Abstract
Prophylactic cranial irradiation (PCI) can reduce the incidence of brain metastasis and improve overall survival in some patients with acute lymphoblastic leukemia or small-cell lung cancer. We examined the potential effects of PCI in a mouse model of breast cancer brain metastasis. The HER2+ inflammatory breast cancer cell line MDA-IBC3 was labeled with green fluorescent protein and injected via tail-vein into female SCID/Beige mice. Mice were then given 0 Gy or 4 Gy of whole-brain irradiation 2 days before tumor-cell injection or 5 days, 3 weeks, or 6 weeks after tumor-cell injection. Mice were sacrificed 4-weeks or 8-weeks after injection and brain tissues were examined for metastasis by fluorescent stereomicroscopy. In the unirradiated control group, brain metastases were present in 77% of mice at 4 weeks and in 90% of mice at 8 weeks; by comparison, rates for the group given PCI at 5 days after tumor-cell injection were 20% at 4 weeks (p=0.01) and 30% at 8 weeks (p=0.02). The PCI group also had fewer brain metastases per mouse at 4 weeks (p=0.03) and 8 weeks (p=0.006) versus the unirradiated control as well as a lower metastatic burden (p=0.01). Irradiation given either before tumor-cell injection or 3-6 weeks afterward had no significant effect on brain metastases compared to the unirradiated control. These results underscore the importance of timing for irradiating subclinical disease. Clinical whole brain strategies to target subclinical brain disease as safely as possible may warrant further study.
Highlights
Breast cancer brain metastasis is a significant clinical problem
Because patients with stage IV HER2+ or triplenegative breast cancer are at high risk of developing brain metastasis and because the prognosis of patients who develop brain metastases is very poor, we investigated whether low dose prophylactic cranial irradiation (PCI) could reduce the incidence of brain metastasis in a mouse model of metastatic breast cancer, in which tail-vein injection of HER2+ breast cancer cells led to a high rate of brain metastasis [20]
Excised brain tissue from each mouse was evaluated for the presence of green fluorescent protein (GFP)-labeled metastases; representative brain images from mice treated at various times after tumor-cell injection and sacrificed at 8 weeks are depicted in Figure 2. (Images of brain metastases at 4 weeks are shown in Supplementary Figure S1; and images of brain sections stained with hematoxylin and eosin are shown in Supplementary Figure S2.)
Summary
Despite improvements in multimodal therapy, only 20-30% of patients with breast cancer will survive for longer than one year after the diagnosis of brain metastasis. As the population ages and methods for extracranial disease control continue to improve, the number of patients with breast cancer who will develop and die from brain metastases continues to rise [1, 2]. The principal factor in determining whether the potential benefit of PCI (increased survival) would outweigh the potential risks (morbidity) would be the risk of developing brain metastases. The risk increases further for breast cancer of specific receptor subtypes: patients with human epidermal growth factor receptor 2-enriched (HER2+) or triple-negative stage IV breast cancer are at a 25-45% risk of developing brain metastasis [17, 18]. It is noted that if toxicity could be reduced with techniques above or even lowered dose, further consideration could be given to selection of patients for whole brain after stereotactic radiosurgery where the risk of further subclinical disease is expected
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