HER2-low在部分三阴性乳腺癌（TNBC）患者中可以发现。然而，其对TNBC的临床特征和肿瘤生物学特征的潜在影响仍不明确。我们回顾性纳入了251名连续TNBC患者，包括157名HER2低表达（HER2low）和94名HER2阴性（HER2neg）患者，以研究其临床和预后特征。然后，我们前瞻性地对另外七个TNBC样本进行了单细胞RNA测序（scRNA-seq）分析（HER2neg vs. HER2low，4 vs. 3），以进一步探索两种TNBC表型之间的肿瘤生物学特征差异。并进一步探讨了其潜在的分子差异性，并在其他TNBC样本中进行验证。与HER2neg TNBC相比，HER2low TNBC患者表现出更恶性的临床特征，包括更大的肿瘤大小（P = 0.04），更多的淋巴结涉及（P = 0.02），更高的病理分级（P < 0.001），更高的Ki67状态表达（P < 0.01）和更差的预后（P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]）。Cox比例风险分析显示，新辅助系统治疗、淋巴结涉及和Ki67水平是HER2low TNBC患者的预后因素，而不是HER2neg TNBC患者。scRNA-seq揭示了HER2low TNBC表现出更多代谢活跃和侵略性标志物，而HER2neg TNBC则表现出更多免疫活动相关的标志物（如免疫球蛋白相关基因IGHG1、IGHG4、IGKC、IGLC2的更高表达）；这在临床TNBC样本中通过免疫荧光法进一步得到了证实。此外，HER2low和HER2neg TNBC表现出不同的肿瘤进化特征。此外，HER2neg TNBC显示出潜在更活跃的免疫微环境，如正活跃的巨噬细胞极化调节、富含CD8+效应T细胞、T细胞受体的丰富多样性和更高水平的免疫治疗靶向标志物，这有助于实现免疫治疗反应。本研究表明，HER2low TNBC患者具有比HER2neg TNBC表型更恶性的临床特征和侵袭性肿瘤生物学特征。 HER2的异质性可能是TNBC患者临床管理中不可忽视的因素。我们的数据为开发更精细的分类和个性化治疗TNBC患者的策略提供了新的见解。© 2023. 作者

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 (HER2low) and 94 HER2-negtive (HER2neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2neg vs. HER2low, 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 HER2neg TNBC, HER2low 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 HER2low TNBC but not in HER2neg TNBC patients. ScRNA-seq revealed that HER2low TNBC which showed more metabolically active and aggressive hallmarks, while HER2neg 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, HER2low and HER2neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2neg TNBC revealed a potentially more active immune microenvironment than HER2low 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 HER2low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2neg 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.© 2023. The Author(s).