Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab
Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab
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DOI：
10.1309/ajcp51hcgpopwscy
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Gong, Gyungyub
中科院分区：
文献类型：
--
作者：
Lee, Hee Jin;Kim, Joo Young;Gong, Gyungyub
目的：尽管肿瘤内人表皮生长因子受体2（HER 2）基因扩增的异质性与曲妥珠单抗治疗的原发性HER 2阳性乳腺癌和转移性HER 2阳性乳腺癌的不良预后相关，但尚未在患者中研究曲妥珠单抗治疗作为辅助治疗的临床病理学意义。我们回顾性研究了443例接受手术、辅助化疗和1年曲妥珠单抗治疗的HER 2阳性乳腺癌患者。结果：HER 2蛋白表达的区域异质性和遗传异质性分别为6.2%和6.8%。两种异质性均与激素受体阳性、HER 2免疫组化评分2+、低水平HER 2基因扩增和缺乏广泛的导管内成分显著相关。遗传异质性也表现出较强的相关性，较低的组织学分级。在激素受体阳性组中，区域异质性影响患者的无病生存期（风险比，4.869; 95%可信区间，1.424-16.646; P = .005），而遗传异质性则没有。评价肿瘤内异质性，尤其是激素受体阳性病例，可能对评估预期接受辅助全身治疗和曲妥珠单抗治疗的HER 2阳性患者的预后有价值。
Objectives: Although intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been associated with a poor prognosis for primary HER2-positive breast cancer and metastatic HER2-positive breast cancer treated with trastuzumab, the clinicopathologic significance in a setting involving trastuzumab treatment as an adjuvant treatment has not been studied in patients.Methods: We retrospectively investigated 443 patients with HER2-positive breast cancer treated with surgery, adjuvant chemotherapy, and 1 year of trastuzumab. Three areas that showed different levels of HER2 protein expression were chosen, and silver in situ hybridization was performed.Results: HER2 regional and genetic heterogeneity was found in 6.2% and 6.8% of tumors, respectively. Both types of heterogeneity were significantly associated with hormone receptor positivity, HER2 immunohistochemistry score of 2+, a low level of HER2 gene amplification, and absence of an extensive intraductal component. Genetic heterogeneity also showed strong correlation with a lower histologic grade. In the hormone receptor-positive group, the regional heterogeneity affected disease-free survival of patients (hazard ratio, 4.869; 95% confidence interval, 1.424-16.646; P = .005), whereas genetic heterogeneity did not.Conclusions: Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.