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中华临床医师杂志(电子版)

中华临床医师杂志(电子版) ›› 2021, Vol. 15 ›› Issue (10) : 740 -747. doi: 10.3877/cma.j.issn.1674-0785.2021.10.005

乳腺癌·临床研究

HER2阳性早期乳腺癌原发灶与腋窝淋巴结生物标志物的一致性和新辅助治疗影响及预后研究
周金妹1, 吴雪雪1, 刘嘉伟2, 张会强1, 吴霞1, 袁洋1, 张少华1, 边莉1, 江泽飞1,†(), 王涛1,†()   
  1. 1. 100071　北京，中国解放军总医院第五医学中心肿瘤学部肿瘤内科四病区
    2. 510080　广州，南方医科大学第二临床医学院
  • 收稿日期:2021-09-22 出版日期:2021-10-15
  • 通信作者: 江泽飞, 王涛
  • 基金资助:
    国家自然科学基金(81572597); 北京市自然科学基金(7192198)

Concordance of biomarkers in primary tumors and axillary lymph nodes of HER2-positive early breast cancer, and effect of neoadjuvant therapy on biomarkers and their prognostic value

Jinmei Zhou1, Xuexue Wu1, Jiawei Liu2, Huiqiang Zhang1, Xia Wu1, Yang Yuan1, Shaohua Zhang1, Li Bian1, Zefei Jiang1,†(), Tao Wang1,†()   

  1. 1. Breast Cancer Department of Oncology Institute, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
    2. the Second Clinical School of Southern Medical University, Guangzhou 510080, China
  • Received:2021-09-22 Published:2021-10-15
  • Corresponding author: Zefei Jiang, Tao Wang
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引用本文：

周金妹, 吴雪雪, 刘嘉伟, 张会强, 吴霞, 袁洋, 张少华, 边莉, 江泽飞, 王涛. HER2阳性早期乳腺癌原发灶与腋窝淋巴结生物标志物的一致性和新辅助治疗影响及预后研究[J]. 中华临床医师杂志(电子版), 2021, 15(10): 740-747.

Jinmei Zhou, Xuexue Wu, Jiawei Liu, Huiqiang Zhang, Xia Wu, Yang Yuan, Shaohua Zhang, Li Bian, Zefei Jiang, Tao Wang. Concordance of biomarkers in primary tumors and axillary lymph nodes of HER2-positive early breast cancer, and effect of neoadjuvant therapy on biomarkers and their prognostic value[J]. Chinese Journal of Clinicians(Electronic Edition), 2021, 15(10): 740-747.

目的

探讨人表皮生长因子受体2（HER2）阳性早期乳腺癌原发灶与腋窝淋巴结生物标志物的一致性和新辅助治疗对其影响及其预后价值。

方法

回顾性分析2013年4月至2019年4月于解放军总医院第五医学中心乳腺肿瘤科行新辅助治疗的128例HER2阳性乳腺癌患者的病理及临床资料。分析乳腺癌乳腺原发灶和同期同侧腋窝转移淋巴结雌激素受体（ER）、孕激素受体（PR）、HER2、Ki67表达水平的一致性，以及新辅助治疗前后ER、PR、HER2、Ki67表达水平的变化和预后价值。采用SPSS20.0进行数据统计学分析，组间及治疗前后差异性比较采用配对样本t检验或χ2检验，采用Kaplan-Meier曲线分析患者的无事件生存期（EFS）。

结果

乳腺原发灶和淋巴结转移灶ER的不一致率为5.5%，PR的不一致率为7.3%，Kappa值分别为0.886和0.824。乳腺原发灶、淋巴结转移灶的Ki67平均值分别为（43.0±20.0）%、（42.5±19.5）%，两者差异无统计学意义（t=0.24，P=0.811），两者Ki67高表达（＞30%）比例差异亦无统计学意义（61.8% vs 63.6%，P=1.000）。ER/PR/HER2表达一致和不一致者的病理完全缓解（pCR）率差异无统计学意义（52.2% vs 55.6%，P=1.000）。43例患者同时具有新辅助治疗前和新辅助治疗后手术病理的免疫组化结果，ER状态无变化。治疗后9例患者PR由阳性转变为阴性，1例由阴性转变为阳性（P=0.021），PR转为阴性者的EFS与持续阳性者无统计学差异（HR=1.34，95%CI：0.19~9.80，P=0.766）。15例（34.9%）患者治疗后手术病理HER2转为阴性，转阴者的EFS与HER2持续阳性者无统计学差异（HR=0.76，95%CI：0.21~2.80，P=0.692）。治疗后患者Ki67表达水平较治疗前明显下降（中位Ki-67表达水平：25% vs 35%，P=0.001），治疗后Ki67较基线下降患者的5年EFS率明显高于无下降组，差异虽然未达统计学意义，但临床意义显著（80.9% vs 71.4%，HR=0.49，95%CI：0.12~1.71，P=0.261）。

结论

HER2阳性乳腺癌原发灶和淋巴结转移灶的ER、PR、HER2、Ki67表达水平一致性较高，新辅助治疗后患者的ER无变化，PR阳性转为阴性和HER2表达转为阴性对患者的预后无明显影响，新辅助治疗后Ki67水平明显下降，下降者可能预后更佳。

关键词: 乳腺肿瘤, 人表皮生长因子受体2阳性, 新辅助治疗, 生物标志物
Objective

To investigate the concordance of biomarkers in the primary tumors and axillary lymph nodes of HER2-positive early breast cancer, the effect of neoadjuvant therapy on biomarkers, and the prognostic value of biomarkers.

Methods

The pathological and clinical data of 128 patients with HER2-positive breast cancer who underwent neoadjuvant therapy at the Breast Oncology Department of the Fifth Medical Center of the PLA General Hospital from April 2013 to April 2019 were retrospectively analyzed. The concordance of the expression levels of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 in the primary breast tumors and matched axillary lymph node metastases of HER2-positive early breast cancer, the changes in the status of ER, PR, HER2, and Ki67 before and after neoadjuvant therapy, and their prognostic value were investigated. SPSS 20.0 was used for statistical analyses. Differences between groups and before and after treatment were compared by t or χ2 test, and the Kaplan-Meier curve was used to analyze the event free survival (EFS) of patients.

Results

The rates of discordance in ER and RP between primary breast tumors and corresponding lymph node metastases were 5.5% and 7.3%, respectively, and the Kappa values were 0.886 and 0.824, respectively. The mean Ki67 indexes of primary breast tumors and lymph node metastases were 43.0%±20.0% and 42.5%±19.5%, respectively; there was no differences in mean Ki67 index (t=0.24, P=0.811) or the proportion patients with Ki67 index over 30% (61.8% vs 63.6%, P=1.000) between primary breast tumors and lymph node metastases. There was no statistically difference in the pathological complete response (pCR) rate between patients with consistent and inconsistent statuses of ER/PR/HER2 (52.2% vs 55.6%, P=1.000). Forty-three patients had both pre-neoadjuvant core-needle biopsy and post-neoadjuvant immunohistochemical results. There was no change in ER status. Changes from positive to negative status for PR were observed in nine cases, and gain of PR status occurred in 1 case (P=0.021). The negative conversion of PR status had no influence on EFS when compared with patients who had sustained positive expression (HR=1.34, 95%CI: 0.19-9.80, P=0.766). Fifteen patients (34.9%) had loss of HER2 expression following neoadjuvant treatment. There was no difference between patients with and those without change in HER2 status in terms of EFS (HR=0.76, 95%CI: 0.21-2.80, P=0.692). We observed a significant decrease in Ki67 index after neoadjuvant treatment: The median Ki-67 index before and after neoadjuvant treatment was 35% vs 25% (P=0.001). After treatment, the 5-year EFS rate was higher in patients with Ki67 reduction than in those with no reduction; although the difference was not statistically significant, it was clinically significant (5-year EFS rate was 80.9% vs 71.4%, HR=0.49, 95%CI: 0.12-1.71, P=0.261).

Conclusion

The expression statuses of ER, PR, HER2 and Ki67 are in high degree of concordance between primary tumors and matched lymph node metastases in HER2-positive breast cancer. After neoadjuvant therapy, the ER status of patients remains unchanged, and the negative conversion of PR and HER2 status has no significant effect on the prognosis. Ki67 index decreases significantly after neoadjuvant treatment, which may predict a better prognosis.

Key words: Breast neoplasms, HER2 positive, Neoadjuvant therapy, Biomarker
表1 128例早期乳腺癌患者基本特征
特征 例数 百分率（%）
临床分期

Ⅰ期

 9 7.0

Ⅱ期

 74 57.8

Ⅲ期

 45 35.2
腋窝淋巴结状态

阴性

 38 29.7

阳性

 90 70.3
新辅助方案

ATH

 63 49.2

TCbH

 63 50.8
pCR率

ATH

 34 54.0

TCbH

 32 49.2
表2 早期乳腺癌患者乳腺原发灶与腋窝转移淋巴结生物标志物的表达情况（例）
部位 例数 ER PR HER2* Ki67
阳性 阴性 阳性 阴性 阳性 阴性 ≤30% ＞30%
乳腺原发灶 55 20 35 15 40 43 2 21 34
腋窝转移淋巴结 55 23 32 17 38 44 1 20 35
P值 0.250 0.625 1.000 1.000
Kappa值 0.886 0.824 - 0.495
表3 早期乳腺癌患者乳腺原发灶与腋窝转移淋巴结的生物标志物一致性对pCR的影响［例（%）］
项目 pCR 未获得pCR
ER/PR/HER2表达一致 24（52.2） 22（47.8）
ER/PR/HER2表达不一致 5（55.6） 4（44.4）
表4 早期乳腺癌患者新辅助治疗前后手术原发灶生物标志物的表达（例）
时间 例数 ER PR Ki67
阳性 阴性 阳性 阴性 ≤30% ＞30%
治疗前 43 23 20 20 23 21 22
治疗后 43 23 20 12 31 24 19
P值 1.000 0.021 0.549
图1 新辅助治疗后手术原发灶ER/PR/HER2状态不同转变患者的无事件生存情况注：ER为雌激素受体；PR为孕激素受体；HER2为人表皮生长因子受体2
图2 新辅助治疗后手术原发灶PR状态不同转变患者的无事件生存情况注：PR为孕激素受体
图3 新辅助治疗后手术原发灶HER2状态不同转变患者的无事件生存情况注：HER2为人表皮生长因子受体2
图4 新辅助治疗后手术Ki67水平不同变化患者的无事件生存情况
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