the field of breast cancer, Triple-Negative Breast Cancer (TNBC) has become a clinical challenge due to its high aggressiveness and lack of effective targets. Although the KEYNOTE-522 study established the standard status of Immune Checkpoint Inhibitors (ICI) combined with chemotherapy in perioperative TNBC, high-risk patients with lymph node-positive and T3/T4 stage disease still face a high risk of recurrence. Recently, Professor Alice Y. Ho from Duke University reported the latest results of the TBCRC-053 (P-RAD) study at an academic conference. This study explores the clinical value of preoperative radiotherapy as an "Immune Primer" combined with Pembrolizumab and chemotherapy in high-risk TNBC.

Body Content 01 Background and Logic: Breaking the “High-Risk Bottleneck” After KEYNOTE-522

Professor Alice Y. Ho pointed out at the beginning of the report that, based on the KEYNOTE-522 study, Pembrolizumab combined with neoadjuvant chemotherapy significantly improved the pathophysiological benefits of early-stage triple-negative breast cancer (TNBC). However, clinical evidence shows that for patients with lymph node-positive and T3 or T4 stage tumors, the risk of recurrence or death remains as high as 20% to 30% under current standard treatments. This data suggests an urgent need to develop more innovative treatment strategies for the high-risk TNBC population. The theoretical foundation of the P-RAD study stems from the immunomodulatory effects of radiotherapy on the tumor microenvironment. Radiotherapy not only directly kills tumor cells but also induces the release of tumor-associated antigens and an “in situ vaccination” effect, thereby enhancing the immune system’s recognition of the tumor. The previous Pearl trial preliminarily confirmed that preoperative radiotherapy could serve as an immune-priming partner for Pembrolizumab. In the Pearl trial, researchers observed that preoperative radiotherapy combined with Pembrolizumab achieved a 59% pathologic complete response (pCR) rate in TNBC, and single-cell sequencing results showed that subtypes originally belonging to “immune cold tumors” transformed into an “immune hot tumor” phenotype after radiotherapy intervention. Based on this, the TBCRC-053 (P-RAD) study aims to verify whether preoperative radiotherapy combined with Pembrolizumab can increase Tumor T-cell Infiltration (TCI), thereby improving the pathologic response rate at the time of surgical resection.

02 Study Design: A Three-Arm Randomized Exploration of the “Primer” Effect of Different Radiation Doses

TBCRC-053 is a multicenter randomized clinical trial. The study included 55 patients with TNBC clinical stages T1c-3, lymph node-positive (N+), and no distant metastasis (M0). Grouping Strategy: Patients were randomly assigned to three cohorts:

  1. 0 Gy Group (Control Group): Received only 1 cycle of Pembrolizumab treatment.
  2. Low-Dose (9 Gy) Group: Received 9 Gy radiotherapy (completed in 3 fractions) combined with 1 cycle of Pembrolizumab.
  3. High-Dose (24 Gy) Group: Received 24 Gy radiotherapy (completed in 3 fractions) combined with 1 cycle of Pembrolizumab. Follow-up Treatment and Assessment: After radiotherapy and the first round of immunotherapy, all patients received standard neoadjuvant chemotherapy according to KEYNOTE-522 (Paclitaxel + Carboplatin, followed by Anthracycline + Cyclophosphamide combined with Pembrolizumab), followed by surgery. The study set strict biomarker sampling points: tumor tissue, lymph node tissue, and peripheral blood samples were collected at baseline, at 2 weeks of treatment (Day 15), and at the time of surgery. Core Endpoints: • Primary Endpoint: The proportion of high-quartile Tumor T-cell Infiltration (TCI) in biopsy specimens at 2 weeks of treatment. • Co-Primary Endpoint: Pathologic response of unirradiated lymph nodes (ypN0). • Secondary Endpoints: Composite pCR rate, Residual Cancer Burden (RCB) 0/1 rate, safety, and translational research biomarkers.

03 Core Data: Radiotherapy Significantly Induces Tumor T-cell Infiltration (TCI)

Professor Ho reported the primary endpoint data of the study. At baseline, the estimated proportion of TCI in untreated TNBC tumors was 25%. TCI Increase Proportions: • Pembrolizumab Monotherapy (0 Gy Group): The TCI proportion at 2 weeks increased from 25% to 44%; although there was growth, it did not reach statistical significance. • Radiotherapy Combined Groups: The TCI proportion in the 9 Gy group jumped significantly to 80%, and the 24 Gy group reached 82%. Compared to Pembrolizumab monotherapy, the addition of radiotherapy significantly induced T-cell recruitment (P-value is statistically significant). Phenotypic Transformation: Sankey Plot analysis showed that under the effect of radiotherapy combined with Pembrolizumab, 71.4% of low TCI (“cold”) tumors successfully transformed into high TCI (“hot”) phenotypes, while this transformation frequency was much lower in the Pembrolizumab monotherapy group. Correlation Between TCI and Prognosis: High TCI levels observed in the 2nd-week biopsy were closely related to the final surgical outcome. The ypN0 rate for patients with high TCI was 94%, compared to only 46% for patients with low TCI; the pCR rate for high TCI patients reached 85%, significantly better than the 38% for low TCI patients. This result confirms the reliability of early TCI as a biomarker for predicting efficacy.

04 Longitudinal Evaluation: Observing the Abscopal Effect and Lymph Node Regression

A unique design of the P-RAD study is that preoperative radiotherapy was applied only to the primary breast lesion, intentionally avoiding positive lymph nodes marked by clips to observe the existence of a distant immune effect (Abscopal effect). Early Nodal Regression Rate: In the biopsy assessment at 2 weeks of treatment: • 9 Gy Group: The regression rate of unirradiated lymph nodes was 42%. • 24 Gy Group: The regression rate further improved to 62%. • Control Group (0 Gy): The lymph node regression rate was relatively low. Data further showed that early regression of lymph nodes was more significant in patients whose primary lesions exhibited high TCI, particularly in the 9 Gy dose group, where this correlation was most clear.

05 Surgical Outcomes: The 9 Gy Dose Group Shows Strong Potential for Pathologic Remission

In the final surgical outcome assessment, the study once again confirmed the incremental value of preoperative radiotherapy: • ypN0 Rate (Pathologic Lymph Node Negative Rate): The 9 Gy group performed the best, reaching 88%, an absolute increase of 15% compared to the 0 Gy group. • Composite pCR Rate: The pCR rate for the 9 Gy group was 76%, a 10% increase compared to the 0 Gy group. • RCB 0/1 Rate: Both radiotherapy groups showed a higher trend than the monotherapy group. It is worth noting that although 24 Gy performed strongly in inducing early TCI and lymph node regression, the 9 Gy dose group showed a better numerical advantage in the final pCR rate. Professor Ho believes this may suggest a “window effect” between radiation dose and immune microenvironment activation; a lower dose of radiation may be sufficient to trigger an effective systemic immune response while maintaining lymphocyte activity.

06 Innovative Exploration: 2-Week Combined Biomarker Predicts 92% pCR

In the report, Professor Ho emphasized the predictive value of “early integrated biomarkers.” The research team combined “high TCI at 2 weeks” with “early regression of unirradiated lymph nodes” to construct an integrated evaluation index. Analysis results showed: In approximately 1/3 of evaluable patients, if they simultaneously met the two conditions of “high TCI” and “early lymph node regression,” their final pCR rate was as high as 92%. This finding is of great clinical significance, meaning we might be able to precisely identify patients who are extremely sensitive to the immuno-radiotherapy combination within the first two weeks of treatment, providing evidence for subsequent de-escalation therapy or individualized regimen adjustments.

07 Expert Summary and Future Vision

Professor Alice Y. Ho concluded the main results of the P-RAD trial’s triple-negative cohort:

  1. Immune Priming Effect: Preoperative radiotherapy (whether 9 Gy or 24 Gy) combined with Pembrolizumab can significantly increase T-cell infiltration levels within the tumors of high-risk, lymph node-positive TNBC patients.
  2. Dose Comparison: The low-dose 9 Gy radiotherapy regimen showed excellent clinical potential in inducing ypN0 (88%) and pCR (76%) and is more convenient to administer.
  3. Abscopal Effect Confirmed: Localized radiotherapy of the primary lesion can induce early regression of unirradiated lymph nodes, confirming the ability of radiotherapy to activate a systemic anti-tumor immune response.
  4. Predictive Value: An early integrated biomarker consisting of TCI and lymph node status at 2 weeks can predict pCR outcomes with 92% accuracy, providing a new path for precision medicine. Professor Ho stated that these data strongly support the redefinition of radiotherapy from a “postoperative local control measure” to a “preoperative immune-priming intervention.” The success of the P-RAD study has laid a solid foundation for validating this regimen in larger sample sizes and randomized controlled trials in the future.
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