乳腺癌HER2基因扩增与临床病理参数的对比分析^*

Comparison of HER2 gene amplification and clinic opathological parameters in breast cancer

摘要

目的 探讨乳腺癌人表皮生长因子受体2(HER2)基因扩增状态与多个临床病理参数之间的关系,为乳腺癌的复发转移风险预测及精准靶向治疗提供科学依据。方法 回顾性分析2020年4月—2024年6月长春肿瘤医院收治的HER2免疫组织化学(IHC)结果为2+(临界)的乳腺癌患者205例。采用FISH检测HER2基因扩增,比较不同HER2扩增状态与年龄、肿瘤直径、TNM分期、病理学分级、淋巴结转移、雌激素受体(ER)/孕激素受体(PR)表达、细胞增殖核抗原(Ki-67)表达的关联,并深入探讨不同年龄(以55岁为界)、肿瘤直径(以3 cm为界)、Ki-67表达(以50%为界)的HER2扩增与淋巴结转移的关系,重点分析不同年龄分层下HER2扩增与临床病理参数的差异。结果 205例患者中,HER2基因扩增阳性44例(21.5%)。不同HER2扩增状态的TNM分期、肿瘤直径、Ki-67表达及ER/PR表达比较,差异均有统计学意义(P＜0.05);淋巴结转移与年龄、肿瘤直径、Ki-67表达有关,差异均有统计学意义(P＜0.05)。年龄＜55岁的患者HER2扩增阳性组的淋巴结转移率高于阴性组,差异有统计学意义(P＜0.05);按肿瘤直径和Ki-67表达分层后,不同年龄层的TNM分期和淋巴结转移率比较,差异有统计学意义(P＜0.05)。结论 乳腺癌HER2基因扩增与多项临床病理参数相关,且对淋巴结转移风险的影响呈年龄依赖性,年轻患者该风险更为显著。这些结果为进一步改善乳腺癌复发转移风险的精准评估及精准医学个体化治疗提供了科学依据及可行性。

Abstract

Objective To investigate the relationship between HER2 gene amplification status and various clinicopathological parameters in breast cancer, and to provide a scientific basis for risk prediction of recurrence and metastasis as well as precision targeted therapy for breast cancer. Methods A retrospective analysis was conducted on 205 breast cancer patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 2+ (equivocal) results admitted to Changchun Cancer Hospital from April 2020 to June 2024. Fluorescence in situ hybridization (FISH) was used to detect HER2 gene amplification. The associations between different HER2 amplification statuses and age, tumor diameter, TNM stage, pathological grade, lymph node metastasis, estrogen receptor (ER)/progesterone receptor (PR) expression, and proliferative marker antigen (Ki-67) expression were compared. Furthermore, the relationship between HER2 amplification and lymph node metastasis was explored in depth according to different age groups (using 55 years as cut-off), tumor diameters (using 3 cm as cut-off), and Ki-67 expression levels (using 50% as cut-off), with a focus on analyzing the differences in clinicopathological parameters associated with HER2 amplification across different age stratifications. Results Among the 205 patients, 44 (21.5%) were positive for HER2 gene amplification. HER2 amplification status was significantly associated with TNM stage, tumor diameter, Ki-67 expression, and ER/PR expression (all P < 0.05). Lymph node metastasis was significantly associated with age, tumor diameter, and Ki-67 expression (all P < 0.05). In patients aged <55 years, the lymph node metastasis rate was significantly higher in the HER2 amplification-positive group than in the negative group (P < 0.05). After stratification by tumor diameter and Ki-67 expression, statistically significant differences in TNM stage and lymph node metastasis rate were observed between different age groups (all P < 0.05). Conclusion HER2 gene amplification in breast cancer is associated with multiple clinicopathological parameters, and its impact on the risk of lymph node metastasis is age-dependent, with a more pronounced risk observed in younger patients. These findings provide a scientific basis and feasibility for improving the precise assessment of recurrence and metastasis risk and for individualized precision medicine in breast cancer.

关键词

乳腺癌 / 荧光原位杂交 / HER2基因扩增 / 临床病理参数

Key words

Breast cancer / Fluorescence in situ hybridization / HER2 gene amplification / Clinical pathological parameters

[1] Sung H, Ferlay J, SiegelR L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] Lei S, Zheng R, Zhang S, et al. Breast cancer incidence and mortality in women in China: temporal trends and projections to 2030[J].Cancer Biol Med, 2021, 18(3): 900-909.
[3] Kashyap D, Bal A, Irinike S, et al. Heterogeneity of the tumor microenvironment across molecular subtypes of breast cancer[J]. Appl Immunohistochem Mol Morphol, 2023, 31(8): 533-543.
[4] Bon G,Di Lisa F S, Filomeno L, et al. HER2 mutation as an emerging target in advanced breast cancer[J]. Cancer Sci, 2024, 115(7): 2147-2158.
[5] Jibiki N, Nakazawa T, Nogami M, et al. Prognosticevaluation of HER2-positive early breast cancers using clinico-pathological criteria[J]. Cancer Diagn Progn, 2024, 4(3): 326-332.
[6] 罗师萍, 张捷, 俞育帅, 等. HER2阳性乳腺癌的靶向治疗进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 876-886.
Luo S P, Zhang J, Yu Y S, et al. Advances in targeted therapy for HER2-positive breast cancer[J]. Chin J Clin Pharmacol Ther, 2023, 28(8): 876-886.
[7] Pan C, Ge L, Zhang H, et al. Case report:a promising neoadjuvant treatment option for individuals with locally advanced HER2-positive breast cancer involves the use of Pyrotinib Maleate in combination with Trastuzumab and Pertuzumab[J]. Heliyon, 2024, 10(14): e34511.
[8] Bai K,Woo J W, Kwon H J, et al. Alteration of HER2 status during breast cancer progression: a clinicopathological analysis focusing on HER2-low status[J]. Lab Invest, 2024, 104(8): 102092.
[9] Yan S, Zhao W, Dong Y, et al. Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression levelalterations[J]. World J Surg Oncol, 2024, 22(1): 248.
[10]Wang C, Chen J, Lv X, et al. Ki-67-Playing a key role in breast cancer but difficult to apply precisely in the real world [J]. BMC Cancer. 2025;25(1):962.
[11]《乳腺癌HER检测指南(版)》编写组. 乳腺癌HER2检测指南(2019版)[J]. 中华病理学杂志, 2019, 48(3): 169-175.
Recommended by Breast Cancer Expert Panel.Guideline for HER2 detection in breast cancer, the 2019 version[J]. Chin J Pathol, 2019, 48(3): 169-175.
[12]Kim S, et al. From tissue-specific to tissue-agnostic: HER2 overexpression and the rise of antibody-drug conjugates[J]. Front Oncol, 2025, 15: 1565872.
[13]Avelino A R M, Pulipati S, Jamouss K, et al. Updates in treatment of HER2-positive metastatic breast cancer[J]. Curr Treat Options Oncol, 2024, 25(12): 1471-1481.
[14]Alroy I, Yarden Y. Biochemistry of HER2 oncogenesis in breast cancer[J]. Breast Dis, 2000, 11(1): 31-48.
[15]罗斯译, 柴利, 阮思蓓, 等. 川南地区乳腺癌患者人表皮生长因子受体2基因状态及其蛋白表达与临床病理特征的关系[J]. 实用医学杂志, 2020, 36(1): 22-26.
Luo S Y, Chai L, Ruan S B, et al. HER-2 status and its clinicopathologic significance in invasive breast cancer patients from southern of Sich-uan: re-evaluation of correlation between FISH and IHC for its results[J]. J Pract Med, 2020, 36(1): 22-26.
[16]Yang L, Zhang Z, Li J, et al. A decision tree-based prediction model for fluorescence in situ hybridization HER2 gene status in HER2 immunohistochemistry-2+ breast cancers: a 2538-case multicenter study on consecutive surgical specimens[J]. J Cancer, 2018, 9(13): 2327-2333.
[17]Efared B, Sidibé I S, Gamrani S, et al. The assessment of HER2 gene status by fluorescence in situ hybridization in invasive breast carcinomas with equivocal HER2 immunostaining: experience from a single institution[J]. Int J Surg Pathol, 2018, 26(7): 593-599.
[18]任晓军, 马玉花, 梁飞, 等. 乳腺癌HER-2不同检测方法的比较研究[J]. 新疆医学, 2023, 53(9): 1072-1075.
Ren X J, Ma Y H, Liang F, et al. Comparative study on different detection methods of HER-2 in breast cancer[J]. Xinjiang Med J, 2023, 53(9): 1072-1075.
[19]李小欢, 张青, 张春蕾, 等. IHC与FISH在乳腺癌HER2蛋白表达和基因扩增检测中的应用[J]. 标记免疫分析与临床, 2024, 31(3): 550-553.
Li X H, Zhang Q, Zhang C L, et al. The DifferenceBetween IHC and FISH in detecting HER2 protein expression and gene amplification in breast cancer[J]. Labeled Immunoass Clin Med, 2024, 31(3): 550-553.
[20]Mukhtar Z, Faisal A, Mudassir G, et al. Correlation between HER2/neu protein overexpression on Immunohistochemistry and Fluorescent in Situ Hybridization (FISH) in breast carcinoma: problems in developing countries[J]. Pak J Med Sci, 2023, 39(6): 1814-1817.
[21]Shi P, Chen C, Yao Y. Correlation between HER-2 gene amplification or protein expression and clinical pathological features of breast cancer[J]. Cancer Biother Radiopharm, 2019, 34(1): 42-46.
[22]伍锦凤, 桂照华, 闫红. 乳腺浸润性癌组织人表皮生长因子受体-2基因扩增状态与蛋白表达的比较及其与临床病理特征的相关性[J]. 实用临床医药杂志, 2021, 25(13): 40-44.
Wu J F, Gui Z H, Yan H. Comparison of human epidermal growth factor receptor-2gene amplification status and protein expression in invasive breast carcinoma and its correlation with clinicopathological characteristics[J]. J Clin Med Pract, 2021, 25(13): 40-44.
[23]魏静远, 王艳茹, 段瑞, 等. 乳腺癌HER-2基因扩增检测方法对比及与临床病理特征的关系[J]. 贵州医药, 2017, 41(11): 1126-1128.
Wei J Y, Wang Y R, Duan R, et al. Comparison of the method to detect the HER-2 gene amplification condition in breast carcinoma and its relationship with clinicopathological characteristics[J]. Guizhou Med J, 2017, 41(11): 1126-1128.
[24]Mo D C, Luo P H, Huang J F, et al. Tucatinib plus trastuzumab and capecitabine for ERBB2 (HER2)-positive metastatic breast cancer with brain metastases[J]. JAMA oncology,2023,9(7):1008-1009.
[25]李明, 张伟, 王芳, 等. 年轻乳腺癌基因组特征研究[J]. 中华肿瘤杂志, 2021, 43(5): 321-328.
Li M, Zhang W, Wang F, et al. Genomic characteristics of young breast cancer patients[J]. Chin J Oncol, 2021,43(5):321-328.
[26]陈红, 刘洋, 周杰. HER2与分子分型关联研究[J]. 中国癌症研究, 2022, 34(2): 89-95.
Chen H, Liu Y, Zhou J. Association between HER2 and molecular subtypes in breast cancer[J]. Chin J Cancer Res, 2022,34(2):89-95.

基金资助

^*吉林省科学技术厅项目(YDZJ202201ZYTS127);吉林省发展和改革委员会项目(2023C041-6、2023C011);吉林省卫生厅项目(2024A036)