| BackgroundNeo-adjuvant chemotherapy(NAC)has become a standard treatment for locally advanced breast cancer,and the applications of NAC are growing in breast cancer now.Although peripheral neutrophil-to-lymphocyte ratio(NLR)has been associated with survival outcomes and response to chemotherapy in various malignancies.However,existing literature has largely focused on baseline parameters.Therefore,it is necessary to investigate the effects of NLR dynamic changes on the response and prognosis of chemotherapy in breast cancer patients during NAC.ObjectivesThe hypothesis of this study is that the NLR change trend during NAC and to evaluate its predictive role in the response and survival of breast cancer patients.Moreover,a nomogram with NLR exhibits a good performance for overall survival(OS)prediction in breast cancer patients receiving NAC to guide treatment.MethodsThis study retrospectively analyzed 500 patients who were initially diagnosed as locally advanced breast cancer(ⅡA-ⅢC stage)in Shandong Cancer Hospital from April 2009 to February 2018 and received 4-8 cycles of NAC.The primary endpoints were pathologic complete response(pCR)and OS.The receiver operating characteristic curve(ROC)was used to identify the cut-off value of NLR.Univariate and multivariate logistic regression analysis was used to describe the association with various clinicopathological factors and pCR.176 patients receiving 8 cycles NAC among 500 patients,a mixed effect regression model was used to conduct longitudinal analysis of NLR value during NAC to analyze the predictive value of its change trend on the response of NAC.500 breast cancer patients were randomly divided into a training set(n=350)and a validation set(n=150).In the training set,univariate and multivariate Cox regression analysis were used to determine the independent prognostic factors of OS.A nomogram for 3-and 5-year OS prediction was constructed using these independent prognostic factors.The performance of the nomogram was evaluated with respect to discrimination(qualified by concordance index,C-index)and calibration and validated within the training set internally.Finally,external validation was conducted independently in the validation set to evaluate the accuracy of the nomogram.Results62(12.4%)patients achieved pCR.Logistic regression analysis showed that pre-NLR(OR=0.52,95%CI:0.29-0.95,p=0.032),ER(OR=0.39,95%CI:0.19-0.794,p=0.010)and Ki-67(OR=2.34,95%CI:1.01-5.50,p=0.050)were independent predictors of pCR,low pre-NLR,ER negative and Ki-67>14%increased the probability of pCR.A mixed effect regression analysis showed that compared with non-pCR,patients with a response of pCR had a-0.032 change in transformed NLR every 2 cycles of NAC(std.error=0.014,p=0.024).Univariate and multivariate Cox regression analysis in training cohort results showed that clinical N3 stage(HR=2.70,95%CI:1.41-5.18,p=0.003),ER negative(HR=2.76,95%CI:1.47-5.15,p=0.001),high pre-NLR(HR=2.36,95%CI:1.31-4.26,p=0.004),high post-NLR(HR=2.76,95%CI:1.47-5.15,p=0.001),non-pCR(HR=9.79,95%CI:1.34-71.64,p=0.025)were independent prognostic factors of inferior OS.A prognostic assessment model was established involving all the independent prognostic factors above,and depicted a nomogram accordingly.The predictive accuracy of nomogram was tested in the training cohort internally.The C-index of training cohort was 0.780(95%CI:0.719-0.841),indicating good differentiation.The calibration is good without obvious over-or-under prediction comparing with the actual rates.In the validation set,C-index was 0.701(95%CI:0.568-0.834),and the predicted probability of the model is consistent with the actual probability.ConclusionNLR kinetics throughout NAC might be a potential biomarker for response.We hypothesize that a sustained decrease in inflammatory burden during NAC is associated with pCR.We have developed a practical nomogram that can provide individual prediction of OS for breast cancer patients receiving NAC,which could help identify high risk patients. |
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