Yang Cuiyan, Wang Haoyu, Tong Yiwei, Wang Zheng, Sun Xi, Li Anqi, Lu Yujie, Han Mengyuan, Zhu Siji, Dong Lei, Shen Kunwei, Chen Xiaosong
Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ther Adv Med Oncol. 2025 Jul 9;17:17588359251353083. doi: 10.1177/17588359251353083. eCollection 2025.
BACKGROUND: Heterogeneity of human epidermal growth factor receptor 2 (HER2) expression exists in triple-negative breast cancer (TNBC). The evolution of the HER2 testing algorithm has led to the new classification of the HER2-low category, with unclear clinicopathological and molecular features in Asian women with HER2-low TNBC. OBJECTIVES: This study aimed to assess the clinicopathological and molecular characteristics of HER2-low TNBC in Asian women. DESIGN: Our study prospectively included 3376 patients with TNBC diagnosed from 2009 to 2021 in the Shanghai Jiao Tong University Breast Cancer Database (a multicenter dataset), and 92 patients from The Cancer Genome Atlas (TCGA) cohort were enrolled. METHODS: Two different independent TNBC cohorts were included, a multicenter cohort (Whole cohort, = 3376) and the TCGA cohort ( = 92). Genomic profiling covering 32 mutations for Homologous Recombination Repair and other cancer predisposition genes was obtained. Clinicopathological features, genomic status of the above genes, treatment response, and disease prognosis were compared between HER2-low and HER2-zero TNBC patients. RESULTS: In Asian females, 1611 (47.72%) TNBC patients were HER2-low. HER2-low was associated with a higher percentage of postmenopausal status (odds ratio (OR) = 1.64, < 0.001), lymph node positivity (OR = 1.14, = 0.003), and invasive ductal carcinoma histology (OR = 1.21, = 0.012). HER2-low group had less mutation (7.02% vs 13.76%, = 0.038) but was associated with a higher rate of mutation (28.07% vs 12.17%, < 0.001) compared with HER2-zero TNBC. No significant difference in breast pathologic complete response rate, breast cancer-free interval, or overall survival was observed between HER2-low and HER2-zero TNBC. In the TCGA cohort, lipid metabolism genes were upregulated in the HER2-low TNBC, enriched in alpha-linolenic acid metabolism (normalized enrichment score = 1.51, = 0.019). CONCLUSION: Our results show that HER2-low TNBC had specific clinicopathological, genomic profiling, and biological features compared with HER2-zero TNBC in Asian women, but without significant differences in treatment response and prognosis, warranting exploring better treatment strategies to improve disease outcomes.
背景：三阴性乳腺癌（TNBC）中存在人表皮生长因子受体2（HER2）表达异质性。HER2检测算法的演变导致了HER2低表达类别新分类，亚洲HER2低表达TNBC女性的临床病理和分子特征尚不清楚。 目的：本研究旨在评估亚洲女性HER2低表达TNBC的临床病理和分子特征。 设计：我们的研究前瞻性纳入了上海交通大学乳腺癌数据库（一个多中心数据集）中2009年至2021年诊断的3376例TNBC患者，并纳入了来自癌症基因组图谱（TCGA）队列的92例患者。 方法：纳入两个不同的独立TNBC队列，一个多中心队列（全队列，n = 3376）和TCGA队列（n = 92）。获得了涵盖32个同源重组修复和其他癌症易感基因的突变的基因组分析结果。比较HER2低表达和HER2零表达TNBC患者的临床病理特征、上述基因的基因组状态、治疗反应和疾病预后。 结果：在亚洲女性中，1611例（47.72%）TNBC患者为HER2低表达。HER2低表达与绝经后状态百分比更高（优势比（OR）= 1.64，P < 0.001）、淋巴结阳性（OR = 1.14，P = 0.003）和浸润性导管癌组织学（OR = 1.21，P = 0.012）相关。与HER2零表达TNBC相比，HER2低表达组BRCA1突变较少（7.02%对13.76%，P = 0.038），但与PIK3CA突变率较高相关（28.07%对12.17%，P < 0.001）。HER2低表达和HER2零表达TNBC之间在乳腺病理完全缓解率、无乳腺癌间期或总生存期方面未观察到显著差异。在TCGA队列中，HER2低表达TNBC中脂质代谢基因上调，在α-亚麻酸代谢中富集（标准化富集分数 = 1.51，P = 0.019）。 结论：我们的结果表明，与亚洲女性HER2零表达TNBC相比，HER2低表达TNBC具有特定的临床病理、基因组分析和生物学特征，但在治疗反应和预后方面无显著差异，需要探索更好的治疗策略以改善疾病结局。
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