Skip to main content

Advertisement

SpringerLink
Log in

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

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 25 May 2019

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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. https://doi.org/10.1001/jamaoncol.2018.0813

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vuong DA, Rades D, Vo SQ, Busse R (2011) Extracranial metastatic patterns on occurrence of brain metastases. J Neurooncol 105:83–90. https://doi.org/10.1007/s11060-011-0563-z

    Article  CAS  PubMed  Google Scholar 

  3. Nayak L, Lee EQ, Wen PY (2012) Epidemiology of brain metastases. Curr Oncol Rep 14:48–54. https://doi.org/10.1007/s11912-011-0203-y

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1200/JCO.2008.19.8481

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1002/cncr.23930

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sanna G, Franceschelli L, Rotmensz N et al (2007) Brain metastases in patients with advanced breast cancer. Anticancer Res 27:2865–2869

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11060-013-1083-9

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1001/jamaoncol.2017.0001

    Article  PubMed  PubMed Central  Google Scholar 

  9. Corona SP, Sobhani N, Ianza A et al (2017) Advances in systemic therapy for metastatic breast cancer: future perspectives. Med Oncol 34:119. https://doi.org/10.1007/s12032-017-0975-5

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1200/JCO.2006.09.9861

    Article  CAS  PubMed  Google Scholar 

  11. Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655. https://doi.org/10.1158/1078-0432.CCR-06-2478

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0140-6736(16)32616-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/s13058-015-0665-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S1470-2045(17)30441-2

    Article  PubMed  PubMed Central  Google Scholar 

  15. Aoyama H (2011) Radiation therapy for brain metastases in breast cancer patients. Breast Cancer 18:244–251. https://doi.org/10.1007/s12282-010-0207-8

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1001/jama.2016.9839

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hall WA, Djalilian HR, Nussbaum ES, Cho KH (2000) Long-term survival with metastatic cancer to the brain. Med Oncol 17:279–286

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s10549-014-3090-8

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1186/s12885-018-4371-0

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s11060-018-2805-9

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/jjco/hyu126

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.4048/jbc.2015.18.1.29

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1700/1217.13502

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1093/annonc/mdn283

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1186/1748-717X-8-64

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1001/jama.2016.9839

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.radonc.2018.01.005

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11060-012-0976-3

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11060-015-2014-8

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1186/1748-717X-9-105

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.adro.2017.11.003

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1259/bjr.20180365

    Article  Google Scholar 

  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. https://doi.org/10.1159/000286281

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1056/NEJMoa1809615

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ijrobp.2018.08.056

    Article  Google Scholar 

  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. https://doi.org/10.1001/jamaoncol.2016.5630

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/bjc.2016.34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Daniel N. Cagney and Nayan Lamba have contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA

    Daniel N. Cagney, Sofia Montoya, Puyao Li, Luke Besse, Allison M. Martin, Rachel H. Brigell, Shyam K. Tanguturi, Daphne A. Haas-Kogan, Brian M. Alexander & Ayal A. Aizer

  2. Harvard Medical School, Boston, MA, USA

    Nayan Lamba

  3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Paul J. Catalano

  4. Department of Biostatistics, and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Paul J. Catalano

  5. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

    Paul D. Brown

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Jose P. Leone & Nancy U. Lin

Authors
  1. Daniel N. Cagney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nayan Lamba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofia Montoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Puyao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luke Besse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Allison M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rachel H. Brigell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul J. Catalano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul D. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jose P. Leone
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shyam K. Tanguturi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daphne A. Haas-Kogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Brian M. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nancy U. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ayal A. Aizer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel N. Cagney.

Ethics declarations

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cagney, D.N., Lamba, N., Montoya, S. et al. Breast cancer subtype and intracranial recurrence patterns after brain-directed radiation for brain metastases. Breast Cancer Res Treat 176, 171–179 (2019). https://doi.org/10.1007/s10549-019-05236-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05236-6

Keywords

Search

Navigation