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Xi E Hu, Ping Yang, Songhao Chen, Gang Wei, Lijuan Yuan, Zhenyu Yang, Li Gong, Li He, Lin Yang, Shujia Peng, Yanming Dong, Xianli He, Guoqiang Bao
Department of General Surgery, The Second Affiliated Hospital of Air Force Medical University, No. 569, Xinsi Road, Baqiao District, Xi'an, Shannxi, China.
Department of Pathology, The Second Affiliated Hospital of Air Force Medical University, No. 569, Xinsi Road, Baqiao District, Xi'an, Shannxi, China.
Breast Cancer Res. 2023 Mar 30;25(1):34. doi: 10.1186/s13058-023-01639-y.
HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear.
We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2) and 94 HER2-negtive (HER2) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2 vs. HER2, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples.
Compared with HER2 TNBC, HER2 TNBC patients exhibited malignant clinical features with larger tumor size (P = 0.04), more lymph nodes involvement (P = 0.02), higher histological grade of lesions (P < 0.001), higher Ki67 status (P < 0.01), and a worse prognosis (P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2 TNBC but not in HER2 TNBC patients. ScRNA-seq revealed that HER2 TNBC which showed more metabolically active and aggressive hallmarks, while HER2 TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes (IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2 and HER2 TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2 TNBC revealed a potentially more active immune microenvironment than HER2 TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8 effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response.
This study suggests that HER2 TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2 phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provide new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.
HER2-低表达可在一些三阴性乳腺癌（TNBC）患者中发现。然而，其在 TNBC 中的临床特征和肿瘤生物学特性方面的潜在影响尚不清楚。
我们回顾性纳入 251 例连续的 TNBC 患者，包括 157 例 HER2-低表达（HER2）和 94 例 HER2 阴性（HER2）患者，以研究其临床和预后特征。然后，我们前瞻性地对另外 7 例 TNBC 样本（HER2 与 HER2、4 与 3）进行单细胞 RNA 测序（scRNA-seq），以进一步探讨两种 TNBC 表型之间肿瘤生物学特性的差异。还探索了潜在的分子差异，并在额外的 TNBC 样本中进行了验证。
与 HER2 TNBC 相比，HER2 TNBC 患者表现出恶性临床特征，肿瘤体积更大（P=0.04），淋巴结受累更多（P=0.02），病变组织学分级更高（P<0.001），Ki67 状态更高（P<0.01），预后更差（P<0.001；HR[95%CI] = 3.44[2.10-5.62]）。Cox 比例风险分析表明，新辅助全身治疗、淋巴结受累和 Ki67 水平是 HER2 TNBC 的预后因素，但不是 HER2 TNBC 患者的预后因素。scRNA-seq 显示，HER2 TNBC 表现出更多代谢活跃和侵袭性的特征，而 HER2 TNBC 则表现出更多与免疫活性相关的特征，免疫球蛋白相关基因（IGHG1、IGHG4、IGKC、IGLC2）表达更高；这在临床 TNBC 样本的免疫荧光中得到了进一步证实。此外，HER2 和 HER2 TNBC 表现出不同的肿瘤进化特征。此外，与 HER2 TNBC 相比，HER2 TNBC 显示出潜在更活跃的免疫微环境，表现为巨噬细胞极化的积极调节、丰富的 CD8 效应 T 细胞、T 细胞受体多样性增加以及免疫治疗靶向标志物水平升高，这有助于实现免疫治疗反应。
本研究表明，与 HER2 表型相比，HER2 TNBC 患者具有更恶性的临床行为和侵袭性肿瘤生物学特性。HER2 的异质性可能是 TNBC 患者临床管理中不可忽视的因素。我们的数据为 TNBC 患者更精细的分类和个体化治疗策略的制定提供了新的见解。
