HER-2 0表达与HER-2低表达早期乳腺癌的长期预后与分子特征比较

背景与目的 新型抗人表皮生长因子受体2（HER-2）抗体偶联药物（ADC）为包括HER-2低表达在内的乳腺癌患者开辟了新的治疗选择。然而，目前HER-2低表达和HER-2 0表达乳腺癌之间的临床病理特征、分子特征及预后差异尚不明确。因此，本研究主要比较HER-2低表达和HER-2 0表达乳腺癌患者的生存预后、临床病理特征以及分子特征之间的差异，旨在进一步揭示HER-2低表达乳腺癌的分子特征及更精准地选择ADC药物获益人群。方法 回顾性分析中南大学湘雅医院2011年1月—2015年12月1 245例经手术治疗的Ⅰ~Ⅲ期早期原发性浸润性乳腺癌患者资料。比较不同HER-2表达水平（0表达、低表达、过表达）患者临床病理特征的差异，分析患者的总生存（OS）和无病生存（DFS）的差异，筛选预后的独立影响因素。通过TCGA数据库分析比较HER-2低表达和HER-2 0表达乳腺癌患者的分子特征及免疫微环境差异。结果 1 245例患者中，HER-2 0表达395例（31.73%）、HER-2低表达562例（45.14%），HER-2过表达288例（23.13%）。与HER-2 0表达患者相比，HER-2低表达患者淋巴结分期更高、激素受体（HR）阳性比例更高、腋窝淋巴结转移更多，Ki-67水平较低（均P<0.05）。生存分析显示，HER-2过表达患者的OS与DFS均明显低于HER-2 0表达患者与HER-2低表达患者（均P<0.05）；HER-2 0表达和HER-2低表达患者的OS和DFS无论在整体上还是不同淋巴结状态或不同HR状态分层患者中均无明显差异（均P>0.05）。多因素Cox风险模型结果提示，年龄、腋窝淋巴结转移是乳腺癌患者OS的独立危险因素；年龄、ER状态、HER-2表达水平、腋窝淋巴结转移是乳腺癌患者DFS的独立危险因素（均P<0.05）。分子特征方面，HER-2低表达和HER-2 0表达在分子突变负荷方面无明显差异，但在免疫浸润方面有一定差异，HER-2 0表达乳腺癌的抗肿瘤免疫反应更为活跃。结论 HER-2低表达和HER-2 0表达乳腺癌的病理特征存在一定差异，但HER-2低表达和HER-2 0表达乳腺癌的预后结局相似；HER-2低表达乳腺癌的分子特征具有异质性，但与HER-2 0表达乳腺癌的分子特征不具有显著特异性。因此，本研究结果尚不支持将HER-2低表达作为新的乳腺癌分子分型。

Comparison of lng-term prognosis and molecular characteristics between early breast cancer with zero HER-2 expression and low HER-2 expression

Background and Aims Novel anti-human epidermal growth factor receptor 2 antibody-drug conjugates (ADCs) have provided new treatment options for breast cancer patients, including those with low HER-2 expression. However, the differences in clinicopathologic characteristics, molecular features, and prognosis between breast cancer patients with low HER-2 expression and those with zero HER-2 expression are still unclear. Therefore, this study was conducted to compare the survival prognosis, clinicopathologic characteristics, and molecular features of breast cancer patients with low HER-2 expression and zero HER-2 expression, in order to further elucidate the molecular characteristics of low HER-2 expression breast cancer and to more accurately identify the population that may benefit from ADC drugs.Methods The data of 1 245 patients with stage Ⅰ-Ⅲ early primary invasive breast cancer who underwent surgical treatment in Xiangya Hospital of Central South University from January 2011 to December 2015 were retrospectively analyzed. The differences in clinicopathologic characteristics among patients with different levels of HER-2 expression (zero expression, low expression, overexpression) were compared. The differences in overall survival (OS) and disease-free survival (DFS) were analyzed, and independent prognostic factors were identified. Molecular characteristics and immune microenvironment differences between low HER-2 expression and zero HER-2 expression breast cancer patients were compared using data from the TCGA database.Results Among the 1 245 patients, 395 (31.73%) had zero HER-2 expression, 562 (45.14%) had low HER-2 expression, and 288 (23.13%) had HER-2 overexpression. Compared to patients with zero HER-2 expression, those with low HER-2 expression had higher lymph node stage, a higher proportion of hormone receptor (HR) positivity, more axillary lymph node metastases, and lower Ki-67 level (all P<0.05). Survival analysis showed that both OS and DFS were significantly lower in patients with HER-2 overexpression compared to those with zero HER-2 expression and low HER-2 expression (all P<0.05); there were no significant differences in OS and DFS between zero HER-2 expression and low HER-2 expression patients, either overall or stratified by lymph node status or HR status (all P>0.05). Multivariate Cox risk model results indicated that age and axillary lymph node metastasis were independent risk factors for OS, while age, ER status, HER-2 expression level, and axillary lymph node metastasis were independent risk factors for DFS (all P<0.05). In terms of molecular characteristics, there were no significant differences in molecular mutation burden between low HER-2 expression and zero HER-2 expression breast cancer, but there were some differences in immune infiltration, with zero HER-2 expression breast cancer exhibiting a more active anti-tumor immune response.Conclusion There are certain differences in the pathological characteristics of low HER-2 expression and zero HER-2 expression breast cancer, but the prognostic outcomes are similar. The molecular characteristics of low HER-2 expression breast cancer are heterogeneous, but do not show significant specificity compared to HER-2 0 expression breast cancer. Therefore, the results of this study do not support the classification of low HER-2 expression as a new molecular subtype of breast cancer.