Gaorav Gupta MD PhD; SABCS 2025: Pre-Op Radiation Improved T-cell Infiltration in Hormone Receptor-positive, HER2-negative Invasive Breast Cancer; Could Boost Systemic Therapy Responses

Gaorav Gupta MD PhD; SABCS 2025: Pre-Op Radiation Improved T-cell Infiltration in Hormone Receptor-positive, HER2-negative Invasive Breast Cancer; Could Boost Systemic Therapy Responses

An interview with:

Gaorav Gupta MD PhD, Associate Professor Radiation Oncology, University of North Carolina at Chapel Hill, North Carolina, USA

SAN ANTONIO, USA—Patients with the most common form of breast cancer could respond better to immunotherapy and chemotherapy if they received neo-adjuvant radiation therapy. This is the implication of findings from the TBCRC-053 (P-RAD) study in patients with hormone receptor-positive, HER2-negative breast cancer which found an increase of T-cell infiltration among patients who had pre-operative radiation compared with those who did not.

The study findings were reported at the 2025 San Antonio Breast Cancer Symposium by Garav Gupta, MD PhD, an Associate Professor at  the University of North Carolina at Chapel Hill, USA. After his talk at the conference he met up with the Audio Journal of Oncology’s Peter Goodwin:

AUDIO JOURNAL OF ONCOLOGY: Garav Gupta MD PhD

IN: [GOODWIN] “I’m at the San Antonio….

OUT:      ……and the Audio Journal of Oncology, Goodbye” 8:58

SABCS 2025 Presentation Number: GS2-05.

TITLE:

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

Authors

Gupta1, A. Y. Ho2, F. Gharibpoor3, Y. Abdou3, J. D. Anampa4, R. C. Blitzblau2, B. C. Calhoun5, D. L. Casey3, S. F. Dent6, L. A. Carey7, J. R. Bellon8, L. E. Warren8, J. Lu9, T. J. Hieken10, A. G. Taghian11, A. Bardia12, T. Traina13, G. Plitas14, K. Gallagher15, K. Daugherty16, A. Thompson17, I. Krop18, A. Wolff19, E. Mittendorf20, J. Fox21, H. Garber22, E. Hwang23, A. J. Khan24, J. P. Loene25, R. Mutter26, S. Patil27, C. Santa-Maria19, B. V. Vincent7, J. L. Wright3, L. Spring28;
1Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Radiation Oncology, Duke University, Durham, NC, 3Radiation Oncology, University of North Carolina, Chapel Hill, NC, 4Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, 5Pathology, University of North Carolina, Chapel Hill, NC, 6Medical Oncology, University of Rochester, Rochester, NY, 7Medical Oncology, University of North Carolina, Chapel Hill, NC, 8Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 9Medical Oncology, Montefiore Medical Center, Bronx, NY, 10Surgery, Mayo Clinic, Rochester, MN, 11Radiation Oncology, Massachusetts General Hospital, Boston, MA, 12Medical Oncology, University of California Los Angeles, Santa Monica, CA, 13Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 14Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 15Surgery, University of North Carolina, Chapel Hill, NC, 16Cancer Center Protocol Office, Massachusetts General Hospital, Boston, MA, 17Surgery, Baylor College of Medicine, Houston, TX, 18Medical Oncology, Yale School of Medicine, New Haven, CT, 19Medical Oncology, Johns Hopkins University, Baltimore, MD, 20Surgery, Dana-Farber Cancer Institute, Boston, MA, 21Radiation Oncology, Montefiore Medical Center, Bronx, NY, 22Medical Oncology, MD Anderson Cancer Center, Houston, TX, 23Surgery, Duke University, Durham, NC, 24Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 25Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 26Radiation Oncology, Mayo Clinic, Rochester, MN, 27Biostatistics, Cleveland Clinic, Cleveland, OH, 28Medical Oncology, Massachusetts General Hospital, Boston, MA.

Abstract

Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to a PD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). 

Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1.

Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively.

Conclusion: The addition of 24Gy preop RT to a PD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC.

Gaorav Gupta MD PhD, AJ Oncology from SABCS 2025

February 3, 2026https://www.audiomedica.com/wp-content/2026/02/Gaorav-Gupta-SABCS-2025-PRODUCTION-MASTER.mp3