Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Precision Cancer Medical Center Affiliated to Fudan University Shanghai Cancer Center, Shanghai, 201315, China.
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cancer Lett. 2024 Apr 28;588:216763. doi: 10.1016/j.canlet.2024.216763. Epub 2024 Feb 24.
More than half of the breast cancer initially labeled as human epidermal growth factor receptor 2 (HER2)-negative actually exhibited low HER2 levels (IHC 1+ or IHC 2+/FISH-) and were classified as HER2-low breast cancer. Previous research emphasized the significant biological heterogeneity in HER2-low breast cancer, highlighting the importance of accurately characterizing HER2-low tumors to promote the precise management of antibody‒drug conjugates. In this study, we established a large-scale targeted sequencing cohort (N = 1907) representing Chinese HER2-low breast cancer patients with detailed clinical annotation. Our research findings revealed that HER2-low breast cancer demonstrated distinct clinical pathological characteristics and mutation landscapes compared to HER2-zero group. When compared to HER2-zero tumors, HER2-low tumors exhibited a higher proportion of Luminal B subtypes and better disease-free survival. In hormone receptor (HR)-positive breast cancer, HER2-low group showed a higher frequency of GATA3 somatic mutations, BRCA2 germline mutations, and mutations in the DNA damage repair pathway. In contrast, in HR-negative breast cancer, the HER2-low group displayed a higher frequency of PIK3CA mutations and PI3K pathway alterations. These findings offered valuable insights for the precise targeted treatment of HER2-low breast cancer in different HR statuses.
超过一半最初被归类为人类表皮生长因子受体 2（HER2）阴性的乳腺癌实际上表现出低水平的 HER2（免疫组化 1+或免疫组化 2+/FISH-），并被归类为 HER2 低表达乳腺癌。先前的研究强调了 HER2 低表达乳腺癌在生物学上存在显著的异质性，突出了准确描述 HER2 低表达肿瘤的重要性，以促进抗体药物偶联物的精准管理。在这项研究中，我们建立了一个大规模的靶向测序队列（N=1907），代表了具有详细临床注释的中国 HER2 低表达乳腺癌患者。我们的研究结果表明，与 HER2 零表达组相比，HER2 低表达乳腺癌表现出不同的临床病理特征和突变景观。与 HER2 零表达肿瘤相比，HER2 低表达肿瘤中 Luminal B 亚型的比例更高，无病生存期更好。在激素受体（HR）阳性乳腺癌中，HER2 低表达组中 GATA3 体细胞突变、BRCA2 种系突变和 DNA 损伤修复途径突变的频率更高。相比之下，在 HR 阴性乳腺癌中，HER2 低表达组中 PIK3CA 突变和 PI3K 途径改变的频率更高。这些发现为不同 HR 状态下 HER2 低表达乳腺癌的精准靶向治疗提供了有价值的见解。
