Immune checkpoint inhibitors (ICIs) in hormone receptor (HR)-positive/HER2-negative early breast cancer have shown promise but are not yet FDA approved. Checkmate 7FL and KEYNOTE-756 randomized phase 3 trials demonstrated improvement in pathologic complete response (pCR) when ICIs were added to neoadjuvant chemotherapy, but this benefit was not uniform, and may be specific to tumors that have high baseline stromal tumor-infiltrating lymphocytes and high baseline PD-L1 expression. The innovative TBCRC053 (P-RAD) study investigated the effects of combining preoperative radiation therapy with pembrolizumab, an ICI, and chemotherapy. The trial sought to evaluate whether this approach could enhance immune response and improve treatment outcomes for patients with node-positive, early-stage breast cancer.
The P-RAD trial included patients with clinical T1 to T4 tumors and biopsy-confirmed nodal metastases. Participants were randomized into 3 treatment arms: no preoperative radiation, low-dose radiation (9 gray), and high-dose radiation (24 gray). All patients received a loading dose of pembrolizumab followed by systemic neoadjuvant chemotherapy, including paclitaxel, doxorubicin, and cyclophosphamide. The primary endpoint was an increase in T-cell infiltration in the tumor, measured 2 weeks after radiation. Secondary endpoints included residual cancer burden (RCB) and PD-L1 expression. Importantly, the trial utilized localized radiation to the primary tumor while shielding lymph nodes to minimize immunosuppressive effects.
The study's results demonstrated a significant increase in tumor-infiltrating T cells and PD-L1 expression in the group receiving pembrolizumab with 24 gray of radiation. This combination also induced broad immune activation, including the formation of tertiary lymphoid structures—clusters of immune cells such as B cells, T cells, and dendritic cells within the tumor microenvironment. Surgical outcomes showed encouraging trends, with higher rates of node clearance, pCR, and RCB of 0 to 1 in the 24 gray group compared with lower radiation doses or no radiation, though these differences were not statistically significant. Notably, tumors with non-luminal A molecular subtypes and those showing PD-L1 induction at the 2-week biopsy were most likely to achieve pCR.
Preoperative radiation with pembrolizumab appears to enhance immune activity and improve outcomes in patients with high-risk, HR-positive/HER2-negative breast cancer. The greatest benefits were observed in non-luminal A tumors and those demonstrating early PD-L1 induction. While these findings are promising, further research is needed to confirm the potential of this combination therapy and to refine its application in clinical practice. This study represents a significant step forward in integrating radiation and immunotherapy to improve disease control in breast cancer.
Source: Gupta GP, Ho AY, Gharibpoor F, et al. Primary results from the HR+/HER2- cohort of TBCRC-053 (P-RAD): a randomized trial of no, low, or high dose preoperative radiation with pembrolizumab and chemotherapy in node-positive, HER2-negative breast cancer. Presented at: San Antonio Breast Cancer Symposium 2025. December 11, 2025; San Antonio, TX. Presentation GS2-05.