A brief, targeted course of radiation could enhance the effectiveness of immune checkpoint inhibitors (ICIs) in patients with hormone receptor (HR)-positive, HER2-negative breast cancer that has spread to regional lymph nodes, according to findings from the phase 2 P-RAD trial.
The study, presented by Gaorav Gupta, MD, PhD, at the San Antonio Breast Cancer Symposium, tested a three-day course of 24 Gy radiation combined with a single dose of pembrolizumab. Researchers observed a significant increase in T-cell infiltration in breast tumors prior to neoadjuvant therapy. Patients who received upfront radiation also demonstrated higher rates of lymph node clearance during surgery compared with those who did not receive radiation.
“Our study suggests that radiation could be used in a new way to prime the immune system and enhance the effects of immunotherapy,” said Gupta, a breast cancer radiologist at the University of North Carolina, Chapel Hill. He emphasized the need for further trials to determine whether this approach can increase the number of patients who respond to immunochemotherapy.
Patients with higher-risk HR-positive, HER2-negative breast cancer may benefit from adding ICIs to neoadjuvant chemotherapy, but only if their tumors show high T-cell infiltration or elevated PD-L1 expression. Radiation has previously been shown to convert immunologically “cold” tumors into “hot” tumors that the immune system can recognize. The P-RAD trial explored whether delivering “boost radiotherapy” upfront alongside an ICI could further prime the immune response.
The trial enrolled 51 patients (median age 49.5) across 10 cancer centers. Participants were randomly assigned to receive no radiation, a 9 Gy dose, or a 24 Gy dose over three days, with a single pembrolizumab infusion. Only primary tumors were radiated, while lymph nodes were shielded. Breast tumor biopsies at two weeks assessed T-cell infiltration, the trial’s primary endpoint. Patients then received 12 weeks of paclitaxel plus pembrolizumab, followed by four cycles of adriamycin-cyclophosphamide plus pembrolizumab, before undergoing surgery.
Among 49 evaluable patients, T-cell infiltration increased with radiation dose. In the 24 Gy group, 53% of patients reached the highest quartile of T-cell infiltration, compared with 40% in the 9 Gy group and 31% in the no-radiation group. Only the difference between the 24 Gy and no-radiation groups reached statistical significance (P = .027). High T-cell infiltration was also associated with elevated PD-L1 expression.
Although the study was not powered to detect surgical outcomes, lymph node clearance trended higher in the 24 Gy group (33%) versus 29% in the 9 Gy group and 24% in the no-radiation group. Gupta explained that radiation may activate antigen-presenting cells within the tumor, which then travel to lymph nodes and stimulate T and B cells to attack cancer there.
Boost radiation also promoted the formation of tertiary lymphoid structures—immune hubs containing T cells, B cells, and dendritic cells—near tumors. These structures have been linked to improved immunotherapy responses in other cancers.
An exploratory analysis revealed that only patients with non-luminal A tumors showed a strong response to boost radiation. Among 15 such patients, seven experienced lymph node clearance at surgery, compared with just one of 16 patients with luminal A tumors. Gupta plans to conduct a follow-up phase 2 study focused on non-luminal A tumors. Biological differences in immune recognition and suppression may explain this discrepancy.
Importantly, upfront radiation did not appear to increase treatment toxicity, surgical wound complications, or patient-reported side effects.
The study was funded by Merck, the Breast Cancer Research Foundation, the Translational Breast Cancer Research Consortium, the Susan G. Komen Foundation, the US Department of Defense, and Natera. Gupta disclosed research funding from Merck, while Carlos Arteaga, MD, of UT Southwestern Medical Center—who called the results “very interesting”—reported funding from Pfizer and Lilly.
