探讨HER-2阳性乳腺癌患者新辅助治疗前、后Ki-67的表达变化与预后的关系。

回顾性分析2014年1月至2017年12月佛山市第一人民医院收治的85例乳腺癌患者的临床资料，术前均经空芯针吸穿刺活组织检查证实为HER-2阳性乳腺浸润性导管癌，之后接受新辅助化疗。采用χ²检验及Fisher确切概率法分析新辅助化疗前Ki-67表达与临床病理特征及新辅助化疗疗效之间的关系。采用χ²检验及Fisher确切概率法比较接受TcbH(多西他赛+卡铂+曲妥珠单克隆抗体)和AC-TH(表柔比星+环磷酰胺序贯多西他赛+曲妥珠单克隆抗体)2种方案的乳腺癌患者临床疗效和病理疗效的差异。根据新辅助化疗后激素受体(HR)状态，分成HR阴性组与HR阳性组，用χ²检验及Fisher确切概率法比较2组临床特征的差异。采用χ²检验及Fisher确切概率法分析新辅助化疗后Ki-67表达变化与患者疗效的相关性，采用Kaplan-Meier法描绘生存曲线并进行生存分析，用Log-rank法进行无复发生存(RFS)的组间比较，并根据HR状态进行亚组分析。(5)采用单因素和多因素Cox比例风险回归模型分析复发的影响因素。

新辅助化疗前Ki-67低表达患者22例，高表达患者63例。新辅助化疗前Ki-67低表达与高表达患者在年龄、月经状态、组织学分级、淋巴结转移状态、ER表达、PR表达、病理疗效及肿瘤大小和临床疗效方面比较，差异均无统计学意义(χ²＝0.000、0.296、0.186、0.276、0.010、0.021、1.401, P均>0.050；P＝0.646、0.569)。接受TcbH和AC-TH方案的患者临床疗效和病理疗效比较，差异均无统计学意义(P＝0.154; χ²＝0.232，P＝0.630)。新辅助化疗后，HR阴性51例，HR阳性34例。2组患者的手术方式、Miller-Payne分级、是否接受放射治疗、复发转移情况、Ki-67状态改变以及新辅助化疗方案比较，差异均无统计学意义(P＝0.157；χ²＝2.215、3.266、0.095、0.516、0.297，P均>0.050)。新辅助化疗后，21例Ki-67表达升高或无变化，64例Ki-67表达降低。Ki-67降低者的临床疗效及病理疗效均优于Ki-67升高或无变化者(P＝0.003; χ²＝8.729，P＝0.003)。亚组分析结果显示，在51例HR阴性患者中，Ki-67降低者病理疗效优于Ki-67升高或无变化者(χ²＝11.141，P＝0.001)，但临床疗效比较，差异无统计学意义(P＝0.071)；而在34例HR阳性患者中，Ki-67降低者临床疗效优于Ki-67升高或无变化者(P＝0.037)，但病理疗效比较，差异无统计学意义(P＝0.672)。生存分析显示：新辅助化疗后Ki-67降低组RFS率明显高于Ki-67升高或无变化组(χ²＝26.275，P<0.001)；在HR阴性及HR阳性患者中，新辅助化疗后Ki-67降低组RFS率均高于Ki-67升高或无变化组(χ²＝11.302、22.127，P均<0.001)。Cox风险比例回归模型分析显示，组织学分级3级、淋巴结转移是患者复发的独立危险因素(HR＝2.764、3.550，95%CI：1.104~6.919、1.026~12.281，P＝0.030、0.045)，新辅助化疗后Ki-67表达降低是独立保护因素(HR＝0.197，95%CI：0.087~0.475，P<0.001)。

新辅助化疗后Ki-67表达变化与临床疗效及病理疗效之间存在相关性，可能是HER-2阳性乳腺癌患者RFS的独立影响因素。

To investigate the correlation between Ki-67 expression change after neoadjuvant chemotherapy (NAC) and the prognosis of HER-2-positive breast cancer patients.

We retrospectively analyzed the clinical data of 85 HER-2-positive breast cancer patients in the First People’s Hospital of Foshan from January 2014 to December 2017. All patients were diagnosed with HER-2-positive invasive ductal carcinoma of the breast by preoperative core-needle aspiration biopsy, and then received NAC. The relationship of Ki-67 expression before NAC with clinicopathological characteristics and the efficacy of NAC was analyzed by χ² test and Fisher’s exact test. The clinical and pathological efficacy of NAC in breast cancer patients receiving different regimens (TcbH group: docetaxel + carboplatin + trastuzumab; AC-TH group: epirubicin + cyclophosphamide followed by docetaxel + trastuzumab) was compared by χ² test and Fisher’s exact test. According to hormonal receptor (HR) status after NAC, the patients were divided into HR-negative group and HR-positive group, and the clinical parameters between two groups were compared by χ² test and Fisher’s exact test. The correlation between the expression changes of Ki-67 after NAC and the efficacy was analyzed by χ² test and Fisher’s exact test, the survival curve was drawn using the Kaplan-Meier method and the Log-rank method was used to compared RFS between groups. The subgroup analysis was performed according to the HR status. Univariate and multivariate Cox proportional hazards regression model was used to analyze the influencing factors of recurrence.

Before NAC, 22 patients had low expression of Ki-67 and 63 had high expression. There was no significant difference in age, menstrual status, histological grade, lymph node metastasis, ER status, PR status, pathological efficacy, tumor size and clinical efficacy between patients with low Ki-67 expression and patients with high Ki-67 expression (χ²=0.000, 0.296, 0.186, 0.276, 0.010, 0.021, 1.401, all P>0.050; P=0.646, 0.569). There was no significant difference in clinical efficacy and pathological efficacy between patients receiving TcbH and patients receiving AC-TH (P=0.154; χ²=0.232, P=0.630). After NAC, HR was negative in 51 cases and positive in 34 cases. There was no significant difference in surgical methods, Miller-Payne grade, radiotherapy, recurrence/metastasis, Ki-67 change and NAC regimen between HR-positive and HR-negative patients (P=0.157; χ²=2.215, 3.266, 0.095, 0.516, 0.297, all P>0.050). After NAC, the expression of Ki-67 was increased or unchanged in 21 cases, and decreased in 64 cases. The clinical efficacy and pathological efficacy of patients with decreased Ki-67 were significantly better than those of patients with increased or unchanged Ki-67 (P=0.003; χ²=8.729, P=0.003). The results of subgroup analysis showed that among 51 HR-negative patients, the pathological efficacy of patients with decreased Ki-67 was significantly better than that of patients with increased or unchanged Ki-67 (χ²=11.141, P=0.001), but clinical efficacy presented no significant difference (P=0.071); among 34 HR-positive patients, the clinical efficacy of patients with decreased Ki-67 was significantly better than that of patients with increased or unchanged Ki-67 (P=0.037), but there was no difference in pathological efficacy (P=0.672). Survival analysis showed that the RFS of patients with decreased Ki-67 after NAC was significantly higher than that of patients with increased or unchanged Ki-67 (χ²=26.275, P<0.001); in HR-negative and HR-positive subgroups, the RFS of patients with decreased Ki-67 after NAC was significantly higher than that of patients with increased or unchanged Ki-67 (χ²=11.302, 22.127, both P<0.001). The Cox hazard proportional regression model analysis showed that histological grade 3 and lymph node metastasis were independent risk factors for recurrence (HR=2.764, 3.550, 95%CI: 1.104-6.919, 1.026-12.281, P=0.030, 0.045). The decreased Ki-67 expression after NAC was an independent protective factor for recurrence (HR=0.197, 95%CI: 0.087-0.475, P<0.001).

The change of Ki-67 expression is correlated with clinical and pathological efficacy of NAC, and it may be considered as an independent factor affecting RFS of HER-2-positive breast cancer patients.