Breast cancer subtype and intracranial recurrence patterns after brain-directed radiation for brain metastases

  • Daniel N. CagneyEmail author
  • Nayan Lamba
  • Sofia Montoya
  • Puyao Li
  • Luke Besse
  • Allison M. Martin
  • Rachel H. Brigell
  • Paul J. Catalano
  • Paul D. Brown
  • Jose P. Leone
  • Shyam K. Tanguturi
  • Daphne A. Haas-Kogan
  • Brian M. Alexander
  • Nancy U. Lin
  • Ayal A. Aizer
Clinical trial



Brain metastases from breast cancer are frequently managed with brain-directed radiation but the impact of subtype on intracranial recurrence patterns after radiation has not been well-described. We investigated intracranial recurrence patterns of brain metastases from breast cancer after brain-directed radiation to facilitate subtype-specific management paradigms.


We retrospectively analyzed 349 patients with newly diagnosed brain metastases from breast cancer treated with brain-directed radiation at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Patients were stratified by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), HER2+ positive (HER2+), or triple-negative breast cancer (TNBC). A per-metastasis assessment was conducted. Time-to-event analyses were conducted using multivariable Cox regression.


Of the 349 patients, 116 had HR+/HER2− subtype, 164 had HER2+ subtype, and 69 harbored TNBC. Relative to HR+/HER2− subtype, local recurrence was greater in HER2+ metastases (HR 3.20, 95% CI 1.78–5.75, p < 0.001), while patients with TNBC demonstrated higher rates of new brain metastases after initial treatment (HR 3.16, 95% CI 1.99–5.02, p < 0.001) and shorter time to salvage whole brain radiation (WBRT) (HR 3.79, 95% CI 1.36–10.56, p = 0.01) and salvage stereotactic radiation (HR 1.86, 95% CI 1.11–3.10, p = 0.02).


We identified a strong association between breast cancer subtype and intracranial recurrence patterns after brain-directed radiation, particularly local progression for HER2+ and distant progression for TNBC patients. If validated, the poorer local control in HER2+ brain metastases may support evaluation of novel local therapy-based approaches, while the increased distant recurrence in TNBC suggests the need for improved systemic therapy and earlier utilization of WBRT.


Breast cancer Brain metastases Recurrence Subtype HER2 Radiation 


Compliance with ethical standards

Conflict of interest

Daniel N. Cagney is a recipient of research support from NH Theraguix. Paul Brown reports personal fees from UpToDate (current) and personal fees as DSMB member Novella Clinical (2016) outside the submitted work. Dr. Leone reports that the institution (University of Iowa) received research funding from Merck. Dr. Leone reports funding from Kazia, Lilly, and Seattle Genetics. Daphne A. Haas-Kogan is advisory board member for Cellworks and reports clinical trial support from Novartis. Dr. Lin reports research grants from Pfizer, Genentech/Roche, Novartis, Seattle Genetics, and consulting fees from Pfizer, Genentech/Roche, Novartis, Seattle Genetics, Daichii, and Puma. Dr Alexander reports personal fees from Foundation Medicine, AbbVie, Schlesinger Associates, Bristol Myers Squibb, Precision Health Economics; grants from Puma, Celgene, Eli Lilly outside the submitted work. Dr. Aizer reports research funding from Varian Medical Systems and consulting fees from Novartis. The remaining authors declare no conflict of interest.

Research involving human participants and/or animals

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

Supplementary material

10549_2019_5236_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)


  1. 1.
    Cagney DN, Martin AM, Catalano PJ et al (2018) Implications of screening for brain metastases in patients with breast cancer and non-small cell lung cancer. JAMA Oncol 4:1001. CrossRefGoogle Scholar
  2. 2.
    Vuong DA, Rades D, Vo SQ, Busse R (2011) Extracranial metastatic patterns on occurrence of brain metastases. J Neurooncol 105:83–90. CrossRefGoogle Scholar
  3. 3.
    Nayak L, Lee EQ, Wen PY (2012) Epidemiology of brain metastases. Curr Oncol Rep 14:48–54. CrossRefGoogle Scholar
  4. 4.
    Leyland-Jones B (2009) Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol 27:5278–5286. CrossRefGoogle Scholar
  5. 5.
    Lin NU, Claus E, Sohl J et al (2008) Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 113:2638–2645. CrossRefGoogle Scholar
  6. 6.
    Sanna G, Franceschelli L, Rotmensz N et al (2007) Brain metastases in patients with advanced breast cancer. Anticancer Res 27:2865–2869Google Scholar
  7. 7.
    Sperduto PW, Kased N, Roberge D 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 112:467–472. CrossRefGoogle Scholar
  8. 8.
    Martin AM, Cagney DN, Catalano PJ et al (2017) Brain metastases in newly diagnosed breast cancer: a population-based study. JAMA Oncol 3:1069–1077. CrossRefGoogle Scholar
  9. 9.
    Corona SP, Sobhani N, Ianza A et al (2017) Advances in systemic therapy for metastatic breast cancer: future perspectives. Med Oncol 34:119. CrossRefGoogle Scholar
  10. 10.
    Muldoon LL, Soussain C, Jahnke K et al (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol 25:2295–2305. CrossRefGoogle Scholar
  11. 11.
    Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655. CrossRefGoogle Scholar
  12. 12.
    Cameron D, Piccart-Gebhart MJ, Gelber RD et al (2017) 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389:1195–1205. CrossRefGoogle Scholar
  13. 13.
    Witzel I, Oliveira-Ferrer L, Pantel K et al (2016) Breast cancer brain metastases: biology and new clinical perspectives. Breast Cancer Res 18:8. CrossRefGoogle Scholar
  14. 14.
    Brown PD, Ballman KV, Cerhan JH et al (2017) Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 18:1049–1060. CrossRefGoogle Scholar
  15. 15.
    Aoyama H (2011) Radiation therapy for brain metastases in breast cancer patients. Breast Cancer 18:244–251. CrossRefGoogle Scholar
  16. 16.
    Brown PD, Jaeckle K, Ballman KV et al (2016) Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316:401–409. CrossRefGoogle Scholar
  17. 17.
    Hall WA, Djalilian HR, Nussbaum ES, Cho KH (2000) Long-term survival with metastatic cancer to the brain. Med Oncol 17:279–286CrossRefGoogle Scholar
  18. 18.
    Niikura N, Hayashi N, Masuda N et al (2014) Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis. Breast Cancer Res Treat 147:103–112. CrossRefGoogle Scholar
  19. 19.
    Jin J, Gao Y, Zhang J et al (2018) Incidence, pattern and prognosis of brain metastases in patients with metastatic triple negative breast cancer. BMC Cancer 18:446. CrossRefGoogle Scholar
  20. 20.
    Darlix A, Griguolo G, Thezenas S et al (2018) Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer. J Neurooncol 138:369–382. CrossRefGoogle Scholar
  21. 21.
    Kuba S, Ishida M, Nakamura Y et al (2014) Treatment and prognosis of breast cancer patients with brain metastases according to intrinsic subtype. Jpn J Clin Oncol 44:1025–1031. CrossRefGoogle Scholar
  22. 22.
    Chong JU, Ahn SG, Lee HM et al (2015) Local control of brain metastasis: treatment outcome of focal brain treatments in relation to subtypes. J Breast Cancer 18:29–35. CrossRefGoogle Scholar
  23. 23.
    Fokas E, Henzel M, Hamm K et al (2012) Brain metastases in breast cancer: analysis of the role of HER2 status and treatment in the outcome of 94 patients. Tumori 98:768–774. CrossRefGoogle Scholar
  24. 24.
    Hines SL, Vallow LA, Tan WW et al (2008) Clinical outcomes after a diagnosis of brain metastases in patients with estrogen- and/or human epidermal growth factor receptor 2-positive versus triple-negative breast cancer. Ann Oncol 19:1561–1565. CrossRefGoogle Scholar
  25. 25.
    Kress MA, Oermann E, Ewend MG et al (2013) Stereotactic radiosurgery for single brain metastases from non-small cell lung cancer: progression of extracranial disease correlates with distant intracranial failure. Radiat Oncol 8:64. CrossRefGoogle Scholar
  26. 26.
    Brown PD, Jaeckle K, Ballman KV et al (2016) Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases a randomized clinical trial. JAMA 316(4):401–409. CrossRefGoogle Scholar
  27. 27.
    Cagney DN, Martin AM, Catalano PJ et al (2018) Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation. Radiother Oncol 126:511–518. CrossRefGoogle Scholar
  28. 28.
    Vern-Gross TZ, Lawrence JA, Case LD et al (2012) Breast cancer subtype affects patterns of failure of brain metastases after treatment with stereotactic radiosurgery. J Neurooncol 110:381–388. CrossRefGoogle Scholar
  29. 29.
    Grubb CS, Jani A, Wu CC et al (2016) Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery. J Neurooncol 127:103–110. CrossRefGoogle Scholar
  30. 30.
    Schuttrumpf LH, Niyazi M, Nachbichler SB et al (2014) Prognostic factors for survival and radiation necrosis after stereotactic radiosurgery alone or in combination with whole brain radiation therapy for 1-3 cerebral metastases. Radiat Oncol 9:105. CrossRefGoogle Scholar
  31. 31.
    Abraham C, Garsa A, Badiyan SN et al (2018) Internal dose escalation is associated with increased local control for non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiosurgery (SRS). Adv Radiat Oncol 3:146–153. CrossRefGoogle Scholar
  32. 32.
    Lux F, Tran VL, Thomas E et al (2018) AGuIX((R)) from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine. Br J Radiol 92(1093):20180365. CrossRefGoogle Scholar
  33. 33.
    Kwon HC, Oh SY, Kim SH et al (2010) Clinical outcomes and breast cancer subtypes in patients with brain metastases. Onkologie 33:146–152. CrossRefGoogle Scholar
  34. 34.
    Schmid P, Adams S, Rugo HS et al (2018) Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108–2121. CrossRefGoogle Scholar
  35. 35.
    Gondi V, Deshmukh S, Brown PD et al (2018) Preservation of neurocognitive function (NCF) with conformal avoidance of the hippocampus during whole-brain radiotherapy (HA-WBRT) for brain metastases: preliminary results of phase III trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys 102:1607. CrossRefGoogle Scholar
  36. 36.
    Priedigkeit N, Hartmaier RJ, Chen Y et al (2017) Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancer brain metastases. JAMA Oncol 3:666. CrossRefGoogle Scholar
  37. 37.
    Thomson AH, McGrane J, Mathew J et al (2016) Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes. Br J Cancer 114:793–800. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Daniel N. Cagney
    • 1
    Email author
  • Nayan Lamba
    • 2
  • Sofia Montoya
    • 1
  • Puyao Li
    • 1
  • Luke Besse
    • 1
  • Allison M. Martin
    • 1
  • Rachel H. Brigell
    • 1
  • Paul J. Catalano
    • 3
    • 4
  • Paul D. Brown
    • 5
  • Jose P. Leone
    • 6
  • Shyam K. Tanguturi
    • 1
  • Daphne A. Haas-Kogan
    • 1
  • Brian M. Alexander
    • 1
  • Nancy U. Lin
    • 6
  • Ayal A. Aizer
    • 1
  1. 1.Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Department of BiostatisticsHarvard T.H. Chan School of Public HealthBostonUSA
  4. 4.Department of Biostatistics, and Computational BiologyDana-Farber Cancer InstituteBostonUSA
  5. 5.Department of Radiation OncologyMayo ClinicRochesterUSA
  6. 6.Department of Medical Oncology, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA

Personalised recommendations