Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer

Author

Daniel L. Smith, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

8-2015

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Wendy Woodward

Committee Member

Sunil Krishnan

Committee Member

Osama Mawlawi

Committee Member

James Bankson

Committee Member

Sendurai Mani

Committee Member

David Yang

Abstract

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – radiation toxicity. The objective of this thesis was to determine if a PCI dose could reduce the incidence of brain metastasis.

A mouse model of metastatic, HER2+ inflammatory breast cancer was used to evaluate the effect of 4-Gy whole-brain irradiation on the incidence of brain metastasis. Mice were irradiated at different time points and were sacrificed at either four or eight weeks after cell injection. The principal endpoints of incidence of brain metastasis, the number of brain metastases per mouse, and the metastatic burden were all significantly decreased in the PCI arm, but unaffected when the whole-brain irradiation was delayed.

To expand on the experimental findings, a computational model of subclinical breast cancer dose-response was developed. After optimization, the model was validated by conducting a limiting dilution assay. By adjusting the model inputs of radiation dose and time of irradiation, a time course of the incidence of brain metastasis and related endpoints was mapped. The model predicts that delaying treatment introduces a dose threshold below which the incidence is unchanged, a finding that is consistent with the experimental data.

This work highlights the importance of the timing of radiation therapy as it relates to the treatment of subclinical disease, specifically breast cancer micrometastases in the brain. The principal findings have the potential to impact how breast cancer patients at high risk of developing brain metastases are managed in the clinic, and PCI clinical trials in these patients could be considered.

Keywords

Prophylactic cranial irradiation, breast cancer, brain metastases, small-animal irradiator, radiation biology, computational biology