In this study, we analyzed the effect of some conventional prognostic factors such as age, tumor size, nodal involvement, tumor grade, hormone status, and the inflammatory predictor, NLR, on the DFS outcome among HER2-positive patients with or without trastuzumab therapy. Patients older than 40 years, with fewer nodes involved and HR-positive tumor were associated with favorable DFS outcome in HER2-positive BC patients receiving trastuzumab treatment. And the pretreatment NLR was identified to be an independent predictive factor among trastuzumab-treated patients. However, pretreatment NLR showed no predictive value among HER2-positive patients without trastuzumab treatment. More information will be needed to validate whether pretreatment NLR could help us to distinguish patients with HER2-positive BC who will benefit from trastuzumab treatment or not.
NLR is a routinely available marker of the systemic inflammatory response, and there is no significant difference of NLR value in distinct breast cancer subtype . The presence of higher NLR in the blood has been recognized as a poor prognostic factor among triple-negative BC patients [10, 11]. Meanwhile, a meta-analysis suggested that NLR was a good prognostic marker for HER2-positive BC and triple-negative BC, but not for luminal A and luminal B subtype BC . However, there were not sufficiently addressed about trastuzumab use for the HER2-positive BC patients in the meta-analysis. Another retrospective study of 187 HER2-positive BC patients receiving adjuvant trastuzumab implied that low pretreatment NLR might be associated with improved DFS outcome, but without significant difference . In this study, first we categorized the HER2-positive BC patients according to whether they had received trastuzumab therapy or not. Data of patients without trastuzumab verified there were no predictive value of pretreatment NLR, but data about trastuzumab-treated patients showed low pretreatment NLR values were associated with improved survival. The reason was not yet well understood. Neutrophils are recognized as not only important contributors to tumor progression, metastasis and production of proangiogenic factors, but also inhibitors of activity of T cells and natural killer cells through production of arginase-1 and hydrogen peroxide [19-23]. Lymphocytes are important factors of immune surveillance and immune response, especially in the tumor microenviroment where tumor-infiltrating lymphocytes might be associated with chemotherapy response and survival outcomes . In the HER2-positive BC treated with trastuzumab, trastuzumab-induced ADCC should be taken into consideration for its contribution to the improved DFS outcome when compared with those without trastuzumab treatment . The intensity of ADCC induced by trastuzumab might be different for various reasons, such as HER2 copy numbers/application, FcγⅢA/FcγⅡA polymorphisms, and so on [26-28]. However, there is no study about the correlation of trastuzumab response and host immune status.
Then we divided patients into three groups for analysis of DFS outcome. As shown in Table 1 and Figure 3, patients in group 1 had similar clinicopathological characteristics and 3-year DFS outcome as that in group 3. However, patients in group 3 were treated with trastuzumab which was supposed to decrease the risk of metastasis around 25% in the adjuvant setting comparing to patients without trastuzumab . Meanwhile, patients in group 2 showed significantly higher 3-year DFS rate than patients in group 1 and group 3 (Figure 3). This implied that HER2-positive BC patients with high pretreatment NLR values might not benefit from trastuzumab treatment or might benefit very little, and HER2-positive patients with low pretreatment NLR value would benefit from trastuzuamb. This might be explained by the trastuzumab-induced ADCC, one of anti-tumor mechanisms of trastuzumab, whose ability might be associated with host immune status. Trastuzumab might induce the ADCC function against metastasis of breast cancer more efficiently, if the host immune status is in good condition (low NLR status), and trastuzumab might not induce the ADCC function if host immune system was in suppressive condition (high NLR status). In brief, we deduced that trastuzumab could bring out stronger anti-tumor immune competence through ADCC function in patients with low pretreatment NLR value than those with high pretreatment NLR value. More evidence and researches are needed for the exploration of trastuzumab’s anti-tumor efficacy under different immune status. The reanalysis of some classical trials, such as HERceptin Adjuvant (HERA) trial, NSABP B-31 and NCCTG 9831, might provide more useful information about NLR in predicting prognosis of HER2-positive BC.
In this study, we also analyzed posttreatment NLR which were obtained one month after the chemotherapy or radiotherapy, and no significant association was found between NLR and DFS outcome in trastuzumab-treated patients (data not shown). In our opinion, the pretreatment NLR which was obtained within one week before any treatment was more representative of baseline immune status than posttreatment NLR which might be affected by chemotherapy and/or radiotherapy, even though NLR was calculated from blood data one month after last chemotherapy or radiotherapy. This was in line with most of studies that showed the low baseline NLR was associated with better survival outcomes [29-32].
There are some limitations in this study. First, this study is a retrospective analysis of HER2-positive patients only in one hospital. Data were uneven among group1, group 2 and group 3. In the group 2, more patients were less than or equal to 40 years old and with large tumor size. Tumor size was not a prognostic factor in this study. Nevertheless age was an independent predictor and younger age was associated with worse survival outcome. However this did not affect the results from multivariate analysis which showed patients in group 2, which had more younger BC patients and was supposed to have a worse prognosis, actually had better 3-year DFS rate. Second, the median follow-up was only 20 months and only 38 events occurred among all these patients. It was not long enough to obtain more events, and longer follow-up time is needed. Third, the time point of trastuzumab therapy was not exactly the same among patients. Some of patients had received trastuzumab during neoadjuvant therapy, and some were treated after operation. Fourth, we did not analyze the tumor infiltrating lymphocytes (TILs) in tumor microenvironment which were well recognized parameter as prognostic factor for HER-2 positive BC. More analysis are needed for validating the correlation between NLR and TILs. Re-analyses of classical clinical trials are needed for the exploration of the relationship between systemic inflammatory/immune markers and trastuzumab-induced ADCC function.