Radiotherapy for Breast Cancer, Systemic Inflammation, and Cancer Recurrence

Abstract

Post-radiotherapy lymphopenia is common. Higher neutrophil:lymphocyte ratio (NLR), a measure of systemic inflammation, has been associated with breast cancer recurrence after radiotherapy (RT) induced lymphopenia in patients with triple negative disease, a highly immunogenic subtype. However, tumor infiltrating lymphocytes are predictive of treatment response in all subtypes. The goal of this study was to determine if local breast RT is associated with an increased NLR, and if systemic inflammation is associated with breast cancer recurrence.We prospectively followed 177 women with Stage I-III breast cancer who were assessed with complete blood cell counts with differential before RT, the last week of RT, 3-6 weeks and 1-year post-RT. NLR was calculated at each time point. 35% of patients received 39.9 Gy in 15 fractions (fxs) with an 8.1 Gy simultaneous integrated boost while 65% received 50 Gy in 25 fxs with a 10-16 Gy boost. 44% of patients received supraclavicular RT. Wilcoxon rank sum tests were performed to determine changes in NLR over time and to compare NLRs among patients who did and did not recur. Univariate and multivariable analyses were performed to identify predictors of increased NLR at each time point, and generalized estimating equation models were performed to account for the correlated measures for recurrence free survival (RFS).53% of subjects were non-Hispanic White (NHW) and 44% were African American. 35% had Stage IIB-IIIC disease. 53%, 25%, and 22% of tumors were ER+/Her2-, Her2+, and triple negative, respectively. Median NLR significantly increased the last week of RT (3.45 range 0.78-42.50) relative to baseline (1.95 range 0.34-11.29; P < 0.001). On multivariable analysis, patients who were NHW (P = 0.02), had triple negative tumors (P = 0.03), or received higher total radiation doses (P = 0.007) had a significant acute systemic inflammatory response to RT, reflected in higher NLR the last week of RT. After RT was complete, median NLR for the entire cohort continued to be significantly higher than baseline measures up to 1 year-post RT (P < 0.005 for all comparisons). Median follow up was 56 months (range 8-167). 5-year RFS was 91.3%. There were no significant differences in NLR at each timepoint between patients who did and did not recur. In the multivariable model, treatment with supraclavicular RT was the only predictor of recurrence (P = 0.04).Our findings indicate a sustained impact of local breast RT on the systemic inflammatory response, particularly in NHW patients with triple negative tumors who receive conventional rather than hypofractionated RT. In this study with a low number of recurrences, NLR did not predict for RFS in our diverse population. However, the persistent inflammatory response detected in the blood during and long after local breast RT may contribute to long-term side effects which occur months to years after treatment.