Breast cancer subtype and intracranial recurrence patterns after brain-directed radiation for brain metastases
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.
KeywordsBreast 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.
- 6.Sanna G, Franceschelli L, Rotmensz N et al (2007) Brain metastases in patients with advanced breast cancer. Anticancer Res 27:2865–2869Google 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle Scholar