A New Strategy in Breast Cancer: Can Upfront Radiotherapy Awaken the Immune System?
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Hormone receptor-positive (HR+), HER2-negative breast cancer is generally considered immunologically “cold”—not sufficiently recognized by the immune system. This biological feature limits the efficacy of immune checkpoint inhibitors (ICIs) in this population. Preclinical data, however, suggest that radiotherapy may increase immune cell infiltration by modulating the tumor microenvironment, turning the tumor immunologically “hot.”
Presented at the San Antonio Breast Cancer Symposium 2026 (SABCS), the P-RAD (Pre-operative Radiation And Pembrolizumab) trial provides the first prospective data showing that short-course “induction” radiotherapy before neoadjuvant treatment increases intratumoral T-cell density and improves lymph node clearance.
1. Study Design and Methodology
This Phase 2 trial, led by Dr. Gaorav Gupta and his team, included patients at high risk of recurrence with positive lymph nodes: 51 patients (median age: 49.5). Patients were randomized to three different arms before neoadjuvant systemic therapy:
- Radiotherapy: A total of 24 Gy over 3 days (8 Gy x 3)
- Concurrent: 1 dose of Pembrolizumab
- Radiotherapy: A total of 9 Gy over 3 days (3 Gy x 3)
- Concurrent: 1 dose of Pembrolizumab
- Radiotherapy: None
- Concurrent: Pembrolizumab alone
Protocol Details: Only the primary breast tumor was irradiated; regional lymph nodes were kept outside the radiation field. A tumor biopsy was taken 2 weeks later, after which all patients received standard neoadjuvant chemotherapy (Paclitaxel + Adriamycin/Cyclophosphamide) and Pembrolizumab.
2. Immune Modulation and Clinical Response
The primary endpoint, “T-Cell Infiltration,” increased in proportion to radiation dose.
Regional Response: Lymph Node Clearance
Despite radiotherapy being delivered only to the primary tumor, rates of complete tumor clearance from lymph nodes at surgery (nodal pCR) suggest systemic immune activation.
- 24 Gy Group: 33% Nodal Clearance
- Control Group: 24% Nodal Clearance
This finding supports the hypothesis that radiotherapy activates antigen-presenting cells in the tumor, enabling them to migrate to lymph nodes and initiate a systemic response there—the “Abscopal Effect” hypothesis.
Subgroup Analysis: Non-Luminal A Tumors
The researchers identified a striking difference in their tumor biology analysis. Radiotherapy’s immune-stimulating effect was particularly evident in the biologically more aggressive or more immunologically responsive Non-Luminal A subgroup.
| Subgroup | Number of Patients | Nodal Clearance |
|---|---|---|
| Non-Luminal A (Received Boost RT) | 15 | 7 (46.6%) |
| Luminal A (Received Boost RT) | 16 | 1 (6.2%) |
3. Safety and Future Perspective
Although the small sample meant the study was not powered to show a definitive survival advantage, it successfully demonstrated the biological concept (Proof-of-Concept). In particular, the formation around the tumor of Tertiary Lymphoid Structures (TLS) containing T cells, B cells and dendritic cells provides histological evidence of a strong immune response.
Dr. Carlos Arteaga’s Comment: “The results are very intriguing, but we need randomized Phase 3 trials to see whether this approach makes a real difference in patient outcomes (survival).”
References and Publication Information
Presentation: Gupta G, et al. "Upfront Radiation Boosts ICI Response in Breast Cancer." San Antonio Breast Cancer Symposium (SABCS) 2025.
Funding: Merck, Breast Cancer Research Foundation, Translational Breast Cancer Research Consortium, Susan G. Komen Foundation.
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Radiotherapy’s Changing Role: From Local Treatment to Systemic Modulator
P-RAD once again demonstrates the importance of interdisciplinary collaboration between Radiation Oncology and Medical Oncology. Using radiotherapy as a biological agent that “awakens” the immune system and enhances systemic treatment, rather than solely as a tool for “local control,” may open new doors, particularly in groups resistant to immune therapies, such as HR+ breast cancer.
In the future, protocols that personalize radiotherapy dose and timing according to the tumor’s molecular subtype (Luminal A vs Non-Luminal A) are likely to become standard.