Prognostic value of tumor-infiltrating lymphocytes in irradiated node-positive breast cancer patients

Introduction: Radiotherapy significantly reduces locoregional recurrence (LRR) and improves survival. Yet, reliable biomarkers predicting radiotherapy response are not well-defined. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising prognostic and predictive marker, but their role in irradiated patients remains underexplored. Methods: This case-cohort study included 1461 node-positive, irradiated breast cancer patients from the Danish Breast Cancer Group (DBCG) internal mammary node (IMN)2 study. IMN irradiation (IMNI) was allocated by tumor laterality. TILs were assessed in treatment-na & iuml;ve primary tumors and dichotomized using a 30 % cut-off. Endpoints included overall mortality (OM), breast cancer-specific mortality (BCM), distant recurrence (DR), and LRR. Flexible parametric survival models estimated adjusted hazard ratios (HRs). Results: TILs were evaluated in 1353 patients; 20 % had high TILs. Low TILs were associated with higher OM (HR 0.53, 95 % CI: 0.36-0.77), BCM (HR 0.45, CI: 0.29-0.71) and DR (HR 0.40, CI: 0.26-0.62), but not LRR (HR 0.82, CI: 0.31-2.17). These associations were strongest in estrogen receptor-negative (ER-) tumors. ER-/low TILs were associated with increased OM (HR 0.31, CI: 0.18-0.56) compared to ER-/high TILs, whereas TILs were not prognostic in ER+ tumors (HR 0.86, CI: 0.56-1.32). A significant survival benefit after IMNI was observed in patients with low TILs tumors (HR 0.64, CI: 0.48-0.85), but TILs did not predict IMNI-benefit. Conclusion: TILs in the pre-immunotherapy setting were not predictive of IMNI-benefit but prognostic for post-radiotherapy outcomes in node-positive patients. The effect was dependent on ER status, as patients with ER-/ low TILs tumors had poorer survival with a trend toward increased DR-risk.