“精准医疗”时代从乳腺癌分子分型探讨抗体-药物偶联物的临床价值及最新研究进展

The research advances and the clinical value of antibody-drug conjugate from molecular subtyping of breast cancer in the era of"precision medicine"

乳腺癌的发病率目前已位居女性恶性肿瘤之首。乳腺癌具有高度异质性,可分为luminal A、luminal B、人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)过表达及三阴性型4种分子分型。然而既往的分子分型方法导致处于HER2低表达状态患者的治疗选择十分有限。近年来,随着抗体-药物偶联物(antibody-drug conjugate,ADC)的飞速发展,使HER2低表达乳腺癌患者获得了新的治疗选择,并促进了当前国内外指南中对HER2表达状态判定标准的更新——基于免疫组化(immunohistochemistry,IHC)和原位杂交(in situ hybridization,ISH)检测技术,将HER2的表达分为HER2阳性(IHC 3+或IHC 2+/ISH+)、HER2低表达(IHC 1+或IHC 2+/ISH-)以及HER2阴性(IHC 0)3种情况。ADC是一种由连接子将单克隆抗体与细胞毒性物质偶联而成的免疫偶联物。在乳腺癌领域,多项大型临床试验已经证明了以HER2为靶点的ADC恩美曲妥珠单抗(T-DM1)、德曲妥珠单抗(T-DXd)以及以滋养层细胞表面抗原2(trophoblast cell surface antigen 2,TROP2)为靶点的ADC戈沙妥珠单抗在不同分子分型乳腺癌患者中的临床获益。随着DESTINY-Breast03等Ⅲ期临床试验发现T-DXd在晚期HER2阳性乳腺癌患者中的临床疗效优于T-DM1(完全缓解率约为T-DM1的2倍,中位无进展生存期约为T-DM1的4倍),T-DXd现今已经替代T-DM1成为HER2阳性乳腺癌二线治疗唯一推荐的药物,也是脑转移局部治疗后二线治疗的选择。Ⅲ期临床试验DESTINY-Breast04证实T-DXd同样可使HER2低表达的乳腺癌患者获益,这进一步改变了晚期乳腺癌的治疗格局,并支持重新定义HER2阴性乳腺癌分子亚型的必要。Ⅲ期临床试验ASCENT证实戈沙妥珠单抗可显著改善三阴性乳腺癌(triple-negative breast cancer,TNBC)患者的生存情况及生活质量,且Ⅱ期临床试验NeoSTAR发现该药在TNBC新辅助治疗中也可能具有良好的抗肿瘤作用。基于循证医学证据,目前T-DM1、T-DXd和戈沙妥珠单抗均已在国外和中国陆续获批上市。其他如HER3-DXd、Dato-DXd及中国研发的纬迪西妥单抗(RC48)等ADC药物也正在乳腺癌等肿瘤中广泛地开展临床研究。此外,尚有多种其他分子靶点的ADC仍正在积极地研发中。本文旨在从不同分子分型乳腺癌患者的ADC药物治疗出发,介绍最新的相关研究进展并探讨ADC在乳腺癌中的临床应用价值。

The incidence of breast cancer currently ranks first among malignant tumors in women.Breast cancer exhibits high heterogeneity and can be classified into four molecular subtypes:luminal A,luminal B,human epidermal growth factor receptor 2(HER2)overexpression and triple-negative.However,previous molecular subtype classifications have limited treatment options for patients with HER2 low expression.In recent years,with the rapid development of antibody-drug conjugates(ADCs),new treatment options have emerged for breast cancer patients with HER2 low expression.This has also led to updates in the criteria for determining HER2 expression status in both domestic and international guidelines,based on immunohistochemistry(IHC)and in situ hybridization(ISH)testing,categorizing HER2 expression as HER2-positive(IHC 3+or IHC 2+/ISH+),HER2 low expression(IHC 1+or IHC 2+/ISH-),and HER2-negative(IHC 0).ADCs are immunotherapeutics composed of a linker that conjugates a monoclonal antibody with a cytotoxic payload.In the field of breast cancer,several large clinical trials have demonstrated clinical benefits of ADCs targeting HER2,such as trastuzumab emtansine(T-DM1),trastuzumab deruxtecan(T-DXd)and sacituzumab govitecan targeting trophoblast cell surface antigen 2(TROP2),in various molecular subtypes of breast cancer.With the phaseⅢDESTINY-Breast03 trial and others,T-DXd has been found to have superior efficacy compared to T-DM1 in advanced HER2-positive breast cancer patients(approximately two times higher complete response rate,and four times longer median progression-free survival).T-DXd has now replaced T-DM1 as the recommended second-line therapy for HER2-positive breast cancer and as a second-line treatment option after local treatment for brain metastasis.The phaseⅢDESTINY-Breast04 trial confirmed that breast cancer patients with HER2 low expression can also benefit from T-DXd,further reshaping the treatment landscape for advanced breast cancer and supporting the need to redefine molecular subtypes of HER2-negative breast cancer.The phaseⅢASCENT trial demonstrated that sacituzumab govitecan significantly improved survival and quality of life in triple-negative breast cancer(TNBC)patients,and the phaseⅡNeoSTAR study suggested its potential as neoadjuvant therapy in TNBC.Based on evidence,T-DM1,T-DXd and sacituzumab govitecan have been approved for marketing in both foreign and Chinese markets.Other ADC drugs,such as HER3-DXd,Dato-DXd and China-developed RC48,are also undergoing extensive clinical trials in the field of breast cancer and other tumors.Furthermore,there are several other ADCs targeting different molecular targets in active development.This article aimed to review the new advances related to ADCs therapy for breast cancer patients with different molecular subtypes and discuss the clinical application value of ADCs in breast cancer.