Brain metastasis in breast cancer: a comprehensive literature review

Abstract

This comprehensive review provides information on epidemiology, size, grade, cerebral localization, clinical symptoms, treatments, and factors associated with longer survival in 14,599 patients with brain metastasis from breast cancer; the molecular features of breast cancers most likely to develop brain metastases and the potential use of these predictive molecular alterations for patient management and future therapeutic targets are also addressed. The review covers the data from 106 articles representing this subject in the era of modern neuroimaging (past 35 years). The incidence of brain metastasis from breast cancer (24 % in this review) is increasing due to advances in both imaging technologies leading to earlier detection of the brain metastases and introduction of novel therapies resulting in longer survival from the primary breast cancer. The mean age at the time of breast cancer and brain metastasis diagnoses was 50.3 and 48.8 years respectively. Axillary node metastasis was noted in 32.8 % of the patients who developed brain metastasis. The median time intervals between the diagnosis of breast cancer to identification of brain metastasis and from identification of brain metastasis to death were 34 and 15 months, respectively. The most common symptoms experienced in patients with brain metastasis consisted of headache (35 %), vomiting (26 %), nausea (23 %), hemiparesis (22 %), visual changes (13 %) and seizures (12 %). A majority of the patients had multiple metastases (54.2 %). Cerebellum and frontal lobes were the most common sites of metastasis (33 and 16 %, respectively). Of the primary tumors for which biomarkers were recorded, 37 % were estrogen receptor (ER)+, 41 % ER-, 36 % progesterone receptor (PR)+, 34 % PR-, 35 % human epithelial growth factor receptor 2 (HER2)+, 41 % HER2-, 27 % triple negative and 18 % triple positive (TP). Treatment in most patients consisted of a multimodality approach often with two or more of the following: whole brain radiation therapy (52 %), chemotherapy (51 %), stereotactic radiosurgery (20 %), surgical resection (14 %), trastuzumab (39 %) for HER2 positive tumors, and hormonal therapy (34 %) for ER and/or PR positive tumors. Factors that had an impact on prognosis included grade and size of the tumor, multiple metastases, presence of extra-cranial metastasis, triple negative or HER2+ biomarker status, and high Karnovsky score. Novel therapies such as application of agents to reduce tumor angiogenesis or alter permeability of the blood brain barrier are being explored with preliminary results suggesting a potential to improve survival after brain metastasis. Other potential therapies based on genetic alterations in the tumor and the microenvironment in the brain are being investigated; these are briefly discussed.

Clinicopathological factors associated with survival in patients with breast cancer brain metastasis

“…The significance of grading has A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 9 been further stressed by the most recent edition of AJCC Cancer Staging Manual, in which the histologic grade has emerged as a component of Prognostic Stage Groups in breast cancer along with pathologic stage and ER, PR and HER2 statuses [22]. In the current study, tumor grade was not significantly associated with brain relapse-free survival, in keeping with two recent studies, [10,16] and likely reflecting the fact that high grade tumors constitute a much higher proportion of breast cancers that subsequently develop brain metastases.…”

“…A recent comprehensive review of 106 studies over the past 35 years revealed an incidence of 24% for brain metastasis from breast cancer [9].…”

Profiles of brain metastases: Prioritization of therapeutic targets

“…Overall, it is estimated that 9–17% of cancer patients will develop brain metastases during the course of their disease and that approximately half will die within 3–27 months from initial diagnosis of CNS involvement 1, 2, 3. The reported median survival times for NSCLC, breast cancer and melanoma after the diagnosis of brain metastasis are 7.8 months, 15 months and 7–7.9 months, respectively 4, 5, 6. The poor survival associated with brain metastases is largely attributed to our incomplete understanding of the molecular mechanisms governing organotropism and the brain itself being a known sanctuary site.…”

“…Unfortunately, once CNS involvement is present, effective treatment options are limited and the prognosis is dismal. These issues are pressing, as the incidence of brain metastasis may be increasing due to longer patient survival owing to newer systemic therapies that control extracranial disease, along with more frequent magnetic resonance imaging surveillance 3, 5…”

Factores pronósticos en pacientes con cáncer de mama y metástasis cerebral como primer sitio de recurrencia

“…Lo anterior probablemente está relacionado con la existencia de mejores opciones de tratamiento y el acceso a terapias anti-HER2 en el contexto neo/adyuvante y paliativo que brinda el esquema del Seguro Popular. 8,15,26,27 Publicaciones recientes indican que el peor pronóstico de los pacientes TN puede deberse a una mayor expresión del receptor activador del factor nuclear k B (RANK) y del ligando de receptor del factor nuclear k B (RANKL), al presentar una menor supervivencia global y una menor supervivencia con metástasis, 28 bajo el entendido de que la proteína promueve la progresión y la metástasis del cáncer de mama. 29 En el presente estudio la edad al diagnóstico no mostró asociaciones significativas.…”