Sep 28

QP 05 - Predicting Outcomes in Breast Cancer: From Multi-Omics to AI-Driven Models

1026 - Intratumoral Immune Remodeling and Tumor Regression following Preoperative Radiation in Estrogen Receptor Positive Breast Cancer: Results from a Prospective Clinical Trial

08:10am - 08:15am ET

Room 258

Presenter(s)

Gopika Senthilkumar, MD, PhD - University of Pennsylvania, Philadelphia, PA

G. Senthilkumar¹, Y. Sun², H. Rui², J. Jorns³, J. A. Bovi⁴, A. Kong⁵, T. R. Kelly⁵, E. S. Paulson⁶, G. Noid⁶, A. Wadhwa⁵, A. D. Currey⁷, and C. Bergom⁸; ¹University of Wisconsin, Madison, WI, ²Thomas Jefferson University, Philadelphia, PA, ³Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, ⁴Thedacare, Appleton, WI, ⁵Medical College of Wisconsin, Milwaukee, WI, ⁶Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, ⁷Department of Radiation Oncology Medical College of Wisconsin, Milwaukee, WI, ⁸WashU Medicine, Depar, St. Louis, MO

Purpose/Objective(s): ER/PR+ breast cancer (BC) is generally considered immunologically "cold," with low baseline tumor-infiltrating lymphocyte (TIL) levels. Radiotherapy (RT) can enhance immune infiltration, and studies of triple-negative and HER2+ BC patients suggest that higher TILs are associated with improved outcomes. However, immune infiltration in ER/PR+ BC is poorly understood, and prior clinical studies report minimal changes in TILs in these tumors post-RT. In this prospective clinical trial, we investigated whether preoperative accelerated partial breast irradiation (APBI) can induce compartment-specific remodeling of various immune populations (CD68+, CD20+, FoxP3+, CD4+, CD8+). We also evaluated whether immune remodeling is associated with changes in tumor response.

Materials/Methods: Patients with early-stage ER/PR+ BC enrolled in the preoperative APBI trial (NCT02728076; 30 Gy in 5 fractions on non-consecutive days, surgery =5 weeks post-RT) were included. Tumor cellularity, stromal TILs, and intratumoral and stromal immune populations were assessed in pre-RT biopsies and post-RT surgical specimens. Paired comparative and correlative analyses were performed using R-Studio.

Results: Thirty-five patients were included (median age 65 years; IQR 56.5–69.0). Tumors were grade 1 (45.7%) or grade 2 (54.3%). Median MRI tumor size was 0.9 cm (IQR 0.7–1.3), and median 21-gene recurrence score was 12.0 (IQR 3.8–15); only one patient had a score >25. Median cellularity was 40% (range 20-60%) at baseline, and post-RT, 45.7% of patients achieved =5% residual cellularity with an overall median of 10% (range 0-50%, p<0.001). Stromal TILs were low at baseline (median 5%; range 1-20%) and were unchanged post-RT in 71.4% of patients, with no significant shifts in stromal immune populations. In contrast, intratumoral immune infiltration increased significantly: CD68+ macrophages (dz=1.18, p<0.001), CD20+ B cells (dz=0.64, p<0.001), FoxP3+ regulatory T cells (dz=0.78, p<0.001), CD4+ T cells (dz=0.39, p=0.023), and CD8+ T cells (dz=0.38, p=0.048). A preferential intratumoral accumulation of CD68+ macrophages relative to stroma was observed (median ?Tumor-?Stroma=0.060; p<0.001), with intratumoral macrophage increases being associated with larger decline in tumor cellularity after treatment (Spearman r=-0.42, p=0.011).

Conclusion: Preoperative APBI induced substantial tumor responses and compartment-specific immune remodeling in early-stage ER/PR+ BC, with significant increases in intratumoral immune infiltrates but not stromal immune cells or TILs. Additionally, preferential intratumoral recruitment of CD68+ macrophages is associated with tumor regression. Future studies will evaluate the relationship between compartment-specific immune populations and long-term outcomes as well as evaluate macrophage-mediated mechanisms post-RT in ER/PR+ BC.