Association of CD4+ radiation-induced lymphocyte apoptosis with fibrosis and telangiectasia after radiotherapy in 272 breast cancer patients with >10-year follow-up

Purpose: 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 2-3 years 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 follow-up. Experimental design: 272 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 LENT-SOMA. RILA in the CD4⁺, CD8⁺ and NK subpopulations from peripheral blood was analyzed by flow cytometry. Multivariate predictive modeling was performed including relevant clinical risk factors. Results: Low CD4⁺ RILA was associated with increased risk for both fibrosis (p=0.011) and telangiectasia (p<0.001). For fibrosis, the association was stronger outside the surgical area (Fib_out; p=0.004) than within (Fib_in; p=0.17). Predictive multivariate modeling including clinical risk factors yielded OR=3.48 (95% CI 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. Conclusions: 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.

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