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雌激素受体阳性、HER2阴性乳腺癌的全身性治疗
Systemic Therapy for Estrogen Receptor–Positive, HER2-Negative Breast Cancer


Harold J. Burstein ... 肿瘤 • 2020.12.24
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雌激素受体(ER)阳性、人表皮生长因子受体2(HER2)阴性(后文称ER阳性)乳腺癌最多发的乳腺癌类型,占50岁以下女性乳腺癌病例的65%和50岁及以上女性乳腺癌病例的75%1。雌激素与ER结合,刺激受体调节下的转录,进而促进肿瘤细胞的生长和增殖。对ER阳性乳腺癌采取的激素疗法可减少雌激素生成、中断ER信号传导、降解ER或者改变ER调节下的信号传导或增殖通路(图1)。

 

图1. 雌激素受体(ER)靶向治疗的作用和耐药机制

雌激素生成和ER信号传导是乳腺癌发生、生长或增殖及转移的驱动因素,也是对早期乳腺癌有效的药物的靶点。与内分泌治疗联合应用的新的靶向治疗可改善晚期乳腺癌的结局,并抑制细胞生长、增殖和转移的关键通路的活性。ER基因ESR1的突变(ESR1 mut),或者c-myc、周期蛋白D和表皮生长因子受体(EGFR)的表观遗传变化与对内分泌治疗耐药相关。视网膜母细胞瘤蛋白(RB)缺失与晚期乳腺癌对周期蛋白依赖性激酶4和6(CDK4/6)抑制剂耐药相关。AKT、成纤维细胞生长因子受体(FGFR)和人表皮生长因子受体2(HER2)代表了内分泌治疗或CDK4/6抑制剂治疗所涉及的过度表达、扩增或突变。FSH表示促卵泡激素,GnRH表示促性腺激素释放激素,IGF-1R表示胰岛素样生长因子1受体,LH表示黄体生成素,mTOR表示哺乳动物雷帕霉素靶蛋白,P表示孕激素,PI3K表示磷脂酰肌醇3激酶,PR表示孕激素受体。

 

ER阳性乳腺癌的病理和遗传特征


ER阳性乳腺癌具有异质性。不同肿瘤在以下方面存在差异:ER数量水平、孕激素受体(PR)表达(由ER驱动)、组织学分级、增殖程度(通过Ki-67标志或其他指标衡量)、基因表达模式及基因组改变的类型和频率。这些特征高度相关(图2和表1),具有重要的临床意义。低级别(分化良好的)肿瘤具有较高的ER和PR表达水平,较低的增殖率,而中级别和高级别肿瘤可能具有较低的ER水平,PR可能不表达,并且具有较高的细胞增殖率(图2)2。大多数ER阳性乳腺癌的组织学亚型为导管癌;而15%的亚型为小叶癌,小叶癌与细胞黏附蛋白E-钙黏素缺失相关,可导致细胞内聚力丧失,肿瘤以“细胞排成一列纵队”的模式生长(图2)。比较少见的组织学亚型(如筛状癌和管状癌)均以ER强表达、低级别和预后极佳为特征3

 

图2. ER阳性、HER2阴性乳腺癌的病理特征

显微照片显示了ER阳性乳腺癌的病理特征谱,以及肿瘤分级,ER、PR和Ki-67表达(细胞增殖指标),以及复发评分(评分范围为0~100分,评分较高表示化疗益处较大,评分较低表示不接受化疗的情况下,复发风险较低)之间的常见关系。导管癌中的导管形成范围为低至高,小叶癌以“细胞排成一列纵队”模式生长。显微照片显示常规的免疫组化生物标志物染色,以及对表达程度的定量估计。与中级别或高级别肿瘤相比,低级别肿瘤的ER和PR表达程度较高,而Ki-67表达百分比较低,表明肿瘤的增殖率较低。2级小叶癌的显微照片(底部一行,右侧照片)显示,免疫组化染色表明正常导管组织有E-钙黏素表达(双星号),但小叶癌细胞无E-钙黏素表达(星号)。H&E表示苏木精和伊红。

 

遗传性癌基因是8%~10% ER阳性乳腺癌的发病原因,这些基因包括CHEK2(1%的病例)及与同源重组缺陷相关的基因,如BRCA1(2%)、BRCA2(2%)、ATM(0.5%~1%)和PALB2(0.5%~1%)4。ER阳性乳腺癌中的遗传性突变发生率在40岁以下患者中最高(约15%),并且随着患者年龄增长而逐渐降低(在40~60岁女性中约为10%;在70岁以上女性中,约为5%)。BRCA1突变与ER阴性、HER2阴性乳腺癌尤为相关,而发生于BRCA2PALB2CHEK2ATM突变携带者的乳腺癌大多为ER阳性,这反映了散发病例的分布5,6。早期遗传性乳腺癌的全身性治疗与非遗传性乳腺癌的全身性治疗并无不同。与散发性乳腺癌一样,遗传性乳腺癌可采取保乳手术和放疗,但有许多携带上述突变的患者为了避免再次发生乳腺癌而选择接受乳房切除术(包括对侧乳房切除术),而非保乳手术7





作者信息

Harold J. Burstein, M.D., Ph.D.
From the Dana–Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School — all in Boston. Address reprint requests to Dr. Burstein at the Dana–Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, or at hal_burstein@dfci.harvard.edu.

 

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