Curing breast cancer often involves surgery, systemic therapy, and radiation therapy. How do doctors know how much of each of these therapies to deliver? Since every patient’s breast cancer is different, shouldn’t the treatments for breast cancer be at least somewhat different for each patient? At UT Southwestern, doctors are finding ways to deliver no more and no less treatment than is necessary to cure their cancer.
For example, before breast cancer surgery, medical oncologists often administer systemic treatments such as anti-hormone or endocrine therapy (ET) in estrogen receptor-positive (ER+) breast cancer patients to determine their response to the treatment. This allows them to customize post-surgery systemic treatment based on the response of the patient to pre-operative endocrine therapy.
Unlike ET, typically no portion of breast cancer radiation therapy (RT) is given pre-operatively, so the response it affords cannot be directly measured to customize how much to give. Instead, RT is usually given after surgery to eliminate microscopic disease after the tumor has been excised. Therefore, it is not feasible to assess which patients are responding well to RT and which patients may harbor radiation-resistant disease that is less responsive to RT. Consequently, patients are often treated in a one-size-fits-all fashion largely based on the tumor’s original size, location, and stage, with no biological clues to predict how the tumor might respond or how to adjust the therapy if necessary.
However, our physicians and scientists have found a way to potentially outsmart cancer cells that evade radiation therapy through two important discoveries:
1. We have established that breast tumors that acquire certain adaptations and genetic alterations that enable them to evade ET also acquire the ability to evade RT. This association between ET and RT resistance may one day enable physicians to predict response to RT in breast cancer patients based on their response to pre-operative ET.
2. In a previous study, we have shown that BRD4, a bromodomain extraterminal domain (BET) family protein, plays a key role in ET resistance and that an experimental drug that blocks the function of this protein overcomes ET resistance in animal models of breast cancer. In the current study, we have shown that BRD4 is also a key mediator of RT resistance, and that the same experimental drug that reversed ET resistance also overcomes RT resistance in animal models. These pre-clinical findings may one day enable identification of breast cancer patients who harbor radioresistant tumors and personalization of RT in such patients by combining a BET inhibitor with RT to overcome radiation resistance.
Rather than viewing ET and RT resistance as separate problems, we are connecting the biological “dots” to potentially personalize breast RT based on response of tumors to pre-operative ET.
Targeting cancer with personalized radiation
Advances in stereotactic radiation therapy and technology are helping the Radiation Oncology team at UT Southwestern's Simmons Cancer Center deliver more effective and less invasive treatments to patients.
Windows of opportunity for personalized care
UT Southwestern medical oncologists currently hold short-term “window of opportunity” trials for some patients with breast cancer to assess response to ET before surgery.
In the future, our radiation oncology researchers want to collaborate on such trials to validate our pre-clinical findings, which established a relationship between ET and RT resistance in breast cancer patients. Future clinic trials will also validate whether combination of a BET inhibitor with RT will overcome radiation resistance in patients harboring RT resistant tumors and prevent or reduce recurrence.
Research efforts to overcome treatment resistance in breast cancer are being supported by grants to our research team from many federal and non-federal organizations, including Department of Defense’s Breast Cancer Research Program Breakthrough Award, METAvivor Breast Cancer Translational Research Award, and Charles Y.C. Pak Foundation Breast Cancer Bone Initiative Award.
Our recent discoveries have the potential to help create more customized and effective breast cancer treatment for patients, and we hope this research will help advance precision radiation oncology to improve patient outcomes.