Association of CD4⁺ Radiation-Induced Lymphocyte Apoptosis with Fibrosis and Telangiectasia after Radiotherapy in 272 Breast Cancer Patients with >10-Year Follow-up.

Abstract

Radiation-induced lymphocyte apoptosis (RILA) has been suggested as a predictive assay for adverse late reactions after radiotherapy. Thus, low RILA values of T-lymphocyte subpopulations have been associated with increased risk for various endpoints at 2 to 3 years of follow-up. The purpose was to test if such associations persist for specific endpoints (subcutaneous fibrosis, telangiectasia) in breast cancer patients with at least 10 years of follow-up.<b>Experimental Design:</b> Two hundred and seventy-two female patients who had received breast-conserving therapy within the German ISE study were included (median follow-up: 11.6 years). Radiotherapy-induced side effects were scored according to the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) classification system. RILA in the CD4⁺, CD8⁺, and natural killer (NK) subpopulations from peripheral blood was analyzed by flow cytometry. Multivariate predictive modeling was performed including relevant clinical risk factors. Low CD4⁺ RILA was associated with increased risk for both fibrosis (<i>P</i> = 0.011) and telangiectasia (<i>P</i> < 0.001). For fibrosis, the association was stronger outside the surgical area (Fib_out; <i>P</i> = 0.004) than within (Fib_in; <i>P</i> = 0.17). Predictive multivariate modeling including clinical risk factors yielded OR of 3.48 (95% confidence interval, 1.84-6.58) for any fibrosis and 8.60 (2.71-27.3) for telangiectasia. Addition of CD4⁺ RILA to the clinical variables improved discrimination (c statistics) from 0.62 to 0.68 for any fibrosis, 0.62 to 0.66 for Fib_in, 0.61 to 0.69 for Fib_out, and from 0.65 to 0.76 for telangiectasia. CD8⁺ and NK RILA were not significantly associated with radiotherapy-related late reactions. The results provide first evidence that low CD4⁺ RILA is associated with increased subcutaneous fibrosis and telangiectasia even after 10 years. This supports the potential usefulness for predicting individual clinical risk.