. Horowitz, Kristian Cibulskis, Keith L. Ligon, Josep Tabernero, Joan Seoane, Elena Martinez-Saez, William T. Curry, Ian F. Dunn, Sun Ha Paek, Sung-Hye Park, Aaron McKenna, Aaron Chevalier, Mara Rosenberg, Frederick G. Barker II, Corey M. Gill, Paul Van Hummelen, Aaron R. Thorner, Bruce E. Johnson, Mai P. Hoang, Toni K. Choueiri, Sabina Signoretti, Carrie Sougnez, Michael S. Rabin, Nancy U. Lin, Eric P. Winer, Anat Stemmer-Rachamimov, Matthew Meyerson, Levi Garraway, Stacey Gabriel, Eric S. Lander, Rameen Beroukhim, Tracy T. Batchelor, José Baselga, David N. Louis, Gad Getz and William C. Hahn
Cancer Discov November 1 2015 (5) (11) 1164-1177; DOI: 10.1158/2159-8290.CD-15-0369
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