HER2低表达三阴性乳腺癌的生物学特征

Biological characteristics of triple negative breast cancer with low expression of HER2

目的探讨HER2低表达三阴性乳腺癌(triple negative breast cancer, TNBC)的生物学特征。方法收集山西省肿瘤医院2017—2019年具有完整临床资料的93例TNBC相关病理切片及石蜡包埋组织, 依据HER2表达状态分为HER2 0和HER2低表达两组, 回顾性分析比较两组临床病理特征及预后差异, 并对肿瘤组织进行基因检测, 阐明体细胞突变状态及两组间的差异。结果入组93例患者, 发病年龄26~86岁。HER2 0组60例, HER2低表达组33例。HER2低表达在腔面大汗腺型(14/23, 60.87%)与非腔面大汗腺型(19/70, 27.14%)分布差异有统计学意义(P=0.005);HER2 0和HER2低表达两组在年龄、pT分期、组织学分级、浸润方式、淋巴结转移及生存分析差异均无统计学意义。HER2低表达在肿瘤内的表达具有异质性, 包括不同比例的微弱、弱到中等强度的不完整到完整膜着色;随着阳性表达细胞占比数量的变化及在总体肿瘤细胞的分布情况不同, 包括聚类型、马赛克型、散点型。93例样本中有71例提取的DNA满足要求, 包括HER2 0组43例、HER2低表达组28例。基因突变以错义突变、单核苷酸变异、碱基C替换成碱基T的点突变为主。两组间突变发生频率>3次的基因差异无统计学意义, CTNNB1和FGFR3基因只在HER2低表达组发生突变, 而ALK、CYP2D6、FAT1基因只在HER2 0组发生突变。HER2低表达组包括HER2 1+18例和HER2 2+10例, 两组之间突变发生频率>3次的基因包括PIK3CA、TP53、SLX4、ATM、BRCA1, PIK3CA在HER2 2+中的突变频率显著高于HER2 1+组(P<0.05), SLX4基因只在HER2 1+组发生突变。结论在组织学形态及分子层面, HER2 0组与HER2低表达组均存在一定差异, HER2低表达组中HER2 1+与HER2 2+病例在基因变异上也存在一定差异, 有助于TNBC进行更精准的分层以及进一步寻找HER2低表达组TNBC的治疗靶点及精准治疗方案。

Objective:To investigate the biological characteristics of triple negative breast cancer(TNBC)with low expression of HER2(HER2-low).Methods:A total of 93 TNBC cases in Shanxi Cancer Hospital from 2017 to 2019 were collected and divided into HER2-negative and HER2-low groups according to HER2 expression status.The clinicopathological features and prognostic differences between the two groups were retrospectively analyzed and compared,and genetic detection of tumor tissues was performed to clarify somatic mutation status and differences between the two groups.Results:Ninety-three patients aged 26 to 86 years were enrolled,including 60 patients in the HER2-negative group and 33 patients in the HER2-low group.The distribution of HER2-low in luminal androgen receptor(LAR)subtype(14/23,60.87%)and non-LAR subtype(19/70,27.14%)was significantly different(P=0.005).There were no significant differences in age,pT stage,histological grade,infiltration mode,lymph node metastasis and survival analysis.The expression of HER2-low in the tumor was heterogeneous,including different proportions of weak,weak to moderate intensity,and incomplete to intact membrane staining.With the change of the proportion of HER2-positive cells,the different distribution of those cells in the total tumor cells was noted,including cluster,mosaic and scattered patterns.The concentration and quality of DNA extracted from 71 of the 93 samples met the requirements for making libraries,including 43 in the HER2-negative group and 28 in the HER2-low group.Genetic mutations were mainly missense mutations,single nucleotide mutations,and point mutations in which base C was replaced by base T.There was no significant difference in genes with mutation frequency>3 times between the two groups.CTNNB1 and FGFR3 genes were only mutated in HER2-low group;while ALK,CYP2D6 and FAT1 genes were only mutated in HER2-negative group.HER2-low group included 18 HER21+cases and 10 HER22+cases.Genes with mutation frequency>3 times between the two groups included PIK3CA,TP53,SLX4,ATM and BRCA1.The mutation frequency of PIK3CA in HER22+was significantly higher than that in HER21+group(P<0.05),and SLX4 gene was only mutated in HER21+group.Conclusions:There are some differences of histological morphology and genetic variation between HER2-negative group and HER2-low group,and also differences in genetic variation between HER21+and HER22+in HER2-low group,which are helpful for more accurate stratification of TNBC and useful for finding the therapeutic target and precise treatment of HER2-low TNBC.