Response to hormone therapy predicts radiation resistance in ER+ breast cancer

DALLAS – March 06, 2023 – How estrogen receptor-positive (ER+) breast cancer responds to hormone therapy may hold keys to understanding how it will respond to radiation therapy, and an experimental drug that increases the effectiveness of hormone therapy also overcomes radiation resistance in breast cancer, a study by UT Southwestern Medical Center researchers shows. The findings of this preclinical study, published in NPJ Precision Oncology, could one day lead to a better approach for personalizing radiation treatments for cancer patients.

“Using tumors’ response to a systemic therapy might allow us to personalize radiation treatments in a way that hasn’t been possible before,” said study leader Prasanna Alluri, M.D., Ph.D., an Assistant Professor of Radiation Oncology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.

ER+ breast cancers are often treated with a systemic therapy such as hormone therapy to shrink tumors, surgery to remove remaining tumors, and finally radiation with or without additional systemic therapy to kill residual microscopic cancer cells. Between 20% and 35% of these cancers show some degree of resistance to hormone therapy.

Doctors can easily learn whether tumors responded to preoperative systemic therapy through imaging. But for radiation therapy, such direct assessment of treatment response is not feasible, Dr. Alluri explained. This results in radiation treatments being administered in a one-size-fits-all fashion, with all patients in a given stage of breast cancer receiving the same intensity and duration of treatment, even though response to radiation can be variable.

Seeking to develop a new approach to predict radiation therapy resistance, Dr. Alluri and his colleagues tested whether there might be a link between the response to hormone and radiation therapies. By introducing mutations in ER+ breast cancer cells that render them resistant to endocrine therapy, the researchers showed that ER+ breast cancer cells that acquired resistance to hormone therapy also exhibited radiation resistance when grown in a laboratory dish.

Similarly, when the researchers implanted hormone therapy-resistant cells into mice, allowing them to develop into tumors, these tumors showed poor response to radiation treatments, again demonstrating a link between response to hormone therapy and radiation therapy.

Earlier research by this team had shown that hormone therapy resistance in ER+ breast cancer tumors is driven by changes in gene expression mediated by a family of proteins known as bromodomains and extraterminal domains (BET). An experimental drug called OTX015 that blocks the function of these proteins reversed hormone therapy resistance. In the current study, Dr. Alluri’s team showed that the BET proteins also play an important role in rendering cells resistant to radiation. Using OTX015, the researchers were able to reverse radiation therapy resistance of hormone therapy-resistant cells grown in a petri dish, as well as hormone therapy-resistant tumors grown in mice.

Dr. Alluri’s team plans to investigate whether the response to other types of systemic drug therapies delivered before surgery for many types of cancers also can be used to predict radiation therapy response – information that could help doctors personalize radiation treatments based on the degree of radiation resistance or sensitivity of a tumor in an individual patient. This approach could advance the field of precision radiation oncology, Dr. Alluri said, where the radiation treatment for each patient is personalized based on individual tumor characteristics.

Other UT Southwestern researchers who contributed to this study include S.M. Udden, GuemHee Baek, Kamal Pandey, Chantal Vidal, Yulun Liu, Asal S. Rahimi, D. Nathan Kim, Chika R. Nwachukwu, and Ram S. Mani.

Dr. Nwachukwu is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine.

This study was supported by Department of Defense Breast Cancer Research Program Breakthrough Awards (W81XWH-21-1-0112, W81XWH-21-1-0114), a grant from the National Institutes of Health (R01CA245294), and a grant from the Cancer Prevention and Research Institute of Texas (RP190454).

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.