HER2低表达乳腺癌的靶向治疗研究进展

郭晴; 张剑

doi:10.19401/j.cnki.1007-3639.2023.02.012

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HER2低表达乳腺癌的靶向治疗研究进展

综述 | 更新时间：2025-12-31

- HER2低表达乳腺癌的靶向治疗研究进展
- Advances in targeted therapy for HER2-low breast cancer
- 中国癌症杂志 2023年33卷第2期页码：181-190
- 作者机构：
  
  复旦大学附属肿瘤医院肿瘤内科，Ⅰ期临床研究中心，复旦大学上海医学院肿瘤学系，上海 200032
- 作者简介：
  
  [ "郭晴（ORCID: 0000-0001-7347-9006），在读研究生。" ]
  张剑（ORCID: 0000-0003-3208-3106），医学博士，主任医师。
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.02.012
  中图分类号： R737.9
- 收稿：2022-05-26，
  
  修回：2022-11-21，
  
  纸质出版：2023-02-28
- 稿件说明：
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郭晴, 张剑. HER2低表达乳腺癌的靶向治疗研究进展[J]. 中国癌症杂志, 2023,33(2):181-190.

Qing GUO, Jian ZHANG. Advances in targeted therapy for HER2-low breast cancer[J]. China Oncology, 2023, 33(2): 181-190.
郭晴, 张剑. HER2低表达乳腺癌的靶向治疗研究进展[J]. 中国癌症杂志, 2023,33(2):181-190. DOI： 10.19401/j.cnki.1007-3639.2023.02.012.

Qing GUO, Jian ZHANG. Advances in targeted therapy for HER2-low breast cancer[J]. China Oncology, 2023, 33(2): 181-190. DOI： 10.19401/j.cnki.1007-3639.2023.02.012.

摘要

乳腺癌是全球女性的第一大恶性肿瘤，发病率在逐年增加。人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）在乳腺癌的生物学行为及发病机制中起着重要作用。乳腺癌HER2低表达是指HER2免疫组织化学染色1+或2+且原位杂交（

in situ

hybridization，ISH）阴性，占全部类型的45% ~ 55%。尽管在目前的临床实践中，HER2低表达大多数仍被报告为HER2阴性或三阴性乳腺癌，但HER2低表达与HER2未检出乳腺癌不仅在HER2蛋白表达水平上不同，在雌激素受体（estrogen receptor，ER）状态、原发肿瘤体积、淋巴结受累情况、新辅助治疗后的病理学完全缓解率（pathologic complete response，pCR）以及无病生存期（disease-free survival，DFS）等方面也存在差异。在针对早期HER2低表达乳腺癌靶向治疗的临床试验中，NSABP B-31及N9831试验表现出乳腺癌患者受益于曲妥珠单抗辅助治疗的可能性，然而，在Ⅲ期前瞻性随机对照研究NSABP B-47中，曲妥珠单抗并未改变HER2低表达乳腺癌患者的无浸润性肿瘤复发生存期（invasive disease-free survival，iDFS）、5年无远处复发间期及总生存期（overall survival，OS）。近年来针对晚期HER2低表达乳腺癌靶向治疗开展的临床试验层出不穷，主要围绕曲妥珠单抗、拉帕替尼、恩美曲妥珠单抗（trastuzumab emtansine，T-DM1）、DS-8201（又名trastuzumab deruxtecan

T-DXd

Enhertu）及SYD985等新型抗体-药物偶联物（antibody-drug conjugate，ADC）类药物。Ⅲ期临床试验CALGB9840表明曲妥珠单抗对HER2非过度表达的乳腺癌缺乏治疗效果，改变鲁妥珠单抗剂量后仍无法克服治疗窗口窄的问题。两项随机Ⅲ期试验（EGF30001和EGF100151）均发现接受拉帕替尼并未改善HER2低表达乳腺癌患者的无进展生存期（progression-free survival，PF

S）。单臂Ⅱ期研究4258g及4374g初步发现HER2低表达乳腺癌患者对T-DM1的敏感性，但由于患者数量较少，结论尚不明确。Ⅲ期临床研究DESTINY-Breast04证实了DS-8201（5.4 mg/kg）与医师选择方案（2∶1随机分配）在HER2低表达转移性乳腺癌中的安全性和有效性。针对SYD985的Ⅰ期临床试验显示了其治疗HER2低表达乳腺癌的效果和安全性（1.2 mg/ kg）。除此之外，以新型ADC药物（RC48-ADC、ARX788、A166等）、双特异性抗体（KN026、ZW25、ertumaxomab等）及乳腺癌疫苗（nelipepimut-S、GP2、AE37等）为代表的一系列新型抗HER2治疗手段的临床研究也正在进行中。本文将对近年HER2低表达乳腺癌靶向治疗药物的主要临床试验进行综述。

Abstract

Breast cancer is the most common cancer in women worldwide with rising prevalence. The human epidermal growth factor receptor 2 (HER2) is crucial to the biological behavior and pathogenic mechanism of breast cancer. Approximately 45%-55% of all subtypes of breast cancer have low expression of HER2

which are classified as HER2 immunohistochemistry staining 1+ or 2+ and

in situ

hybridization (ISH) negative. Although in most cases

HER2 low expression (HER2-low) breast cancer is still classified as HER2 negative or triple negative in clinical practice

HER2-low differs from HER2 not detected (HER2-0) breast cancer not only in HER2 expression levels

there are also differences in terms of estrogen receptor (ER) status

primary tumor volume

lymph node involvement

and pathologic complete response (pCR) following neoadjuvant therapy and disease-free survival (DFS). In clinical trials targeting early-stage HER2-low breast cancer

the NSABP B-31 and N9831 trials demonstrated the possibilities for breast cancer patients to benefit from adjuvant trastuzumab therapy; however

in phase Ⅲ prospective randomized controlled study NSABP B-47

trastuzumab did not alter invasive disease-free survival (iDFS)

5-year interval without distant recurrence

or overall survival (OS) in patients with HER2-low breast cancer. Recent years have seen the emergence of clinical trials for targeted treatments for advanced HER2-low breast cancer

focusing mostly on trastuzumab

lapatinib

and antibody-drug conjugate (ADC)

such as trastuzumab emtansine (T-DM1)

DS-8201 (also known as tr

astuzumab deruxtecan

T-DXd

Enhertu)

and SYD985. Phase Ⅲ trial CALGB9840 demonstrated a lack of therapeutic effect of trastuzumab and a narrow therapeutic window that could not be overcome by changing the dose of lumretuzumab in HER2 non-over-expressed breast cancer

respectively. Two randomized phase Ⅲ trials (EGF30001 and EGF100151) both found that receiving lapatinib did not improve progression-free survival (PFS) in patients with HER2-low breast cancer. T-DM1 sensitivity was initially observed in patients with HER2-low breast cancer in the single-arm phase Ⅱ studies 4258g and 4374g

but results were still uncertain because of the small number of patients. The phase Ⅲ clinical study DESTINY-Breast04 proved the safety and efficacy of DS-8201 (5.4 mg/kg) in HER2-low metastatic breast cancer. The phase Ⅰ clinical trial proved the efficacy and safety of 1.2 mg/kg SYD985 intravenously in HER2-low breast cancer. Additionally

there are currently ongoing clinical trials for several novel anti-HER2 therapeutics

including novel ADC drugs (RC48-ADC

ARX788

A166

etc.)

bispecific antibodies (KN026

ZW25

ertumaxomab

etc.)

and breast cancer vaccines (nelipepimut-S

GP2

AE37

etc.). In this paper

we will review the major clinical trials of targeted therapies for HER2-low breast cancer.

关键词

Keywords

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