Abstract PD6-10: A high ratio of CD8/FOXP3 predicts an unfavorable response to postoperative radiotherapy after breast-conserving surgery: Results from the randomized SweBCG91RT trial
Authors: Tullberg Axel Stenmark , Puttonen Henri AJ , Holmberg Erik , Lundstedt Dan , Killander Fredrika , Niméus Emma , Kóvacs Anikó , Karlsson Per 
Published: March 2020

Purpose: The effect of postoperative radiotherapy (RT) based on the immune phenotype of tumor-infiltrating lymphocytes (TILs) has not been investigated. The purpose of this study was to analyze how the balance between CD8+ T cells and T regulatory cells (FOXP3+), which have opposite effects on the anti-tumoral defense, affects the risk of ipsilateral breast tumor recurrence (IBTR) and of any recurrence as well as the interaction with RT in a large randomized RT trial.

Methods: In the SweBCG91RT trial, patients with breast cancer stage I and II were randomized to breast conserving surgery (BCS) and postoperative RT or BCS only and followed for a median time of 15.2 years. Tumor blocks were retrieved and stromal TILs were assessed through hematoxylin-eosin stained slides. CD8+ T cells and T regulatory cells were evaluated through staining for CD8 and FOXP3 and the percentage of stroma occupied by CD8+ T cells and T regulatory cells respectively was then calculated. Cutoffs at 5% and 2.5% were used to define high levels of CD8+ T cells (CD8High) and T regulatory cells (FOXP3High), respectively. In total, 943 patients were analyzed.

Results: Among patients who did not receive RT, an increased risk of IBTR and of any recurrence was seen in the CD8Low/FOXP3Low (HR 2.64, CI95% 1.26-5.56, p=0.010 and HR 2.52, CI95% 1.34-4.77, p=0.004, respectively) and CD8High/FOXP3High (HR 1.94, CI95% 0.81-4.63, p=0.135 and HR 2.76, CI95% 1.36-5.57, p=0.005, respectively) groups compared to CD8High/FOXP3Low (HR 1.0) in multivariable analyses including grade and age. The effect of RT on risk of IBTR was more pronounced in the groups with CD8Low/FOXP3Low (HR 0.37, CI95% 0.24-0.57, p&lt;0.001) and CD8High/FOXP3High (HR 0.43, CI95% 0.16-1.13, p=0.086) compared to CD8High/FOXP3Low (HR 0.92, CI95% 0.25-3.40, p=0.905). A potentially unfavorable effect of RT on the risk of any recurrence was observed in the CD8High/FOXP3Low (HR 1.74, CI95% 0.75-4.06, p=0.20) group in contrast to the effect of RT in patients with CD8High/FOXP3High (HR 0.53, CI95% 0.28-1.01, p=0.054) and CD8Low/FOXP3Low (HR 0.48, CI95% 0.34-0.68, p&lt;0.001). A significant interaction between immune phenotype and the effect of RT was found for any recurrence (p=0.024) but not for IBTR (p=0.66).

Conclusions: Our findings suggest that patients with a favorable immune phenotype (CD8High/FOXP3Low) may not derive any benefit from adjuvant RT which could be explained by an interaction through which RT may suppress an activated immune response. These results may have an impact on decisions regarding postoperative RT in early breast cancer.

Citation Format: Axel Stenmark Tullberg, Henri AJ Puttonen, Erik Holmberg, Dan Lundstedt, Fredrika Killander, Emma Niméus, Anikó Kóvacs, Per Karlsson. A high ratio of CD8/FOXP3 predicts an unfavorable response to postoperative radiotherapy after breast-conserving surgery: Results from the randomized SweBCG91RT trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-10.