Huang Riqing, Hu Anqi, Rong Qixiang, Shu Ditian, Chen Meiting, Yang Wei, Zhang Yue, Zheng Qiufan, An Xin, Xue Cong, Li Haifeng, Shi Yanxia
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, No.651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, No.651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.
J Transl Med. 2025 Jan 13;23(1):63. doi: 10.1186/s12967-025-06082-5.
HER2-targeted antibody-drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC in metastatic breast cancer.
This comprehensive real-world retrospective study collected clinical data from patients diagnosed with metastatic breast cancer and performed genomic profiling using targeted next-generation sequencing. The study analyzed the associations between genomic alterations and clinical outcomes of HER2 ADC treatment.
Sixty-three patients were included in this study, 33 with HER2-low breast cancer and 30 with HER2-positive breast cancer, respectively. The most frequently altered genes were TP53 (69%), PIK3CA (45%), MYC (35%), and ERBB2 (35%). Patients with amplifications in cell cycle-related genes showed inferior median progression-free survival (PFS) than those without amplifications (2.07 months vs. 8.40 months; HR = 5.24; 95% CI 2.11-13.01; p < 0.001), particularly in HER2-low patients (2.07 months vs. 8.27 months; HR = 4.23; 95% CI 1.50-11.91; p = 0.004). Additionally, ERBB2/CDK12 co-amplification exhibited a superior median PFS in all patients (19.33 months vs. 5.43 months; HR = 0.13; 95% CI 0.04-0.45; p < 0.001) and in HER2-positive patients (19.33 months vs. 6.87 months; HR = 0.18; 95% CI 0.05-0.72; p = 0.007). Multivariate analysis indicated that amplification in cell cycle-related genes was an independent predictor of inferior PFS (HR = 4.46; 95% CI 1.08-18.40; p = 0.039), while the presence of ERBB2/CDK12 co-amplification was independently correlated with superior PFS (HR = 0.16; 95% CI 0.04-0.65; p = 0.010).
Amplification in cell cycle genes may contribute to primary resistance of HER2 ADC in HER2-low breast cancer. ERBB2/CDK12 co-amplification may be a potential biomarker for favorable responses in HER2-positive breast cancer.
HER2靶向抗体药物偶联物（ADC）彻底改变了转移性乳腺癌的治疗格局。然而，这些疗法的疗效可能会因基因组改变而受到影响。因此，本研究旨在确定预测转移性乳腺癌对HER2 ADC敏感性的因素。
这项全面的真实世界回顾性研究收集了被诊断为转移性乳腺癌患者的临床数据，并使用靶向二代测序进行基因组分析。该研究分析了基因组改变与HER2 ADC治疗临床结果之间的关联。
本研究纳入了63例患者，分别为33例HER2低表达乳腺癌患者和30例HER2阳性乳腺癌患者。最常发生改变的基因是TP53（69%）、PIK3CA（45%）、MYC（35%）和ERBB2（35%）。细胞周期相关基因扩增的患者中位无进展生存期（PFS）低于无扩增的患者（2.07个月对8.40个月；HR = 5.24；95%CI 2.11 - 13.01；p < 0.001），尤其是HER2低表达患者（2.07个月对8.27个月；HR = 4.23；95%CI 1.50 - 11.91；p = 0.004）。此外，ERBB2/CDK12共扩增在所有患者（19.33个月对5.43个月；HR = 0.13；95%CI 0.04 - 0.45；p < 0.001）和HER2阳性患者（19.33个月对6.87个月；HR = 0.18；95%CI 0.05 - 0.72；p = 0.007）中显示出较好的中位PFS。多因素分析表明，细胞周期相关基因扩增是PFS较差的独立预测因素（HR = 4.46；95%CI 1.08 - 18.40；p = 0.039），而ERBB2/CDK12共扩增的存在与较好的PFS独立相关（HR = 0.16；95%CI 0.04 - 0.65；p = 0.010）。
细胞周期基因扩增可能导致HER2低表达乳腺癌对HER2 ADC产生原发性耐药。ERBB2/CDK12共扩增可能是HER2阳性乳腺癌良好反应的潜在生物标志物。
