目的

探讨乳腺癌患者外周血中循环肿瘤细胞(CTC)变化情况与乳腺癌新辅助化疗(NAC)疗效的关系。

方法

根据纳入、排除标准,选取第三军医大学大坪医院野战外科研究所乳腺甲状腺外科2014 年12 月至2016 年6 月收治的女性乳腺浸润性癌患者共94 例进行前瞻性研究。 抽取患者NAC 前后健侧上肢静脉血5 ml,利用膜滤过法(ISET)检测外周血CTC。 首次化疗前及2 ～4 个周期治疗后常规行影像学检查,以实体瘤疗效评价标准(RECIST)评价疗效,无效则改行手术治疗,有效则完成6 个周期化疗后行手术治疗。 以病理学Miller-Payne 标准作为评估疗效的金标准,根据NAC 后CTC数目变化情况,将CTC 降低定义为有效,CTC 不变或者升高定义为无效。 采用χ² 检验比较乳腺癌患者临床病理特征与CTC 检出情况的关系。 采用McNemar 检验比较NAC 前后CTC 阳性率的差异。 治疗前后CTC 数目为非正态分布,采用M(P₂₅ ～P₇₅)表示,并用Wilcoxon 符号秩和检验比较NAC 前后CTC 数目的差异。 CTC 检测与病理学金标准评估疗效的一致性分析采用Kappa 检验,并采用McNemar 检验、敏感度和特异度评价CTC 检测。

结果

NAC 前外周血CTC 阳性率为62.8%(59/94)。 与HER-2 阴性及Ki67 低表达患者相比,HER-2 阳性[80.0%(36/45)比46.9%(23/45),χ²=10.971,P＜0.001]及Ki67高表达患者[77.4%(41/53)比44.0%(18/41),χ² =11.072,P＜0.001]中CTC 阳性率更高。 NAC 后CTC 阳性率[23.4%(22/94)比62.8%(59/94),χ²=35.100,P＜0.001]及检出数目[0(0 ～0)个比3(0 ～6)个,Z=-6.120,P ＜0.001]均较治疗前显著降低。 CTC 检测评估NAC 疗效的敏感度为76.5%(39/51),特异度为69.8%(30/43);与金标准进行一致性分析,2 种评价方法中等相符(Kappa=0.463,P＜0.001)。

结论

乳腺癌患者NAC 后CTC 的变化情况与NAC 疗效有一定关系。 CTC 检测有望成为一种新型评估NAC 疗效的方法。

Objective

To explore the relationship between circulating tumor cell (CTC) in peripheral blood of breast cancer patients and the curative effect of neoadjuvant chemotherapy for breast cancer.

Methods

Totally 94 breast cancer patients in Department of Breast and Thyroid Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, from December 2014 to June 2016 were enrolled for a prospective study according to the inclusion and exclusion criteria. Venous blood samples of 5 ml was collected from upper limb in healthy side of patients before and after neoadjuvant chemotherapy (NAC), and isolation by size of epithelial tumor cells (ISET) was adopted in detecting circulating tumor cells in peripheral blood. Conventional imaging examination was given before the first chemotherapy and after 2-4 cycles of NAC to evaluate the curative effect of NAC according to Response Evaluation Criteria in Solid Tumors(RECIST guideline version). If the chemotherapy was ineffective, the patients shifted to surgical treatment, otherwise,the patients completed 6 cycles of NAC and then underwent surgical treatment. According to pathological evaluation standard of Miller-Payne as a gold standard for curative effect evaluation, CTC reduction was defined as effective and CTC invariant or increase was defined as ineffective by the changes of CTC number after NAC.χ² test was used to analyze the association between the presence of CTC and clinicopathological characteristics of breast cancer patients. McNemar test was used to compare the positive rate of CTC before and after NAC.The number of CTC before and after treatment were expressed as M(P₂₅ -P₇₅) because of its skewed distribution, and compared using Wilcoxon signed-rank test. Kappa test and McNemar test were used to evaluate the consistency between CTC detection and pathological gold standard. The sensitivity and specificity were calcuted to evaluate the CTC detection.

Results

The detection rate of CTC in peripheral blood before NAC was 62.8% (59/94). The detection rate of CTC in HER-2 positive patients was significantly higher than that in HER-2 negative patients [80.0%(36/45) vs 46.9%(23/49),χ²=10.971,P＜0.001]. The detection rate of CTC in patients with high Ki67 expression was significantly higher than that in patients with low Ki67 expression [77.4%(41/53) vs 44.0%(18/41), χ²=10.971, P＜0.001]. The detection rate of CTC and the number of detected CTC after NAC were significantly lower than those before NAC [23.4%(22/94) vs 62.8%(59/94), χ² =35.100,P＜0.001; 0(0-0)vs 3(0-6), Z=-6.120,P＜0.001]. The sensitivity of CTC detection in NAC efficacy evaluation was 76.5%(39/51) and the specificity was 69.8%(30/34), and the consistency with the gold standard was described as moderate (Kappa=0.463, P＜0.001).

Conclusions

The alteration of CTC after NAC is related to the curative effect of NAC. CTC detection has the potential to become a new way to assess the efficacy of NAC.