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Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases

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Abstract

Purpose

Brain metastases (BM) are a complication of advanced breast cancer (BC). Histology of melanoma BM offers prognostic value; however, understanding the microenvironment of breast cancer brain metastases (BCBM) is less characterized. This study reports on four histological biomarkers, gliosis, immune infiltrate, hemorrhage, necrosis, and their prognostic significance in BCBM.

Methods

A biobank of 203 human tissues from patients who underwent craniotomy for BCBM was created across four academic institutions. Degree of gliosis, immune infiltrate, hemorrhage, and necrosis were identified and scored via representative H&E stain (0–3+). Overall survival (OS) was estimated using the Kaplan–Meier method. Cox proportional hazards regression evaluated prognostic value of the biomarkers in the context of standard clinical characteristics.

Results

BCBM subtype (available for n = 158) was 36% Her2+, 26% hormone receptor (HR)+/Her2− 38% HR−/Her2− (triple negative, TN). Gliosis was observed in 82% (116/141) of BCBM, with immune infiltrate 44% (90/201), hemorrhage 82% (166/141), and necrosis 87% (176/201). Necrosis was significantly higher in TNBC (p < 0.01). Presence of gliosis, immune infiltrate, and hemorrhage correlated with improved OS (p = 0.03, p = 0.03, p = 0.1), while necrosis correlated with inferior OS (p = 0.01). Improved OS was associated with gliosis in TN (p = 0.02), and immune infiltrate (p = 0.001) and hemorrhage (p = 0.07) in HER2+. In a multivariable model for OS, incorporating these biomarkers with traditional clinical variables improved the model fit (p < 0.001).

Conclusion

Gliosis confers superior prognosis in TNBC BM; immune infiltrate and hemorrhage correlate with superior prognosis in HER2+ BCBM. Understanding the metastatic microenvironment of BCBM refines prognostic considerations and may unveil novel therapeutic strategies.

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References

  1. Tabouret E, Chinot O, Metellus P, Tallet A, Viens P, Goncalves A (2012) Recent trends in epidemiology of brain metastases: an overview. Anticancer Res 32(11):4655–4662

    PubMed  Google Scholar 

  2. Sperduto PW, Kased N, Roberge D, Chao ST, Shanley R, Luo X et al (2013) The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer. J Neurooncol 112(3):467–472

    Article  PubMed  Google Scholar 

  3. Hamilton R, Krauze M, Romkes M, Omolo B, Konstantinopoulos P, Reinhart T et al (2013) Pathologic and gene expression features of metastatic melanomas to the brain. Cancer 119(15):2737–2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vaz-Luis I, Seah D, Olson EM, Wagle N, Metzger-Filho O, Sohl J et al (2013) Clinicopathological features among patients with advanced human epidermal growth factor-2-positive breast cancer with prolonged clinical benefit to first-line trastuzumab-based therapy: a retrospective cohort study. Clin Breast Cancer 13(4):254–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Duchnowska R, Peksa R, Radecka B, Mandat T, Trojanowski T, Jarosz B et al (2016) Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res 18(1):43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M et al (2016) Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17(7):976–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM et al (2014) Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci USA 111(3):984–989

    Article  CAS  PubMed  Google Scholar 

  8. Gril B, Paranjape AN, Woditschka S, Hua E, Dolan EL, Hanson J et al (2018) Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases. Nat Commun 9(1):2705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lyle LT, Lockman PR, Adkins CE, Mohammad AS, Sechrest E, Hua E et al (2016) Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin Cancer Res 22(21):5287–5299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by the NIH/NCI K23 (CKA) and NIH 5K23CA157728-05.

Author information

Author notes

  1. Maria J. Sambade and Grace Prince shared co-first authorship.

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Maria J. Sambade, Allison M. Deal, Amy Garrett, Matthew Ewend, Lisa A. Carey, Stergios J. Moschos, Benjamin Vincent & Carey Anders

  2. Department of Medicine, University of North Carolina, 170 Manning Drive, CB#7305 Physician’s Office Building, 3119, Chapel Hill, NC, 27599-7305, USA

    Grace Prince, Lisa A. Carey, Stergios J. Moschos, Benjamin Vincent & Carey Anders

  3. Department of Pathology, University of North Carolina, Chapel Hill, NC, USA

    Dimitri Trembath & Bentley Midkiff

  4. Atlanta Cancer Care, Atlanta, Georgia

    Megan McKee

  5. Medical University of South Carolina, Charleston, SC, USA

    Kevin Keith

  6. Department of Pediatric Oncology, University of North Carolina, Chapel Hill, NC, USA

    Juanita Ramirez

  7. Eli Lilly, Indianapolis, IN, USA

    Kimberly Blackwell

  8. Duke Cancer Institute, Duke University, Durham, NC, USA

    Sarah Sammons

  9. Department of Medicine, Dana Farber Cancer Institute, Boston, MA, USA

    Jose Pablo Leone

  10. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Adam Brufsky

  11. Department of Medicine, University of Michigan, Ann Arbor, MI, USA

    Aki Morikawa

  12. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Edi Brogi

  13. Division of Breast Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew Seidman

  14. Department of Neurosurgery, University of North Carolina, Chapel Hill, NC, USA

    Matthew Ewend

  15. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    Ronald L. Hamilton

Authors
  1. Maria J. Sambade
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  2. Grace Prince
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  3. Allison M. Deal
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  4. Dimitri Trembath
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  5. Megan McKee
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  6. Amy Garrett
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  7. Kevin Keith
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  8. Juanita Ramirez
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  9. Bentley Midkiff
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  10. Kimberly Blackwell
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  11. Sarah Sammons
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  12. Jose Pablo Leone
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  13. Adam Brufsky
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  14. Aki Morikawa
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  15. Edi Brogi
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  16. Andrew Seidman
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  17. Matthew Ewend
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  18. Lisa A. Carey
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  19. Stergios J. Moschos
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  20. Ronald L. Hamilton
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  21. Benjamin Vincent
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  22. Carey Anders
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Corresponding author

Correspondence to Carey Anders.

Ethics declarations

Conflict of interest

Adam Brufksy is a consultant for Lilly, Amgen, Hexal, Novartis, Roche, Pfizer, Immunomedics, Eisai, and Celgene, and owns stock in Bioarray Technologies. Kimberly Blackwell is employed by Lilly. Jose Pablo Leone receives research funding from Merck. Aki Morikawa receives research funding from Lilly, Genentech, Novartis, Merrimack, and Bayer. Matthew Ewend owns stock in Falcon Therapeutics. Carey Anders is an uncompensated consultant/advisory board member for Novartis, Merrimack, Lily, Nektar, Cascadian, Seattle Genetics, and Genentech, a compensated consultant/advisory board member for Merck, PUMA, and Eisai, receives unrelated research funding from Novartis, Merrimack, PUMA, Lily, Merck, Cascadian, Seattle Genetics, Nektar, Tesaro, and G1-Therapeutics, and receives honoraria from UptoDate and Jones and Bartlett Publishing. The other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Ethical standard

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent or waiver of consent granted by local IRB was obtained from all individual participants included in the study.

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Sambade, M.J., Prince, G., Deal, A.M. et al. Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases. Breast Cancer Res Treat 176, 321–328 (2019). https://doi.org/10.1007/s10549-019-05211-1

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  • DOI: https://doi.org/10.1007/s10549-019-05211-1

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