Preoperative radiation may improve treatment response in patients with HR-positive, HER2-negative breast cancer

Preoperative radiation may improve treatment response in patients with HR-positive, HER2-negative breast cancer

Preoperative radiation improved T-cell infiltration (TCI) in patients with hormone receptor (HR)-positive, HER2-negative breast cancer when given in combination with pembrolizumab (Keytruda) and chemotherapy and resulted in improved response to treatment before surgery. This is according to the results of the phase II clinical trial P-RAD, presented at the San Antonio Breast Cancer Symposium (SABCS), December 9-12, 2025.

Many patients with HR-positive, HER2-negative breast cancer - the most common type of breast cancer - experience late recurrences and there is an urgent need to improve outcomes for this patient group. Immunotherapy has shown early promising signs, but new strategies are needed to make it more effective in this form of breast cancer. Immune checkpoint inhibitors rely on TCI to effectively fight cancer, and based on previous research showing radiation-mediated TCI enhancement, we wanted to test this in breast cancer.”

Gaorav Gupta, MD, PhD,moderator,Associate Professor of Radiation Oncology and Co-Director of the Breast Cancer Research Program at the University of North Carolina Lineberger Comprehensive Cancer Center

In this clinical trial, Gupta and colleagues from the Translational Breast Cancer Research Consortium enrolled patients with HR-positive, HER2-negative breast cancer that had spread to regional lymph nodes. The mean patient age was 49.5 years, with an age range of 23 to 78 years. They randomly assigned 51 patients in a 1:1:1 ratio to receive either no radiation, a low dose of radiation (9 Gy), or a high dose of radiation (24 Gy) along with pembrolizumab before starting chemotherapy. The patients were given doses of radiation over a period of three days.

All patients subsequently received pembrolizumab and paclitaxel for 12 weeks, followed by four cycles of pembrolizumab and doxorubicin and cyclophosphamide. Researchers evaluated two co-primary endpoints: TCI at the time of a biopsy taken two weeks after radiation and pathologic complete response in the lymph nodes (ypN0) at the time of definitive surgery to remove the cancer. Secondary endpoints were pathologic complete response (pCR) and residual cancer burden.

After radiation and immunotherapy treatment, among the 49 patients evaluable for TCI, the proportion of tumors with the highest TCI quartile increased as a function of radiation dose: 31%, 40%, and 53% in the 0 Gy, 9 Gy, and 24 Gy arms, respectively.

The mean TCI increased in all patients after treatment, meaning that radiation allowed more T cells to enter and attack the tumor. However, there was only a statistically significant improvement in TCI in patients in the 24 Gy arm compared to untreated tumors.

Gupta and colleagues also observed dose-dependent responses in lymph nodes. In all 48 evaluable patients, the rate of tumor healing from surgically removed lymph nodes was 29%, with the trend increasing with increasing radiation dose: 24% at 0 Gy, 29% at 9 Gy, and 33% at 24 Gy.

Secondary endpoints also improved with increasing radiation doses. The pCR and residual cancer burden rates in all patients were 18% and 27%, respectively. In the arm they were 6% and at 0 Gy 18%; 29% and 29% at 9 Gy; and 19% and 33% at 24 Gy, respectively. Due to the limited number of patients, these differences in surgical response rates did not reach statistical significance.

"Modern radiotherapy is safe, precise and widely available for the treatment of breast cancer. Our study suggests that radiation could be used in a new way - to 'prime' the immune system and enhance the effects of immunotherapy in HR-positive, HER2-negative breast cancer," said Gupta. "We have found early evidence that a focused radiation dose of 24 Gy, delivered over three days, in combination with pembrolizumab, increases immune activity and improves tumor healing before surgery “These results provide the foundation for future clinical trials examining this promising approach to improving long-term outcomes for breast cancer patients.”

Limitations of the study include the limited number of enrolled participants.

The study was funded by Merck, the Breast Cancer Research Foundation, the Translational Breast Cancer Research Consortium, the Susan G. Komen Foundation and the Department of Defense Breast Cancer Research Program. Gupta has received research funding from both Merck and Breakpoint Therapeutics and also receives royalties from Naveris, Inc. Gupta discloses an ownership interest in Naveris, Inc.

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