# Combined Radiation and Endocrine Therapies Elicit Benefit in ER+ Breast Cancer

## TL;DR

Combining radiation and endocrine therapies in ER+ breast cancer may reduce recurrence by inducing oxidative stress and slowing tumor growth.

## Contribution

The study demonstrates that concurrent use of radiation and endocrine therapies enhances anti-cancer effects through oxidative stress.

## Key findings

- Combination therapy induces apoptosis and slows tumor growth more effectively than individual treatments.
- DNA damage was almost exclusive to the combination of endocrine and radiation therapy.
- Radiation combined with estrogen deprivation prolonged time to tumor regrowth in ZR75-1 models.

## Abstract

Recurrence remains a major challenge for a significant proportion of estrogen receptor-positive breast cancer patients. The purpose of this study is to exploit the oxidative stress phenotype induced by radiation and endocrine therapies through concurrent use. We established that oxidative stress is induced by both therapies and can be advantageous in combination at inducing apoptosis and slowing tumor growth. These results provide rationale for further investigation into leveraging oxidative stress and discovering markers predictive of efficacy.

Background: Standard treatment for patients with early-stage estrogen receptor-positive (ER+) breast cancer often includes sequential adjuvant radiation and endocrine therapies. Unfortunately, ~1/3 of patients eventually experience disease recurrence, partly due to residual disease in the form of drug-tolerant persister cancer cells. The anti-cancer efficacy of radiation therapy is partly attributable to the production of oxyradicals that damage biomolecules. We previously showed that endocrine therapy increases mitochondrial content in ER+ breast cancer cells; we postulated that this may also increase oxidative stress. Methods: Herein, we tested the efficacy of concurrent endocrine and radiation therapies, including both conventional (CDR) and ultra-high dose rate (UHDR) radiation. Results: We found that estrogen deprivation and radiation inhibit cell growth, induce apoptosis, and force cells into an oxidatively stressed state. DNA damage was almost exclusive to cells treated with the combination of endocrine and radiation therapy. Radiation slowed tumor growth in two xenograft models, and combination with estrogen deprivation prolonged the time to regrowth in ZR75-1 tumors. Conclusions: These findings indicate that simultaneous treatment with endocrine and radiation therapies can be advantageous, warranting further evaluation to identify tumor features predictive of response to individual and combination treatments.